Kevin Burgess

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Name: Burgess, Kevin
Organization: Texas A & M University , USA
Department: Department of Chemistry
Title: Professor(PhD)

TOPICS

Co-reporter:Anyanee Kamkaew;Feng Li;Zheng Li
MedChemComm (2010-Present) 2017 vol. 8(Issue 10) pp:1946-1952
Publication Date(Web):2017/10/18
DOI:10.1039/C7MD00328E
Tropomyosin receptor kinases receptor C is expressed at high levels on the surface of tumors from metastatic breast cancer, metastatic melanoma, glioblastoma, and neuroblastoma. Previous studies have shown synthetic TrkC ligands bearing agents for photodynamic therapy could be used to completely ablate 4T1 metastatic breast tumors and suppress metastatic spread in vivo. Modification of these probes (A in the text) to make them suitable for near infrared optical imaging in vivo would require a substantial increase in molecular mass (and hence increased vulnerability to undesirable absorption, metabolism and immunogenicity effects), or significant changes to the probe design which might compromise binding to TrkC in histochemical studies and on live cells. The research featured here was undertaken to investigate if the second strategy could be achieved without compromising binding to TrkC-expressing tissues. Specifically, an “aza-BODIPY” probe was synthesized to replace a spacer fragment in the original probe A. In the event, this new probe design (1a in the text) binds TrkC+ breast cancer in live cell cultures, in histochemical studies and in an in vivo murine model. Probe 1a binds TrkC+ tissues with good contrast with respect to healthy tissues, and much more strongly than an isomeric, non-TrkC binding, probe (1b) prepared as a negative control.
Co-reporter:Anyanee Kamkaew, Nanyan Fu, Weibo Cai, and Kevin Burgess
ACS Medicinal Chemistry Letters 2017 Volume 8(Issue 2) pp:
Publication Date(Web):December 9, 2016
DOI:10.1021/acsmedchemlett.6b00368
Actively targeting probe 1b, an unsymmetrical bivalent dipeptide mimic, selectively bound melanoma over healthy skin tissue in histological samples from patients and Sinclair swine. Modifications to 1b gave agents 2–4 that contain a near-IR aza-BODIPY fluor. Contrary to our expectations, symmetrical probe 3 gave the highest melanoma-to-healthy skin selectivity in histochemistry and experiments with live cells; this was surprising because 2, not 3, is unsymmetrical like the original lead 1. Optical imaging of 3 in a mouse melanoma model failed to show tumor accumulation in vivo, but the probe did selectively accumulate in the tumor (some in lung and less in the liver) as proven by analysis of the organs post mortem.Keywords: cancer; melanoma; small molecule ligand; Targeting;
Co-reporter:Dongyue Xin and Kevin Burgess  
Organic & Biomolecular Chemistry 2016 vol. 14(Issue 22) pp:5049-5058
Publication Date(Web):13 May 2016
DOI:10.1039/C6OB00693K
Each amino acid in a peptide contributes three atom units to main-chains, hence natural cyclic peptides can be 9, 12, 15, …. i.e. 3n membered-rings, where n is the number of amino acids. Cyclic peptides that are 9 or 12-membered ring compounds tend to be hard to prepare because of strain, while their one amino acid homologs (15-membered cyclic pentapeptides) are not conformationally homogeneous unless constrained by strategically placed proline or D-amino acid residues. We hypothesized that replacing one genetically encoded amino acid in a cyclic tetrapeptide with a rigid β-amino acid would render peptidomimetic designs that rest at a useful crossroads between synthetic accessibility and conformational rigidity. Thus this research explored non-proline containing 13-membered ring peptides 1 featuring one anthranilic acid (Anth) residue. Twelve cyclic peptides of this type were prepared, and in doing so the viability of both solution- and solid-phase methods was demonstrated. The library produced contained a complete set of four diastereoisomers of the sequence 1aaf (i.e. cyclo-AlaAlaPheAnth). Without exception, these four diastereoisomers each adopted one predominant conformation in solution; basically these conformations feature amide N–H vectors puckering above and below the equatorial plane, and approximately oriented their N– atoms towards the polar axis. Moreover, the shapes of these conformers varied in a logical and predictable way (NOE, temperature coefficient, D/H exchange, circular dichroism). Comparisons were made of the side-chain orientations presented by compounds 1aaa in solution with ideal secondary structures and protein–protein interaction interfaces. Various 1aaa stereoisomers in solution present side-chains in similar orientations to regular and inverse γ-turns, and to the most common β-turns (types I and II). Consistent with this, compounds 1aaa have a tendency to mimic various turns and bends at protein–protein interfaces. Finally, proteolytic- and hydrolytic stabilities of the compounds at different pHs indicate they are robust relative to related linear peptides, and rates of permeability through an artificial membrane indicate their structures are conducive to cell permeability.
Co-reporter:Dongyue Xin, Jian Yuan, Kwok-Yin Wong, and Kevin Burgess
The Journal of Organic Chemistry 2016 Volume 81(Issue 17) pp:8077-8081
Publication Date(Web):August 23, 2016
DOI:10.1021/acs.joc.6b01475
This study features solid phase syntheses of cyclic tetrapeptides containing anthranilic acid (Anth) on relatively inexpensive resins derived from polystyrene. It proved to be difficult to hydrolyze a supported Anth-methyl ester unless a phase transfer catalyst was added to facilitate transport of hydroxide into the swollen hydrophobic gel state of the resin. We suggest this may be an under-appreciated strategy for improving syntheses on polystyrene supports.
Co-reporter:Xun Li, Jaru Taechalertpaisarn, Dongyue Xin, and Kevin Burgess
Organic Letters 2015 Volume 17(Issue 3) pp:632-635
Publication Date(Web):January 27, 2015
DOI:10.1021/ol5036547
Representative minimalist mimics 1 were prepared from amino acids. Scaffold 1 was not designed to mimic any particular secondary structure, but simulated accessible conformations of this material were compared with common ideal secondary structures and with >125000 different protein–protein interaction (PPI) interfaces. This data mining exercise indicates that scaffolds 1 can mimic features of sheet-turn-sheets, somewhat fewer helical motifs, and numerous PPI interface regions that do not resemble any particular secondary structure.
Co-reporter:Anyanee Kamkaew and Kevin Burgess  
Chemical Communications 2015 vol. 51(Issue 53) pp:10664-10667
Publication Date(Web):05 Jun 2015
DOI:10.1039/C5CC03649F
Attempts to make a diamino disulfonic acid derivative of an aza-BODIPY showed it was difficult to add BF2 to a disulfonated azadipyrromethene, and sulfonation of an aza-BODIPY resulted in loss of the BF2 fragment. We conclude the electron-deficient character of aza-BODIPY dyes destabilizes them relative to BODIPY dyes. Consequently, sulfonation of the aza-BODIPY core is not a viable strategy to increase water solubility. This assertion was indirectly supported via stability studies of a BODIPY and an aza-BODIPY in aqueous media. To afford the desired compound type, an aza-BODIPY with two amino and two sulfonic acid groups was prepared via modification of the aryl substituents with cysteic acid.
Co-reporter:Chin Siang Kue, Anyanee Kamkaew, Hong Boon Lee, Lip Yong Chung, Lik Voon Kiew, and Kevin Burgess
Molecular Pharmaceutics 2015 Volume 12(Issue 1) pp:212-222
Publication Date(Web):December 9, 2014
DOI:10.1021/mp5005564
This contribution features a small molecule that binds TrkC (tropomyosin receptor kinase C) receptor that tends to be overexpressed in metastatic breast cancer cells but not in other breast cancer cells. A sensitizer for 1O2 production conjugated to this structure gives 1-PDT for photodynamic therapy. Isomeric 2-PDT does not bind TrkC and was used as a control throughout; similarly, TrkC– cancer cells were used to calibrate enhanced killing of TrkC+ cells. Ex vivo, 1- and 2-PDT where only cytotoxic when illuminated, and 1-PDT, gave higher cell death for TrkC+ breast cancer cells. A 1 h administration-to-illumination delay gave optimal TrkC+/TrkC–-photocytotoxicity, and distribution studies showed the same delay was appropriate in vivo. In Balb/c mice, a maximum tolerated dose of 20 mg/kg was determined for 1-PDT. 1- and 2-PDT (single, 2 or 10 mg/kg doses and one illumination, throughout) had similar effects on implanted TrkC– tumors, and like those of 2-PDT on TrkC+ tumors. In contrast, 1-PDT caused dramatic TrkC+ tumor volume reduction (96% from initial) relative to the TrkC– tumors or 2-PDT in TrkC+ models. Moreover, 71% of the mice treated with 10 mg/kg 1-PDT (n = 7) showed full tumor remission and survived until 90 days with no metastasis to key organs.
Co-reporter:Anyanee Kamkaew, Sopida Thavornpradit, Thamon Puangsamlee, Dongyue Xin, Nantanit Wanichacheva and Kevin Burgess  
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 30) pp:8271-8276
Publication Date(Web):03 Jul 2015
DOI:10.1039/C5OB01104C
This study features aza-BODIPY (BF2-chelated azadipyrromethene) dyes with two aromatic substituents linked by oligoethylene glycol fragments to increase hydrophilicity of aza-BODIPY for applications in intracellular imaging. To prepare these, two chalcones were attached α,ω onto oligoethylene glycol fragments, then reacted with nitromethane anion. Conjugate addition products from this reaction were then subjected to typical conditions for synthesis of aza-BODIPY dyes (NH4OAc, nBuOH, 120 °C); formation of boracycles in this reaction was concomitant with creation of macrocycles containing the oligoethylene glycol fragments. Similar dyes with acyclic oligoelythene glycol substituents in the same position were used to compare the efficiencies of the intra- and inter-molecular aza-BODIPY forming reactions, and the characteristics of the products. All the fluors with oligoethylene glycol fragments, i.e. cyclic or acyclic, localized in the endoplasmic reticulum of a fibroblast cell line (WEHI-13VAR), the human pancreatic cancer cell line (PANC-1, rough ER predominates) and human liver cancer cell line (HepG2, smooth ER prevalent). These fluors are potentially useful for near IR (λmax emis at 730 nm) ER staining probes.
Co-reporter:Dongyue Xin, Arjun Raghuraman, and Kevin Burgess
The Journal of Organic Chemistry 2015 Volume 80(Issue 9) pp:4450-4458
Publication Date(Web):April 13, 2015
DOI:10.1021/acs.joc.5b00300
Minimalist structures, H and I, were designed as protein interface mimics. Attributes of these chemotypes are (i) greater rigidity than conventional peptides, (ii) chiral and nonplanar heterocyclic backbones that are less prone to the hydrophobic aggregation effects, and (iii) potential to be prepared with a variety of side chains corresponding to natural amino acids. Intermediates, however, in the oligo(pyrrolidinone-piperidine)s H syntheses were vulnerable to epimerization. The origins of this epimerization were determined, then the study was focused on oligo(piperidinone–piperidine) compounds I. Mimics I were prepared via iterative couplings; a penta(piperidinone–piperidine) was prepared in this way. A series of lower homologues of this pentamer were crystallized and studied (single crystal X-ray), and four of them were used in a circular dichroism (CD) study. Thus, an estimate of 36 Å for the N-to-C distance of a typical conformation of the penta(piperidinone–piperidine) was made. CD spectra of four progressively longer oligomers allowed assignment of elipticity changes around 300 nm that can be attributed to increased conformational ordering of the longer oligomers in solution.
Co-reporter:Dongyue Xin, Andreas Holzenburg and Kevin Burgess  
Chemical Science 2014 vol. 5(Issue 12) pp:4914-4921
Publication Date(Web):10 Sep 2014
DOI:10.1039/C4SC01295J
Small molecule probes for perturbing protein–protein interactions (PPIs) in vitro can be useful if they cause the target proteins to undergo biomedically relevant changes to their tertiary and quaternary structures. Application of the Exploring Key Orientations (EKO) strategy (J. Am. Chem. Soc., 2013, 135, 167–173) to a piperidinone–piperidine chemotype 1 indicated specific derivatives were candidates to perturb a protein–protein interface in the α-antithrombin dimer; those particular derivatives of 1 were prepared and tested. In the event, most of them significantly accelerated oligomerization of monomeric α-antithrombin, which is metastable in its monomeric state. This assertion is supported by data from gel electrophoresis (non-denaturing PAGE; throughout) and probe-induced loss of α-antithrombin's inhibitor activity in a reaction catalyzed by thrombin. Kinetics of α-antithrombin oligomerization induced by the target compounds were examined. It was found that probes with O-benzyl-protected serine side-chains are the most active catalysts in the series, and reasons for this, based on modeling experiments, are proposed. Overall, this study reveals one of the first examples of small molecules designed to act at a protein–protein interface relevant to oligomerization of a serpin (i.e. α-antithrombin). The relevance of this to formation of oligomeric serpin fibrils, associated with the disease states known as “serpinopathies”, is discussed.
Co-reporter:Dongyue Xin and Kevin Burgess
Organic Letters 2014 Volume 16(Issue 8) pp:2108-2110
Publication Date(Web):March 31, 2014
DOI:10.1021/ol5005643
Conditions were developed for syntheses of β-enamino esters, thioesters, and amides. These reactions involve hydroxybenzotriazole derivatives in buffered media. Illustrative syntheses of some heterocyclic systems are given, including some related to protein–protein interface mimics.
Co-reporter:Dongyue Xin;Dr. Lisa M. Perez; Thomas R. Ioerger; Kevin Burgess
Angewandte Chemie 2014 Volume 126( Issue 14) pp:3668-3672
Publication Date(Web):
DOI:10.1002/ange.201400927

Abstract

Minimalist secondary structure mimics are typically made to resemble one interface in a protein–protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol−1 above the minimum energy solution state.

Co-reporter:Sakunchai Khumsubdee, Kevin Burgess
Tetrahedron 2014 70(6) pp: 1326-1335
Publication Date(Web):
DOI:10.1016/j.tet.2013.12.040
Co-reporter:Dongyue Xin;Dr. Lisa M. Perez; Thomas R. Ioerger; Kevin Burgess
Angewandte Chemie International Edition 2014 Volume 53( Issue 14) pp:3594-3598
Publication Date(Web):
DOI:10.1002/anie.201400927

Abstract

Minimalist secondary structure mimics are typically made to resemble one interface in a protein–protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol−1 above the minimum energy solution state.

Co-reporter:Anyanee Kamkaew, Siang Hui Lim, Hong Boon Lee, Lik Voon Kiew, Lip Yong Chung and Kevin Burgess  
Chemical Society Reviews 2013 vol. 42(Issue 1) pp:77-88
Publication Date(Web):26 Sep 2012
DOI:10.1039/C2CS35216H
BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with 3O2. In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.
Co-reporter:Sakunchai Khumsubdee and Kevin Burgess
ACS Catalysis 2013 Volume 3(Issue 2) pp:237
Publication Date(Web):January 22, 2013
DOI:10.1021/cs3007389
As methodology development matures, it can be difficult to discern the most effective ways of performing certain transformations from the rest. This review summarizes the most important contributions leading to asymmetric hydrogenations of simple unsaturated acid and ester substrates, with the objective of highlighting at least the best types of catalysts for each. Achievements in the area are described, and these reveal situations where further efforts should be worthwhile and ones where more research is only likely to give diminishing returns. In general, our conclusions are that the most useful types of catalysts for unsaturated acids and esters tend to be somewhat different, simple substrates have been studied extensively, and the field is poised to address more complex reactions. These could be ones involving alternative (particularly cyclic) structures, chemoselectivity issues, and more complex substrate stereochemistries.Keywords: alkene acids; alkene esters; homogeneous; hydrogenations; stereoselective
Co-reporter:Anyanee Kamkaew
Journal of Medicinal Chemistry 2013 Volume 56(Issue 19) pp:7608-7614
Publication Date(Web):September 24, 2013
DOI:10.1021/jm4012142
A molecule 1 (IY-IY-PDT) was designed to contain a fragment (IY-IY) that targets the TrkC receptor and a photosensitizer that acts as an agent for photodynamic therapy (PDT). Molecule 1 had submicromolar photocytotoxicities to cells that were engineered to stably express TrkC (NIH3T3-TrkC) or that naturally express high levels of TrkC (SY5Y neuroblastoma lines). Control experiments showed that 1 is not cytotoxic in the dark and has significantly less photocytotoxicity toward cells that do not express TrkC (NIH3T3-WT). Other controls featuring a similar agent 2 (YI-YI-PDT), which is identical and isomeric with 1 except that the targeting region is scrambled (a YI-YI motif, see text), showed that 1 is considerably more photocytotoxic than 2 on TrkC+ cells. Imaging live TrkC+ cells after treatment with a fluorescent agent 1 (IY-IY-PDT) proved that 1 permeates into TrkC+ cells and is localized in the lysosomes. This observation indirectly indicates that agent 1 enters the cells via the TrkC receptor. Consistent with this, the dose-dependent PDT effects of 1 can be competitively reduced by the natural TrkC ligand, neurotrophin NT3.
Co-reporter:Ye Zhu
Advanced Synthesis & Catalysis 2013 Volume 355( Issue 1) pp:107-115
Publication Date(Web):
DOI:10.1002/adsc.201200709

Abstract

Iridium-catalyzed asymmetric hydrogenations of chiral alkenes were used to access four pivotal α,ω-functionalized chirons, that contain widely occurring stereochemical 1,2,3-Me,OH,Me motifs. A chiral analogue of Crabtree’s catalyst was used in key hydrogenation steps to form these motifs with high stereochemical purities. An application of one of these chirons is illustrated here with a synthesis of (−)-invictolide.

Co-reporter:Luis Cerdán;Virginia Martínez-Martínez;, Inmaculada García-Moreno;Angel Costela;María E. Pérez-Ojeda;Iñigo López Arbeloa;Liangxing Wu
Advanced Optical Materials 2013 Volume 1( Issue 12) pp:984-990
Publication Date(Web):
DOI:10.1002/adom.201300383

Herein, for the first time, outstanding laser performance is demonstrated in liquid solution and solid state by naturally assembling excimers of organic fluorophores (rosamine dyes). Highly efficient and photostable laser dye properties, with broadened tunability covering 80 nm in the red spectral region (590–670 nm), is attributed to the coexistence of monomers and excimers induced under high optical gain conditions. Amplified spontaneous emission measurements in rosamine-doped polymer thin films show that the excimer exhibits a threshold lower and a gain higher than those corresponding to the monomer species. These laser properties make rosamines excellent candidates for biophotonic and spectroscopic applications, overcoming the main drawbacks exhibited by other long-wavelength (>600 nm) laser dyes, including low absorption at the standard pump wavelength (532 nm), low laser efficiency, and poor chemo- and photostability.

Co-reporter:Dongyue Xin, Eunhwa Ko, Lisa M. Perez, Thomas R. Ioerger and Kevin Burgess  
Organic & Biomolecular Chemistry 2013 vol. 11(Issue 44) pp:7789-7801
Publication Date(Web):14 Oct 2013
DOI:10.1039/C3OB41848K
Peptide mimics that display amino acid side-chains on semi-rigid scaffolds (not peptide polyamides) can be referred to as minimalist mimics. Accessible conformations of these scaffolds may overlay with secondary structures giving, for example, “minimalist helical mimics”. It is difficult for researchers who want to apply minimalist mimics to decide which one to use because there is no widely accepted protocol for calibrating how closely these compounds mimic secondary structures. Moreover, it is also difficult for potential practitioners to evaluate which ideal minimalist helical mimics are preferred for a particular set of side-chains. For instance, what mimic presents i, i + 4, i + 7 side-chains in orientations that best resemble an ideal α-helix, and is a different mimic required for a i, i + 3, i + 7 helical combination? This article describes a protocol for fitting each member of an array of accessible scaffold conformations on secondary structures. The protocol involves: (i) use quenched molecular dynamics (QMD) to generate an ensemble consisting of hundreds of accessible, low energy conformers of the mimics; (ii) representation of each of these as a set of Cα and Cβ coordinates corresponding to three amino acid side-chains displayed by the scaffolds; (iii) similar representation of each combination of three side-chains in each ideal secondary structure as a set of Cα and Cβ coordinates corresponding to three amino acid side-chains displayed by the scaffolds; and, (iv) overlay Cα and Cβ coordinates of all the conformers on all the sets of side-chain “triads” in the ideal secondary structures and express the goodness of fit in terms of root mean squared deviation (RMSD, Å) for each overlay. We refer to this process as Exploring Key Orientations on Secondary structures (EKOS). Application of this procedure reveals the relative bias of a scaffold to overlay on different secondary structures, the “side-chain correspondences” (e.g. i, i + 4, i + 7 or i, i + 3, i + 4) of those overlays, and the energy of this state relative to the minimum located. This protocol was tested on some of the most widely cited minimalist α-helical mimics (1–8 in the text). The data obtained indicates several of these compounds preferentially exist in conformations that resemble other secondary structures as well as α-helices, and many of the α-helical conformations have unexpected side-chain correspondences. These observations imply the featured minimalist mimics have more scope for disrupting PPI interfaces than previously anticipated. Finally, the same simulation method was used to match preferred conformations of minimalist mimics with actual protein/peptide structures at interfaces providing quantitative comparisons of predicted fits of the test mimics at protein–protein interaction sites.
Co-reporter:Sakunchai Khumsubdee, Yubo Fan, and Kevin Burgess
The Journal of Organic Chemistry 2013 Volume 78(Issue 19) pp:9969-9974
Publication Date(Web):September 19, 2013
DOI:10.1021/jo4013783
Imidazolinylidene, imidazolylidine, benzimidazolylidene complexes 1a–c were prepared and tested in asymmetric hydrogenations of a series of largely unfunctionalized alkenes. Similarities and differences in the catalytic performance of these complexes were rationalized in terms of the predicted mechanisms of these reactions, and their relative tendencies to generate protons under the hydrogenation conditions.
Co-reporter:Arjun Raghuraman, Dongyue Xin, Lisa M. Perez, and Kevin Burgess
The Journal of Organic Chemistry 2013 Volume 78(Issue 10) pp:4823-4833
Publication Date(Web):May 8, 2013
DOI:10.1021/jo400323k
Oligo-pyrrolinone–pyrrolidines (generic structure 1) have the potential to interfere with protein–protein interactions (PPIs), but to reduce this to practice it is necessary to be able to synthesize these structures with a variety of different side chains corresponding to genetically encoded proteins. This paper describes expansion of the synthetic scope of 1, the difficulties encountered in this process, particularly issues with epimerization and slow coupling rates, and methods to overcome them. Finally, spectroscopic and physicochemical properties as well as proteolytic stabilities of molecules in this series were measured; these data highlight the suitability of oligo-pyrrolinone–pyrrolidines for the development of pharmacological probes or pharmaceutical leads.
Co-reporter:Sakunchai Khumsubdee, Hua Zhou, and Kevin Burgess
The Journal of Organic Chemistry 2013 Volume 78(Issue 23) pp:11948-11955
Publication Date(Web):November 12, 2013
DOI:10.1021/jo401996m
Asymmetric hydrogenation routes to homologues of The Roche ester tend to be restricted to hydrogenations of itaconic acid derivatives, that is, substrates that contain a relatively unhindered, 1,1-disubstituted alkene. This is because in hydrogenations mediated by RhP2 complexes, the typical catalysts, it is difficult to obtain high conversions using the alternative substrate for the same product, the isomeric trisubstituted alkenes (D in the text). However, chemoselective modification of the identical functional groups in itaconic acid derivatives are difficult; hence, it would be favorable to use the trisubstituted alkene. Trisubstituted alkene substrates can be hydrogenated with high conversions using chiral analogs of Crabtree’s catalyst of the type IrN(carbene). This paper demonstrates that such reactions are scalable (tens of grams) and can be manipulated to give optically pure homo-Roche ester chirons. Organocatalytic fluorination, chlorination, and amination of the homo-Roche building blocks was performed to demonstrate that they could easily be transformed into functionalized materials with two chiral centers and α,ω-groups that provide extensive scope for modifications. A synthesis of (S,S)- and (R,S)-γ-hydroxyvaline was performed to illustrate one application of the amination product.
Co-reporter:Ye Zhu and Kevin Burgess
Accounts of Chemical Research 2012 Volume 45(Issue 10) pp:1623
Publication Date(Web):October 5, 2012
DOI:10.1021/ar200145q
The large volume of research studying hydrogenation catalysis might suggest that stereoselective hydrogenation of alkenes is a solved problem, but we believe the most important parts of asymmetric hydrogenation methodology remain unmastered. The most popular chiral catalysts, Rh- and Ir-diphosphine complexes, do not hydrogenate the largest categories of prochiral alkenes, hindered tri- and tetra-substituted ones, at useful rates unless the substrate has a “classical” coordinating functional group (CFG), for example, amides or homoallylic alcohols, to anchor the substrate to the metal. Therefore, while many methods are available for the asymmetric hydrogenation of alkenes with appropriate CFGs, synthetic chemistry would benefit from chiral hydrogenations of substrates with functional groups that typically do not coordinate in Rh- and Ir-diphosphine complexes.In this Account, we demonstrate the application of chiral analogues of Crabtree’s catalyst to asymmetric hydrogenations of coordinating unfunctionalized, trisubstituted alkenes. Crabtree’s catalyst, a complex of iridium with 1,5-cyclooctadiene, tris-cyclohexylphosphine, and pyridine, differs from Rh- and Ir-diphosphine complexes, which we broadly refer to as “chiral analogues of Wilkinson’s catalyst.” Crabtree’s catalyst analogues hydrogenate substrates that do not contain functionalities generally recognized as CFGs, and we propose reasons for this chemistry based on the catalytic mechanisms. Thus, chiral analogues of Crabtree’s catalyst facilitate many hydrogenations that would not be possible using Rh- or Ir-diphosphine complexes. Directed hydrogenations have been used in acyclic stereocontrol for decades, but the realization that these catalysts can be used for acyclic stereocontrol without the types of directing groups that are necessary for other hydrogenations significantly broadens the scope of hydrogenations for this purpose. Recently, we have prepared chirons for polyketide-derived natural products using an N,carbene-Ir complex (1). This approach has led to catalytic syntheses of several important chirons to facilitate preparations of these ubiquitous natural products.
Co-reporter:Eunhwa Ko ; Arjun Raghuraman ; Lisa M. Perez ; Thomas R. Ioerger
Journal of the American Chemical Society 2012 Volume 135(Issue 1) pp:167-173
Publication Date(Web):December 27, 2012
DOI:10.1021/ja3067258
Small molecule probes that selectively perturb protein–protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized that conformational resemblance of semirigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semirigid scaffold. Conformations of one such chemotype (1aaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. On the basis of these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs.
Co-reporter:Dmytro Fedoseyenko, Arjun Raghuraman, Eunhwa Ko and Kevin Burgess  
Organic & Biomolecular Chemistry 2012 vol. 10(Issue 5) pp:921-924
Publication Date(Web):19 Dec 2011
DOI:10.1039/C2OB06692K
A graphical abstract is available for this content
Co-reporter:Ye Zhu and Kevin Burgess  
RSC Advances 2012 vol. 2(Issue 11) pp:4728-4735
Publication Date(Web):13 Apr 2012
DOI:10.1039/C2RA01350A
Iridium catalyzed, enantioselective hydrogenations of functionalized, acid-sensitive vinyl ethers are reported. These reactions are mediated by the chiral N-carbene–oxazoline complex 1 that, unlike similar N,P-ligated catalysts (6 and 7), gives hydrogenation products (with enantioselectivities up to 96%) without significant acid-mediated degradation. In general, higher enantioselectivities were observed for the allylic alcohol derivatives (2) than the α-methoxycinnamate-based compounds (4).
Co-reporter:Eunhwa Ko, Anyanee Kamkaew, and Kevin Burgess
ACS Medicinal Chemistry Letters 2012 Volume 3(Issue 12) pp:1008
Publication Date(Web):October 9, 2012
DOI:10.1021/ml300227d
A small molecule motif was used in “active targeting” to deliver cytotoxic substances into tumor cells that express the TrkC receptor. Underlying this study was the hypothesis that internalization of targeted conjugates into cells would be facile if mediated by receptor binding and receptor–ligand internalization. Initial experiments using 6-mercaptopurine gave encouraging data but demonstrated the importance of maintaining solubility and high cytotoxicity. Conjugates of the targeting agent with a cytotoxic rosamine (similar to a rhodamine) were more successful. Targeting of TrkC was observed, validated in a series of competition experiments featuring other TrkC ligands, and accumulation into lysosomes was observed, as expected for receptor-mediated internalization.Keywords: cancer; neurotrophin; small molecule ligand; targeting; TrkC
Co-reporter:Eunhwa Ko, Jing Liu and Kevin Burgess  
Chemical Society Reviews 2011 vol. 40(Issue 8) pp:4411-4421
Publication Date(Web):11 Apr 2011
DOI:10.1039/C0CS00218F
Many “new generation” peptidomimetics are designed to present amino acid side chains only; they do not have structural features that resemble peptide main chains. These types of molecules have frequently been presented in the literature as mimics of specific secondary structures. However, many “side-chain only” peptidomimetics do notrest in single conformational states, but exist in a limited number of freely interconverting forms. These different conformations may resemble different secondary structures, so referring to them as, for instance, turn- or helical-mimics understates the ways they could adapt to various binding situations. Sets of scaffolds that can be used to mimic aspects of nearly every secondary structure, i.e. universal peptidomimetics, can be constructed. These may assume a privileged place in library design, particularly in high throughput screening for pharmacological probes for which binding conformations, or even the target itself, is unknown at the time the library is designed (critical review, 101 references).
Co-reporter:Arjun Raghuraman ; Eunhwa Ko ; Lisa M. Perez ; Thomas R. Ioerger
Journal of the American Chemical Society 2011 Volume 133(Issue 32) pp:12350-12353
Publication Date(Web):July 22, 2011
DOI:10.1021/ja2033734
Peptidomimetics 1–3 were prepared from amino acid-derived tetramic acids 7 as the key starting materials. Calculations show that preferred conformations of 1 can align their side-chain vectors with amino acids in common secondary structures more effectively than conformations of 3. A good fit was found for a preferred conformation of 2 (an extended derivative of 1) with a sheet/β-turn/sheet motif.
Co-reporter:Eunhwa Ko and Kevin Burgess
Organic Letters 2011 Volume 13(Issue 5) pp:980-983
Publication Date(Web):January 26, 2011
DOI:10.1021/ol103022m
Two amino acid derived synthons were combined to give homopropargylic amines 2. Platinum dichloride was used to cyclize these intermediates into pyrroles 3 which collapsed to the target secondary structure mimics 1 on treatment with base. Side chains of these compounds overlay with an idealized type 1 β-turn and with an inverse γ-turn.
Co-reporter:Anyanee Kamkaew, Rola Barhoumi, Robert C. Burghardt and Kevin Burgess  
Organic & Biomolecular Chemistry 2011 vol. 9(Issue 19) pp:6513-6518
Publication Date(Web):16 Aug 2011
DOI:10.1039/C1OB05874F
Two cationic polyfluorene derivatives, quaternary amine 1 and guanidine 2 sheathed systems, were prepared as potential carriers to mediate import of proteins into cells without requiring covalent attachment to the protein. Neither polymer showed significant cytotoxicities (IC50 100 μM) when exposed to Clone 9 rat liver cells. Both polymers were shown to mediate import of a series of four proteins chosen because they have different pI values, sizes, and variable organic fluor attachments. Once inside the cells, the quaternary amine system 1 released more of its cargo into regions outside the lysosomes. In one exploratory experiment, pyrenebutyrate was shown to accelerate import of a protein system by polymer 1.
Co-reporter:Jiney Jose, Aurore Loudet, Yuichiro Ueno, Liangxing Wu, Hsiang-Yun Chen, Dong Hee Son, Rola Barhoumi, Robert Burghardt and Kevin Burgess  
Organic & Biomolecular Chemistry 2011 vol. 9(Issue 10) pp:3871-3877
Publication Date(Web):03 Mar 2011
DOI:10.1039/C0OB00967A
Lipophilic energy transfer cassettes like 1 and 2 are more conveniently synthesized than the corresponding hydrophilic compounds, but they are not easily used in aqueous media. To overcome the latter issue, cassettes 1 and 2 were separately encapsulated in silica nanoparticles (ca. 22 nm) which freely disperse in aqueous media. Photophysical properties of the encapsulated dyes 1–SiO2 and 2–SiO2 were recorded. The nanoparticles 1–SiO2 permeated into Clone 9 rat liver cells and targeted only the ER. A high degree of energy transfer was observed in this organelle such that most of the light fluoresced from the acceptor part, i.e. the particles appeared red. Silica nanoparticles 2–SiO2 also permeated into Clone 9 rat liver cells and they targeted mitochondria but were also observed in endocytic vesicles (lysosomes or endosomes). In these organelles they fluoresced red and red/green respectively. Thus the cargo inside the nanoparticles influences where they localize in cells, and the environment of the nanoparticles in the cells changes the fluorescent properties of the encapsulated dyes. Neither of these findings were anticipated given that silica nanoparticles of this type are generally considered to be non-porous.
Co-reporter:Aurore Loudet, Yuichiro Ueno, Liangxing Wu, Jiney Jose, Rola Barhoumi, Robert Burghardt, Kevin Burgess
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 6) pp:1849-1851
Publication Date(Web):15 March 2011
DOI:10.1016/j.bmcl.2011.01.040
A dye cassette fluoresces green (ca 520 nm) in the cytoplasm, endoplasmic reticulum (ER), and lysosomes, but red in mitochondria, that is, it illustrates ‘organelle specific energy transfer’. This phenomenon may open new horizons in intracellular imaging.
Co-reporter:Zhanxiang Liu, Kevin Burgess
Tetrahedron Letters 2011 Volume 52(Issue 48) pp:6325-6327
Publication Date(Web):30 November 2011
DOI:10.1016/j.tetlet.2011.09.024
Product inhibition was encountered for some substrates in the resolution of methyl sulfinylacetates mediated by lipase Amano AK, so an apparatus to continually extract the carboxylate product was devised. This was applied to resolve some sulfoxides with high enantiodifferentiation.
Co-reporter:Ye Zhu, Sakunchai Khumsubdee, Amber Schaefer, and Kevin Burgess
The Journal of Organic Chemistry 2011 Volume 76(Issue 18) pp:7449-7457
Publication Date(Web):August 18, 2011
DOI:10.1021/jo201215c
This project was undertaken to demonstrate the potential of asymmetric hydrogenations mediated by the chiral, carbene-oxazoline analogue of Crabtree’s catalyst “cat” in asymmetric hydrogenations of allylic amine derivatives of amino acids. Peripheral features of the substrates (protecting groups, functional groups related by redox processes, and alkene geometries) were varied to optimize the stereochemical vectors exerted by the substrate and align them with the catalyst vector. N-Acetyl-protected, O-TBDPS-protected allylic substrates 9a–e emerged as the best for this reaction; syn-products were formed from the E-alkenes, while the Z-isomers gave anti-target materials, both with high diastereoselectivities. This study featured asymmetric catalysis to elaborate optically active substrates into more stereochemically complex chirons; we suggest that the approach used, optimization of stereocontrol by varying peripheral aspects of the substrate, tends to be easier than de novo catalyst design for each substrate type. In other words, optimization of the substrate vector is likely to be more facile than enhancement of the catalyst vector via ligand modifications.
Co-reporter:Cliferson Thivierge, Aurore Loudet, and Kevin Burgess
Macromolecules 2011 Volume 44(Issue 10) pp:4012-4015
Publication Date(Web):April 21, 2011
DOI:10.1021/ma200174w
Four systems 1a−1d were prepared to investigate the optical properties of copolymers comprised of polyfluorene doped with BODIPY-based fluors. The underlying hypothesis was energy harvested via the strong absorptivity of the major component, fluorene, would be primarily emitted from the BODIPY parts at much higher wavelengths. Optimization of the polymerization process as a function of the mol % of BODIPY indicated that the brightest polymers were formed when approximately 4 fluorene units were copolymerized with every BODIPY precursor. These polymers were cast into nanoparticles of ca. 40 nm diameter. Treatment of clone 9 rat liver cells with suspensions of these particles resulted in uptake without encapsulation in lysosomes, or organelle targeting.
Co-reporter:Cliferson Thivierge, Junyan Han, Roxanne M. Jenkins, and Kevin Burgess
The Journal of Organic Chemistry 2011 Volume 76(Issue 13) pp:5219-5228
Publication Date(Web):May 27, 2011
DOI:10.1021/jo2005654
Photophysical data and orbital energy levels (from electrochemistry) were compared for molecules with the same BODIPY acceptor part (red) and perpendicularly oriented xanthene or BODIPY donor fragments (green). Transfer of energy, hence the photophysical properties of the cassettes, including the pH dependent fluorescence in the xanthene-containing molecules, correlates with the relative energies of the frontier orbitals in these systems. Intracellular sensing of protons is often achieved via sensors that switch off completely at certain pH values, but probes of this type are not easy to locate inside cells in their “off-state”. A communication from these laboratories (J. Am. Chem. Soc., 2009, 131, 1642–3) described how the energy transfer cassette 1 could be used for intracellular imaging of pH. This probe is fluorescent whatever the pH, but its exact photophysical properties are governed by the protonation states of the xanthene donors. This work was undertaken to further investigate correlations between structure, photophysical properties, and pH for energy transfer cassettes. To achieve this, three other cassettes 2–4 were prepared: another one containing pH-sensitive xanthene donors (2) and two “control cassettes” that each have two BODIPY-based donors (3 and 4). Both the cassettes 1 and 2 with xanthene-based donors fluoresce red under slightly acidic conditions (pH < ∼6) and green when the medium is more basic (>∼7), whereas the corresponding cassettes with BODIPY donors give almost complete energy transfer regardless of pH. The cassettes that have BODIPY donors, by contrast, show no significant fluorescence from the donor parts, but the overall quantum yields of the cassettes when excited at the donor (observation of acceptor fluorescence) are high (ca. 0.6 and 0.9). Electrochemical measurements were performed to elucidate orbital energy level differences between the pH–fluorescence profiles of cassettes with xanthene donors, relative to the two with BODIPY donors. These studies confirm energy transfer in the cassettes is dramatically altered by analytes that perturb relative orbital levels. Energy transfer cassettes with distinct fluorescent donor and acceptor units provide a new, and potentially useful, approach to sensors for biomedical applications.
Co-reporter:Junyan Han and Kevin Burgess
Chemical Reviews 2010 Volume 110(Issue 5) pp:2709
Publication Date(Web):October 16, 2009
DOI:10.1021/cr900249z
Co-reporter:Eunhwa Ko ; Jing Liu ; Lisa M. Perez ; Genliang Lu ; Amber Schaefer
Journal of the American Chemical Society 2010 Volume 133(Issue 3) pp:462-477
Publication Date(Web):December 23, 2010
DOI:10.1021/ja1071916
This paper concerns peptidomimetic scaffolds that can present side chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analogue local pairs of amino acids (including noncontiguous ones) in any secondary structure; i.e., they are universal peptidomimetics. To illustrate this concept, we designed a set of four peptidomimetic scaffolds. Libraries based on them were made bearing side chains corresponding to many of the protein-derived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together, peptidomimetics based on these four scaffolds can adopt conformations that resemble almost any combination of local amino acid side chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high-throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) are outlined.
Co-reporter:Ye Zhu ; Yubo Fan
Journal of the American Chemical Society 2010 Volume 132(Issue 17) pp:6249-6253
Publication Date(Web):April 8, 2010
DOI:10.1021/ja101233g
Acidities of iridium hydride intermediates were shown to be critical in some transformations mediated by the chiral analogues of Crabtree’s catalyst, 1−3. To do this, several experiments were undertaken to investigate the acidities of hydrogenation mixtures formed using these iridium-oxazoline complexes. DFT calculations indicated that the acidity difference for Ir−H intermediates in these hydrogenations were astounding; iridium hydride from the N-heterocyclic carbene catalyst 1 was calculated to be around seven pKa units less acidic than those from the P-based complexes 2 and 3. Consistent with this, the carbene complex 1 was shown to be more effective for hydrogenations of acid-sensitive substrates. In deuteration experiments, less “abnormal” deuteration was observed, corresponding to fewer complications from acid-mediated alkene isomerization preceding the D2-addition step. Finally, simple tests with pH indicators provided visual evidence that phosphine-based catalyst precursors give significantly more acidic reaction mixtures than the corresponding N-heterocyclic carbene ones. These observations indicate carbene-for-phosphine (and similar) ligand substitutions may impact the outcome of catalytic reactions by modifying the acidities of the metal hydrides formed.
Co-reporter:Yuichiro Ueno ; Jiney Jose ; Aurore Loudet ; César Pérez-Bolívar ; Pavel Anzenbacher ; Jr.
Journal of the American Chemical Society 2010 Volume 133(Issue 1) pp:51-55
Publication Date(Web):November 24, 2010
DOI:10.1021/ja107193j
This paper concerns the development of water-compatible fluorescent imaging probes with tunable photonic properties that can be excited at a single wavelength. Bichromophoric cassettes 1a−1c consisting of a BODIPY donor and a cyanine acceptor were prepared using a simple synthetic route, and their photophysical properties were investigated. Upon excitation of the BODIPY moiety at 488 nm the excitation energy is transferred through an acetylene bridge to the cyanine dye acceptor, which emits light at approximately 600, 700, and 800 nm, i.e., with remarkable dispersions. This effect is facilitated by efficient energy transfer that gives a “quasi-Stokes” shift between 86 and 290 nm, opening a huge spectral window for imaging. The emissive properties of the cassettes depend on the energy-transfer (ET) mechanism: the faster the transfer, the more efficient it is. Measurements of rates of ET indicate that a through-bond ET takes place in the cassettes 1a and 1b that is 2 orders of magnitude faster than the classical through-space, Förster ET. In the case of cassette 1c, however, both mechanisms are possible, and the rate measurements do not allow us to discern between them. Thus, the cassettes 1a−1c are well suited for multiplexing experiments in biotechnological methods that involve a single laser excitation source. However, for widespread application of these probes, their solubility in aqueous media must be improved. Consequently, the probes were encapsulated in calcium phosphate/silicate nanoparticles (diameter ca. 22 nm) that are freely dispersible in water. This encapsulation process resulted in only minor changes in the photophysical properties of the cassettes. The system based on cassette 1a was chosen to probe how effectively these nanoparticles could be used to deliver the dyes into cells. Encapsulated cassette 1a permeated Clone 9 rat liver cells, where it localized in the mitochondria and fluoresced through the acceptor part, i.e., red. Overall, this paper reports readily accessible, cyanine-based through-bond ET cassettes that are lypophilic but can be encapsulated to form nanoparticles that disperse freely in water. These particles can be used to enter cells and to label organelles.
Co-reporter:Ye Zhu, Aurore Loudet, and Kevin Burgess
Organic Letters 2010 Volume 12(Issue 19) pp:4392-4395
Publication Date(Web):September 7, 2010
DOI:10.1021/ol1018773
(−)-Spongidepsin 1, a cytotoxic marine natural product, was prepared via two iridium-catalyzed hydrogenation reactions; both were highly stereoselective, giving convenient access to pivotal intermediates. This synthesis was modified to give several spongidepsin analogues, and their cytotoxicities were compared with those of the natural product.
Co-reporter:Jing Liu ; Fouad Brahimi ; H. Uri Saragovi
Journal of Medicinal Chemistry 2010 Volume 53(Issue 13) pp:5044-5048
Publication Date(Web):June 11, 2010
DOI:10.1021/jm100148d
Bivalent molecules containing two β-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC receptor.
Co-reporter:Jiney Jose, Aurore Loudet, Yuichiro Ueno, Rola Barhoumi, Robert C. Burghardt and Kevin Burgess  
Organic & Biomolecular Chemistry 2010 vol. 8(Issue 9) pp:2052-2059
Publication Date(Web):03 Mar 2010
DOI:10.1039/B925845K
Five new water-soluble derivatives of Nile Red 1–5 were prepared. These benzophenoxazine dyes fluoresce between 640 and 667 nm with quantum yields of 0.17–0.33 in pH 7.4 phosphate buffer, and at slightly shorter wavelengths and higher quantum yields in EtOH. Two dyes, 3 and 4 permeated into Clone 9 cells and selectively stained mitochondria and golgi, respectively.
Co-reporter:Jian Zhao
Journal of the American Chemical Society 2009 Volume 131(Issue 37) pp:13236-13237
Publication Date(Web):August 31, 2009
DOI:10.1021/ja905458n
Roche ester derivatives were converted to trisubstituted alkenes with allylic chiral centers. Hydrogenation of these substrates with chiral analogues of Crabtree’s catalyst, specifically, an optically active carbene oxazoline derivative, were found to be mostly catalyst controlled. However, the peripheral functionalities and protecting groups had significant effects and could be adjusted to give high stereoselectivities. The upshot of this work is that α,ω-functionalized chirons to introduce 1,2-dimethyl functionalities into acyclic chains have been developed.
Co-reporter:Liangxing Wu ; Aurore Loudet ; Rola Barhoumi ; Robert C. Burghardt
Journal of the American Chemical Society 2009 Volume 131(Issue 26) pp:9156-9157
Publication Date(Web):June 15, 2009
DOI:10.1021/ja9029413
Two water-soluble “through-bond energy transfer cassettes” (TBET-cassettes) were prepared. They have good extinction coefficients at the donor part and transfer energy to the acceptor parts with good “overall quantum yields” (0.30 and 0.24 in pH 7.4 phosphate buffer). Fluorescence resonance energy transfer from one protein functionalized with an appropriate donor can be used to excite the TBET-cassettes on different proteins to probe protein−protein interactions under conditions that would not be possible for single-dye acceptor systems.
Co-reporter:Jian Zhao and Kevin Burgess
Organic Letters 2009 Volume 11(Issue 10) pp:2053-2056
Publication Date(Web):April 15, 2009
DOI:10.1021/ol900308w
Catalyst control dominates in the asymmetric hydrogenations of largely unfunctionalized trisubstituted alkenes formed from lactic acid and glyceraldehyde, affording syn- and anti-aldol products of the type shown above.
Co-reporter:Junyan Han, Oswaldo Gonzalez, Angelica Aguilar-Aguilar, Eduardo Peña-Cabrera and Kevin Burgess  
Organic & Biomolecular Chemistry 2009 vol. 7(Issue 1) pp:34-36
Publication Date(Web):30 Oct 2008
DOI:10.1039/B818390B
Chemoselective cross-coupling reactions were demonstrated for C–S bonds in the BODIPY dyes 1 and 4, and similar reactions were applied to make the two-dye cassette system 11.
Co-reporter:Jiney Jose;Yuichiro Ueno
Chemistry - A European Journal 2009 Volume 15( Issue 2) pp:418-423
Publication Date(Web):
DOI:10.1002/chem.200801104

Abstract

Four water-soluble 2-hydroxy-Nile Blue derivatives, 1 a, 1 b, 2 a, and 2 b, were prepared by condensation reactions performed under relatively mild conditions (90 °C, N,N-dimethylformamide with no added acid). These fluorescent probes had more favorable fluorescence characteristics than two known water-soluble Nile Blue derivatives. Specifically, they were superior to the known dyes with respect to their quantum yields in aqueous media and the sharpness of their fluorescence emissions. Concentration-dependant UV absorption and fluorescence emission studies indicated that the dyes did not aggregate in aqueous solution at concentrations of less than 1–4 μM. The new water-soluble materials 1 a, 1 b, 2 a, and 2 b emit in a desirable region of the fluorescence spectrum (λ=670–675 nm). Overall they are potentially interesting for labeling biomolecules in aqueous environments.

Co-reporter:Jiney Jose, Yuichiro Ueno, Juan C. Castro, Lingling Li, Kevin Burgess
Tetrahedron Letters 2009 50(47) pp: 6442-6445
Publication Date(Web):
DOI:10.1016/j.tetlet.2009.08.130
Co-reporter:Liangxing Wu and Kevin Burgess  
Chemical Communications 2008 (Issue 40) pp:4933-4935
Publication Date(Web):19 Sep 2008
DOI:10.1039/B810503K
BODIPY dyes were synthesized from pyrrole-2-carbaldehyde derivatives in high yields; this constitutes a new approach to this dye framework.
Co-reporter:Ye Zhu
Advanced Synthesis & Catalysis 2008 Volume 350( Issue 7-8) pp:979-983
Publication Date(Web):
DOI:10.1002/adsc.200700546

Abstract

A carbene-oxazoline catalyst 1 proved to be an effective catalyst for reduction of an enol ether that the literature suggested could not be hydrogenated effectively by P,N-Ir catalysts. Thus, a series of ester and alcohol substrates were hydrogenated using catalyst 1. Good to excellent enantioselectivities and high conversions were obtained.

Co-reporter:Aurore Loudet, Junyan Han, Rola Barhoumi, Jean-Philippe Pellois, Robert C. Burghardt and Kevin Burgess  
Organic & Biomolecular Chemistry 2008 vol. 6(Issue 24) pp:4516-4522
Publication Date(Web):30 Oct 2008
DOI:10.1039/B809006H
Substances that mediate the import of proteins into cells, “carriers”, have many potential applications. The most potentially useful carriers do not have to be covalently linked to their protein cargoes. However, a common problem with all carrier molecules is that they tend to deposit the cargo proteins into endosomes; diffuse distribution in the cytosol is the desired outcome. This paper describes the import of four different labeled (Alexa Fluor® 488) proteins (avidin, recombinant streptavidin, bovine serum albumin, and β-galactosidase), with the well-known non-covalent carrier called pep-1 (also known as Chariot™), with R8 (a molecule that is not widely appreciated to import protein cargoes via a non-covalent mode of action), and with a new molecule called azo-R8. The data collected from fluorescence microscopy and flow cytometry indicate that all three non-covalent carriers can facilitate transport. At 37 °C, import into endocytic compartments dominates, but at 4 °C weak, diffuse fluorescence is observed in the cytosol, indicative of a favorable mode of action.
Co-reporter:Jianguang Zhou;James W. Ogle;Yubo Fan;Vorawit Banphavichit(Bee);Ye Zhu Dr.
Chemistry - A European Journal 2007 Volume 13(Issue 25) pp:
Publication Date(Web):21 JUN 2007
DOI:10.1002/chem.200700390

Asymmetric hydrogenations of monoenes and dienes were performed to obtain terminal deoxypolyketide fragments A and the corresponding internal chirons B and C. The chiral N-heterocyclic carbene catalyst 1 was used throughout. Modest selectivities for hydrogenations of simple monoenes relayed into high selectivities for preparations of the terminal deoxypolyketide fragments in which either two hydrogenations or one and an optically pure starting material were used. Curiously, the face selectivities for hydrogenation of α,β-unsaturated esters were consistently opposite to those that had been observed for styrene and stilbene derivatives in previous work, and to closely related allylic alcohol and ether derivatives in this work. Plausible mechanisms for this differing behavior were deduced by using DFT calculations. It appears that the origin of the unusual stereoselectivity for the ester derivatives is transient metal-coordination of the ester carbonyl whereas there is no evidence that the allylic alcohol or ethers coordinate. The routes developed to α,ω-functionalized internal deoxypolyketide fragments are extremely practical. These begin with the Roche ester being converted into alkene and, in one case, diene derivatives. Catalyst control prevails in the hydrogenations of these substrates, but there is a significant “substrate vector” (a term we used to describe the influence of the substrate on a catalyst-controlled reaction). This is determined by minimization of 1,3-allylic strain and, in some cases, syn pentane interactions. This substrate vector can be constructively paired with the (dominant) catalyst vector by use of the appropriate enantiomer of 1. In the hydrogenation of a diene derivative, two chiral centers could be formed simultaneously with overall 11:1.0 selectivity; this is the first time this has been achieved in any asymmetric synthesis of a deoxypolyketide fragment. Throughout, diastereoselectivities of the crude material in the syntheses of α,ω-functionalized internal deoxypolyketide fragments were in excess of 11:1.0 and chromatographically purified samples could be isolated in high yields with dr (dr=diastereomeric ratio) values consistently in excess of 40:1.0.

Co-reporter:Jianguang Zhou Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 7) pp:
Publication Date(Web):3 JAN 2007
DOI:10.1002/anie.200603635

A match made in heaven: All the possible stereoisomers of α,ω-functionalized 2,4-dimethylpentane dyad and 2,4,6-trimethylheptane triad chirons (see picture; A and B, respectively; FG=functional group, PG=protecting group) can be reached by using a combination of a chiral catalyst and substrate effects in the hydrogenation of mainly nonfunctionalized alkenes. Excellent diastereo- and enantioselectivities were achieved.

Co-reporter:Junyan Han;Jiney Jose;Erwen Mei Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 10) pp:
Publication Date(Web):19 JAN 2007
DOI:10.1002/anie.200603307

The long and the short of it: Luminol chemiluminesces with a beautiful blue color; however, to be useful for biotechnological applications, the emission must be shifted to much longer wavelengths. Energy-transfer cassettes like that shown in the picture provide one solution.

Co-reporter:Yu Angell Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 20) pp:
Publication Date(Web):5 APR 2007
DOI:10.1002/anie.200700399

Click, click: Using a carbonate base as an additive in the copper-accelerated click reaction of alkynes and azides led to an oxidative coupling to form predominately 5,5′-bistriazoles (see scheme). The reaction proved more facile for propargylic ethers and less hindered substrates. Use of an optically active azide gave separable atropisomeric products and provides a convenient access to optically pure derivatives.

Co-reporter:Junyan Han;Jiney Jose;Erwen Mei Dr.
Angewandte Chemie 2007 Volume 119(Issue 10) pp:
Publication Date(Web):19 JAN 2007
DOI:10.1002/ange.200603307

Lieber rot als blau: Luminol chemiluminesziert mit wunderschöner blauer Farbe, doch um in biotechnologischen Anwendungen nützlich zu sein, muss die Emission zu viel längeren Wellenlängen verschoben werden. Energietransfer-Kassetten wie die im Bild gezeigte bieten eine mögliche Lösung.

Co-reporter:Yu Angell Dr.
Angewandte Chemie 2007 Volume 119(Issue 20) pp:
Publication Date(Web):5 APR 2007
DOI:10.1002/ange.200700399

Nur per Klick: Mit einer Carbonatbase als Additiv führt die kupferbeschleunigte Klickreaktion zwischen Alkinen und Aziden durch oxidative Kupplung vorwiegend zu 5,5′-Bistriazolen (siehe Schema). Die besten Ergebnisse wurden mit Propargylethern und sterisch weniger gehinderten Substraten erhalten. Mit einem optisch aktiven Azid entstanden trennbare atropisomere Produkte. Dies zeigt einen bequemen Weg zu optisch reinen Derivaten auf.

Co-reporter:Jianguang Zhou Dr.
Angewandte Chemie 2007 Volume 119(Issue 7) pp:
Publication Date(Web):3 JAN 2007
DOI:10.1002/ange.200603635

Perfekt kombiniert: Alle möglichen Stereoisomere von α,ω-funktionalisierten 2,4-Dimethylpentan-Dyaden- und 2,4,6-Trimethylheptan-Triaden-Chironen (siehe Bild; A bzw. B; FG=funktionelle Gruppe, PG=Schutzgruppe) lassen sich mit der Kombination eines chiralen Katalysators mit Substrateffekten in der Hydrierung weitgehend nicht funktionalisierter Alkene erhalten. Die Diastereo- und Enantioselektivitäten sind dabei ausgezeichnet.

Co-reporter:Samuel J. Reyes and Kevin Burgess  
Chemical Society Reviews 2006 vol. 35(Issue 5) pp:416-423
Publication Date(Web):21 Mar 2006
DOI:10.1039/B516721N
Libraries of monovalent compounds can be reacted with each other to give libraries of bivalent ones. If those reactions are efficient, and if the products do not need to be purified, large numbers of bivalent compounds can be produced rapidly, and one might say there is a “combinatorial advantage” to doing so. However, selective formation of heterobivalent products must be possible otherwise statistical mixtures will form. This tutorial review describes methods that will give heterobivalent compounds almost exclusively. Although there are relatively few methods that will give that desired selectivity, such methods are becoming increasingly important as the potential applications of bi- and multivalent compounds emerge.
Co-reporter:Genliang Lu, Sang Lam and Kevin Burgess  
Chemical Communications 2006 (Issue 15) pp:1652-1654
Publication Date(Web):2006/03/07
DOI:10.1039/B518061A
Iterative copper-catalyzed cycloadditions of azides to alkynes were used to join functionalized triethylene glycol molecules to give “linkers” of defined lengths equipped with several different end-group functionalities.
Co-reporter:Guan-Sheng Jiao Dr.;Lars H. Thoresen Dr.;Taeg Gyum Kim Dr.;Wade C. Haal;Feng Gao Dr.;Michael R. Topp ;Robin M. Hochstrasser ;Michael L. Metzker
Chemistry - A European Journal 2006 Volume 12(Issue 30) pp:
Publication Date(Web):3 AUG 2006
DOI:10.1002/chem.200600197

We have designed fluorescent “through-bond energy-transfer cassettes” that can harvest energy of a relatively short wavelength (e.g., 490 nm), and emit it at appreciably longer wavelengths without significant loss of intensity. Probes of this type could be particularly useful in biotechnology for multiplexing experiments in which several different outputs are to be observed from a single excitation source. Cassettes 14 were designed, prepared, and studied as model systems to achieve this end. They were synthesized through convergent routes that feature coupling of specially prepared fluorescein- and rhodamine-derived fragments. The four cassettes were shown to emit strongly, with highly efficient energy transfer. Their emission maxima cover a broad range of wavelengths (broader than the four dye cassettes currently used for most high-throughput DNA sequencing), and they exhibit faster energy-transfer rates than a similar through-space energy-transfer cassette. Specifically, energy-transfer rates in these cassettes is around 6–7 ps, in contrast to a similar through-space energy-transfer system shown to have a decay time of around 35 ps. Moreover, the cassettes are considerably more stable to photobleaching than fluorescein, even though they each contain fluorescein-derived donors. This was confirmed by bulk fluorescent measurements, and in single-molecule-detection studies. Modification of a commercial automated DNA-sequencing apparatus to detect the emissions of these four energy-transfer cassettes enabled single-color dye–primer sequencing.

Co-reporter:Xiuhua Cui, James W. Ogle and Kevin Burgess  
Chemical Communications 2005 (Issue 5) pp:672-674
Publication Date(Web):06 Jan 2005
DOI:10.1039/B413296C
The carbene complex 1 can mediate hydrogenations of dienes with up to 20∶1.0 diastereoselectivity and 99% ee; the scope and limitations of these reactions were investigated.
Co-reporter:Xiuhua Cui;Yubo Fan;Michael B. Hall
Chemistry - A European Journal 2005 Volume 11(Issue 23) pp:
Publication Date(Web):15 SEP 2005
DOI:10.1002/chem.200500762

Hydrogenation of 2,3-diphenylbutadiene (1) with the chiral carbene–oxazoline–iridium complex C has been studied by means of a combined experimental and computational approach. A detailed kinetic profile of the reaction was obtained with respect to consumption of the substrate and formation of the intermediate half-reduction products, 2,3-diphenylbut-1-ene (2) and the final product, 2,3-diphenylbutane (3). The data generated from these analyses, and from NMR experiments, revealed several facets of the reaction. After a brief induction period (presumably involving reduction of the cyclooctadiene ligand on C), the diene concentration declines in a zero-order process primarily to give monoene intermediates. When all the diene is consumed, the reaction accelerates and compound 3 begins to accumulate. Interestingly, the prevalent enantiomer of the monoene intermediate 2 is converted mostly to meso-3 so the enantioselectivity of the reaction appears to reverse. The reaction seems to be first-order with respect to the catalyst when the catalyst concentration is less than 0.0075 M; diffusion of hydrogen across the gas–liquid interface complicates the analysis at higher catalyst concentrations. Similarly, these diffusion effects complicated measurements of reaction rate versus applied pressure of dihydrogen; other factors like stir speed and flask geometry come into play under some, but not all, the conditions examined. Density functional theory (DFT) calculations, using the PBE method, were used to probe the reaction. These studies indicate a transoid4-diene–dihydride complex forms in the first stages of the catalytic cycle. Further reaction requires dissociation of one alkene ligand to give a η2-diene–dihydride–dihydrogen intermediate. A catalytic cycle that features Ir3+/Ir5+ seems to be involved thereafter.

Co-reporter:Michael Welch;Carlos Martinez;Alex Zhang;Song Jin;Richard Gibbs
Chemistry - A European Journal 2005 Volume 11(Issue 24) pp:
Publication Date(Web):6 DEC 2005
DOI:10.1002/chem.200590080
Co-reporter:Guan-Sheng Jiao and Kevin Burgess  
Chemical Communications 2004 (Issue 11) pp:1304-1305
Publication Date(Web):07 May 2004
DOI:10.1039/B402559H
The fluoresceinated furanopyrimidin-2-one nucleobase 4 incorporated into an oligonucleotide undergoes unexpectedly facile hydrolytic ring-opening in aqueous buffer at slightly elevated temperatures.
Co-reporter:Hong Boon Lee, Mookda Pattarawarapan, Sudipta Roy and Kevin Burgess  
Chemical Communications 2003 (Issue 14) pp:1674-1675
Publication Date(Web):18 Jun 2003
DOI:10.1039/B304454H
Efficient solid phase syntheses of the constrained β-turn peptidomimetics 1–3 were devised, and the conformational properties of three representative compounds in DMSO were determined.
Co-reporter:Chi-Wai Wan Dr.;Armin Burghart Dr.;Jiong Chen Dr.;Fredrik Bergström;Lennart B.-Å. Johansson ;Matthew F. Wolford Dr.;Taeg Gyum Kim Dr.;Michael R. Topp ;Robin M. Hochstrasser
Chemistry - A European Journal 2003 Volume 9(Issue 18) pp:
Publication Date(Web):11 SEP 2003
DOI:10.1002/chem.200304754

Compounds based on the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY) framework are excellent fluorescent markers. When BODIPY dyes of this type are conjugated to functionalities that absorb at relatively short wavelengths, those functionalities can, in some molecules, transmit the absorbed energy to the BODIPY which then fluoresces. In such cases the BODIPY fragment acts as an acceptor while the other group serves as a donor. Energy transfer efficiencies in such donor–acceptor cassette systems must vary with the relative orientation of the two components, and with the structure of the linkers that attach them. This study was designed to probe these issues for the special case in which the linkers between the donor and acceptor fragments are conjugated. To do this, the cassettes 310 were prepared. Electrochemical studies were performed to provide insight into the degree of donor–acceptor conjugation in these systems. X-ray Crystallographic studies on single crystals of compounds 7 and 9 revealed the favored conformations of the donor and acceptor fragments in the solid state. Absorption, fluorescence, and time-resolved fluorescence spectra of the compounds were recorded, and quantum yields for the cassettes excited at the donor λmax were measured. Fluorescence steady-state anisotropy data were determined for cassettes 3 and 9 to provide information about the mutual direction of the transition dipole moments.

Co-reporter:Lars H. Thoresen Dr.;Guan-Sheng Jiao Dr.;Wade C. Haal Dr.;Michael L. Metzker
Chemistry - A European Journal 2003 Volume 9(Issue 19) pp:
Publication Date(Web):16 SEP 2003
DOI:10.1002/chem.200304944

Syntheses of a unique set of energy transfer dye labeled nucleoside triphosphates, compounds 13, are described. Attempts to prepare these compounds were only successful if the triphosphorylation reaction was performed before coupling the dye to the nucleobase, and not the other way around. Compounds were prepared as both the 2′-deoxy (a) and 2′,3′-dideoxy- (b) forms. They feature progressively longer rigid conjugated linkers connecting the nucleobase and the hydroxyxanthone moiety. UV spectra of the parent nucleosides 1214 show that as the length of the linker increases so does the absorption of the donor in the 320–330 nm region, but with relatively little red-shift of the maxima. Fluorescence spectra of the same compounds show that radiation in the 320–330 nm region results in predominant emission from the fluorescein. When the linker is irradiated at 320 nm, the only significant emission observed corresponds to the hydroxyxanthone part of the molecules at 520 nm; this corresponds to an effective Stokes' shift of 200 nm. As the absorption at 320–330 nm by the linker increases with length, so does the intensity of the fluorescein emission. A gel assay was used to gauge relative incorporation efficiencies of compounds 13, dTTP, ddTTP, and 6-TAMRA-ddTTP. Throughout, the thermostable polymerase TaqFS was used, as it is the one most widely applied in high throughput DNA sequencing. This assay showed that only compounds 3 were incorporated efficiently; these have the longest linkers. Of these, the 2′-deoxy nucleoside 3 a was incorporated and did not prevent the polymerase from extending the chain further. The 2′,3′-dideoxy nucleoside 3 b was incorporated only about 430 times less efficiently than ddTTP under the same conditions, and caused chain termination. The implications of these studies on modified sequencing protocols are discussed.

Co-reporter:Thomas Caulfield, Kevin Burgess
Current Opinion in Chemical Biology 2001 Volume 5(Issue 3) pp:241-242
Publication Date(Web):1 June 2001
DOI:10.1016/S1367-5931(00)00197-6
Co-reporter:Duen-Ren Hou Dr.;Joseph Reibenspies Dr.;Thomas J. Colacot Dr.
Chemistry - A European Journal 2001 Volume 7(Issue 24) pp:
Publication Date(Web):10 DEC 2001
DOI:10.1002/1521-3765(20011217)7:24<5391::AID-CHEM5391>3.0.CO;2-1

Phosphine oxazoline ligands 1 aj were converted to the corresponding [Ir(cod)(phosphine oxazoline)]+ complexes 2 aj. X-ray diffraction analyses of complexes 2 b, 2 h, 2 i, and 2 j were performed. The tert-butyl-, 1,1-diphenylethyl-, and phenyl-oxazoline complexes (2 b, 2 h, and 2 i, respectively) had typical square planar metal environments with chair-like metallocyclic rings. However, the 3,5-di-tert-butylphenyl oxazoline complex 2 j was distorted toward a tetrahedral metal geometry. This library of complexes was tested in asymmetric hydrogenations of several arylalkenes. High enantioselectivities and conversions were observed for some substrates. A possible special role for the HPh2C-oxazoline substituent in asymmetric hydrogenations was identified and is discussed. In attempts to rationalize why high enantioselectivities were not observed for some alkenes, a series of deuterium labeling experiments were performed to probe for competing reactions that occurred prior to the hydrogenation step. Double bond migrations were inferred for several substrates, and this is a significant complication in asymmetric hydrogenations of arylalkenes that had not been discussed prior to this study. A mechanistic rationale is proposed involving competing double bond migration for some but not all substrates. Appreciation of this complication will be valuable in further studies aimed at optimization of enantioselection in asymmetric hydrogenations of unfunctionalized alkenes.

Co-reporter:Mookda Pattarawarapan Dr.
Angewandte Chemie 2000 Volume 112(Issue 23) pp:
Publication Date(Web):30 NOV 2000
DOI:10.1002/1521-3757(20001201)112:23<4469::AID-ANGE4469>3.0.CO;2-X
Co-reporter:Eunhwa Ko, Jing Liu and Kevin Burgess
Chemical Society Reviews 2011 - vol. 40(Issue 8) pp:NaN4421-4421
Publication Date(Web):2011/04/11
DOI:10.1039/C0CS00218F
Many “new generation” peptidomimetics are designed to present amino acid side chains only; they do not have structural features that resemble peptide main chains. These types of molecules have frequently been presented in the literature as mimics of specific secondary structures. However, many “side-chain only” peptidomimetics do notrest in single conformational states, but exist in a limited number of freely interconverting forms. These different conformations may resemble different secondary structures, so referring to them as, for instance, turn- or helical-mimics understates the ways they could adapt to various binding situations. Sets of scaffolds that can be used to mimic aspects of nearly every secondary structure, i.e. universal peptidomimetics, can be constructed. These may assume a privileged place in library design, particularly in high throughput screening for pharmacological probes for which binding conformations, or even the target itself, is unknown at the time the library is designed (critical review, 101 references).
Co-reporter:Anyanee Kamkaew and Kevin Burgess
Chemical Communications 2015 - vol. 51(Issue 53) pp:NaN10667-10667
Publication Date(Web):2015/06/05
DOI:10.1039/C5CC03649F
Attempts to make a diamino disulfonic acid derivative of an aza-BODIPY showed it was difficult to add BF2 to a disulfonated azadipyrromethene, and sulfonation of an aza-BODIPY resulted in loss of the BF2 fragment. We conclude the electron-deficient character of aza-BODIPY dyes destabilizes them relative to BODIPY dyes. Consequently, sulfonation of the aza-BODIPY core is not a viable strategy to increase water solubility. This assertion was indirectly supported via stability studies of a BODIPY and an aza-BODIPY in aqueous media. To afford the desired compound type, an aza-BODIPY with two amino and two sulfonic acid groups was prepared via modification of the aryl substituents with cysteic acid.
Co-reporter:Liangxing Wu and Kevin Burgess
Chemical Communications 2008(Issue 40) pp:NaN4935-4935
Publication Date(Web):2008/09/19
DOI:10.1039/B810503K
BODIPY dyes were synthesized from pyrrole-2-carbaldehyde derivatives in high yields; this constitutes a new approach to this dye framework.
Co-reporter:Dongyue Xin, Andreas Holzenburg and Kevin Burgess
Chemical Science (2010-Present) 2014 - vol. 5(Issue 12) pp:NaN4921-4921
Publication Date(Web):2014/09/10
DOI:10.1039/C4SC01295J
Small molecule probes for perturbing protein–protein interactions (PPIs) in vitro can be useful if they cause the target proteins to undergo biomedically relevant changes to their tertiary and quaternary structures. Application of the Exploring Key Orientations (EKO) strategy (J. Am. Chem. Soc., 2013, 135, 167–173) to a piperidinone–piperidine chemotype 1 indicated specific derivatives were candidates to perturb a protein–protein interface in the α-antithrombin dimer; those particular derivatives of 1 were prepared and tested. In the event, most of them significantly accelerated oligomerization of monomeric α-antithrombin, which is metastable in its monomeric state. This assertion is supported by data from gel electrophoresis (non-denaturing PAGE; throughout) and probe-induced loss of α-antithrombin's inhibitor activity in a reaction catalyzed by thrombin. Kinetics of α-antithrombin oligomerization induced by the target compounds were examined. It was found that probes with O-benzyl-protected serine side-chains are the most active catalysts in the series, and reasons for this, based on modeling experiments, are proposed. Overall, this study reveals one of the first examples of small molecules designed to act at a protein–protein interface relevant to oligomerization of a serpin (i.e. α-antithrombin). The relevance of this to formation of oligomeric serpin fibrils, associated with the disease states known as “serpinopathies”, is discussed.
Co-reporter:Dongyue Xin and Kevin Burgess
Organic & Biomolecular Chemistry 2016 - vol. 14(Issue 22) pp:NaN5058-5058
Publication Date(Web):2016/05/13
DOI:10.1039/C6OB00693K
Each amino acid in a peptide contributes three atom units to main-chains, hence natural cyclic peptides can be 9, 12, 15, …. i.e. 3n membered-rings, where n is the number of amino acids. Cyclic peptides that are 9 or 12-membered ring compounds tend to be hard to prepare because of strain, while their one amino acid homologs (15-membered cyclic pentapeptides) are not conformationally homogeneous unless constrained by strategically placed proline or D-amino acid residues. We hypothesized that replacing one genetically encoded amino acid in a cyclic tetrapeptide with a rigid β-amino acid would render peptidomimetic designs that rest at a useful crossroads between synthetic accessibility and conformational rigidity. Thus this research explored non-proline containing 13-membered ring peptides 1 featuring one anthranilic acid (Anth) residue. Twelve cyclic peptides of this type were prepared, and in doing so the viability of both solution- and solid-phase methods was demonstrated. The library produced contained a complete set of four diastereoisomers of the sequence 1aaf (i.e. cyclo-AlaAlaPheAnth). Without exception, these four diastereoisomers each adopted one predominant conformation in solution; basically these conformations feature amide N–H vectors puckering above and below the equatorial plane, and approximately oriented their N– atoms towards the polar axis. Moreover, the shapes of these conformers varied in a logical and predictable way (NOE, temperature coefficient, D/H exchange, circular dichroism). Comparisons were made of the side-chain orientations presented by compounds 1aaa in solution with ideal secondary structures and protein–protein interaction interfaces. Various 1aaa stereoisomers in solution present side-chains in similar orientations to regular and inverse γ-turns, and to the most common β-turns (types I and II). Consistent with this, compounds 1aaa have a tendency to mimic various turns and bends at protein–protein interfaces. Finally, proteolytic- and hydrolytic stabilities of the compounds at different pHs indicate they are robust relative to related linear peptides, and rates of permeability through an artificial membrane indicate their structures are conducive to cell permeability.
Co-reporter:Dongyue Xin, Eunhwa Ko, Lisa M. Perez, Thomas R. Ioerger and Kevin Burgess
Organic & Biomolecular Chemistry 2013 - vol. 11(Issue 44) pp:NaN7801-7801
Publication Date(Web):2013/10/14
DOI:10.1039/C3OB41848K
Peptide mimics that display amino acid side-chains on semi-rigid scaffolds (not peptide polyamides) can be referred to as minimalist mimics. Accessible conformations of these scaffolds may overlay with secondary structures giving, for example, “minimalist helical mimics”. It is difficult for researchers who want to apply minimalist mimics to decide which one to use because there is no widely accepted protocol for calibrating how closely these compounds mimic secondary structures. Moreover, it is also difficult for potential practitioners to evaluate which ideal minimalist helical mimics are preferred for a particular set of side-chains. For instance, what mimic presents i, i + 4, i + 7 side-chains in orientations that best resemble an ideal α-helix, and is a different mimic required for a i, i + 3, i + 7 helical combination? This article describes a protocol for fitting each member of an array of accessible scaffold conformations on secondary structures. The protocol involves: (i) use quenched molecular dynamics (QMD) to generate an ensemble consisting of hundreds of accessible, low energy conformers of the mimics; (ii) representation of each of these as a set of Cα and Cβ coordinates corresponding to three amino acid side-chains displayed by the scaffolds; (iii) similar representation of each combination of three side-chains in each ideal secondary structure as a set of Cα and Cβ coordinates corresponding to three amino acid side-chains displayed by the scaffolds; and, (iv) overlay Cα and Cβ coordinates of all the conformers on all the sets of side-chain “triads” in the ideal secondary structures and express the goodness of fit in terms of root mean squared deviation (RMSD, Å) for each overlay. We refer to this process as Exploring Key Orientations on Secondary structures (EKOS). Application of this procedure reveals the relative bias of a scaffold to overlay on different secondary structures, the “side-chain correspondences” (e.g. i, i + 4, i + 7 or i, i + 3, i + 4) of those overlays, and the energy of this state relative to the minimum located. This protocol was tested on some of the most widely cited minimalist α-helical mimics (1–8 in the text). The data obtained indicates several of these compounds preferentially exist in conformations that resemble other secondary structures as well as α-helices, and many of the α-helical conformations have unexpected side-chain correspondences. These observations imply the featured minimalist mimics have more scope for disrupting PPI interfaces than previously anticipated. Finally, the same simulation method was used to match preferred conformations of minimalist mimics with actual protein/peptide structures at interfaces providing quantitative comparisons of predicted fits of the test mimics at protein–protein interaction sites.
Co-reporter:Anyanee Kamkaew, Rola Barhoumi, Robert C. Burghardt and Kevin Burgess
Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 19) pp:NaN6518-6518
Publication Date(Web):2011/08/16
DOI:10.1039/C1OB05874F
Two cationic polyfluorene derivatives, quaternary amine 1 and guanidine 2 sheathed systems, were prepared as potential carriers to mediate import of proteins into cells without requiring covalent attachment to the protein. Neither polymer showed significant cytotoxicities (IC50 100 μM) when exposed to Clone 9 rat liver cells. Both polymers were shown to mediate import of a series of four proteins chosen because they have different pI values, sizes, and variable organic fluor attachments. Once inside the cells, the quaternary amine system 1 released more of its cargo into regions outside the lysosomes. In one exploratory experiment, pyrenebutyrate was shown to accelerate import of a protein system by polymer 1.
Co-reporter:Jiney Jose, Aurore Loudet, Yuichiro Ueno, Rola Barhoumi, Robert C. Burghardt and Kevin Burgess
Organic & Biomolecular Chemistry 2010 - vol. 8(Issue 9) pp:NaN2059-2059
Publication Date(Web):2010/03/03
DOI:10.1039/B925845K
Five new water-soluble derivatives of Nile Red 1–5 were prepared. These benzophenoxazine dyes fluoresce between 640 and 667 nm with quantum yields of 0.17–0.33 in pH 7.4 phosphate buffer, and at slightly shorter wavelengths and higher quantum yields in EtOH. Two dyes, 3 and 4 permeated into Clone 9 cells and selectively stained mitochondria and golgi, respectively.
Co-reporter:Dmytro Fedoseyenko, Arjun Raghuraman, Eunhwa Ko and Kevin Burgess
Organic & Biomolecular Chemistry 2012 - vol. 10(Issue 5) pp:NaN924-924
Publication Date(Web):2011/12/19
DOI:10.1039/C2OB06692K
A graphical abstract is available for this content
Co-reporter:Jiney Jose, Aurore Loudet, Yuichiro Ueno, Liangxing Wu, Hsiang-Yun Chen, Dong Hee Son, Rola Barhoumi, Robert Burghardt and Kevin Burgess
Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 10) pp:NaN3877-3877
Publication Date(Web):2011/03/03
DOI:10.1039/C0OB00967A
Lipophilic energy transfer cassettes like 1 and 2 are more conveniently synthesized than the corresponding hydrophilic compounds, but they are not easily used in aqueous media. To overcome the latter issue, cassettes 1 and 2 were separately encapsulated in silica nanoparticles (ca. 22 nm) which freely disperse in aqueous media. Photophysical properties of the encapsulated dyes 1–SiO2 and 2–SiO2 were recorded. The nanoparticles 1–SiO2 permeated into Clone 9 rat liver cells and targeted only the ER. A high degree of energy transfer was observed in this organelle such that most of the light fluoresced from the acceptor part, i.e. the particles appeared red. Silica nanoparticles 2–SiO2 also permeated into Clone 9 rat liver cells and they targeted mitochondria but were also observed in endocytic vesicles (lysosomes or endosomes). In these organelles they fluoresced red and red/green respectively. Thus the cargo inside the nanoparticles influences where they localize in cells, and the environment of the nanoparticles in the cells changes the fluorescent properties of the encapsulated dyes. Neither of these findings were anticipated given that silica nanoparticles of this type are generally considered to be non-porous.
Co-reporter:Junyan Han, Oswaldo Gonzalez, Angelica Aguilar-Aguilar, Eduardo Peña-Cabrera and Kevin Burgess
Organic & Biomolecular Chemistry 2009 - vol. 7(Issue 1) pp:NaN36-36
Publication Date(Web):2008/10/30
DOI:10.1039/B818390B
Chemoselective cross-coupling reactions were demonstrated for C–S bonds in the BODIPY dyes 1 and 4, and similar reactions were applied to make the two-dye cassette system 11.
Co-reporter:Aurore Loudet, Junyan Han, Rola Barhoumi, Jean-Philippe Pellois, Robert C. Burghardt and Kevin Burgess
Organic & Biomolecular Chemistry 2008 - vol. 6(Issue 24) pp:NaN4522-4522
Publication Date(Web):2008/10/30
DOI:10.1039/B809006H
Substances that mediate the import of proteins into cells, “carriers”, have many potential applications. The most potentially useful carriers do not have to be covalently linked to their protein cargoes. However, a common problem with all carrier molecules is that they tend to deposit the cargo proteins into endosomes; diffuse distribution in the cytosol is the desired outcome. This paper describes the import of four different labeled (Alexa Fluor® 488) proteins (avidin, recombinant streptavidin, bovine serum albumin, and β-galactosidase), with the well-known non-covalent carrier called pep-1 (also known as Chariot™), with R8 (a molecule that is not widely appreciated to import protein cargoes via a non-covalent mode of action), and with a new molecule called azo-R8. The data collected from fluorescence microscopy and flow cytometry indicate that all three non-covalent carriers can facilitate transport. At 37 °C, import into endocytic compartments dominates, but at 4 °C weak, diffuse fluorescence is observed in the cytosol, indicative of a favorable mode of action.
Co-reporter:Anyanee Kamkaew, Sopida Thavornpradit, Thamon Puangsamlee, Dongyue Xin, Nantanit Wanichacheva and Kevin Burgess
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 30) pp:NaN8276-8276
Publication Date(Web):2015/07/03
DOI:10.1039/C5OB01104C
This study features aza-BODIPY (BF2-chelated azadipyrromethene) dyes with two aromatic substituents linked by oligoethylene glycol fragments to increase hydrophilicity of aza-BODIPY for applications in intracellular imaging. To prepare these, two chalcones were attached α,ω onto oligoethylene glycol fragments, then reacted with nitromethane anion. Conjugate addition products from this reaction were then subjected to typical conditions for synthesis of aza-BODIPY dyes (NH4OAc, nBuOH, 120 °C); formation of boracycles in this reaction was concomitant with creation of macrocycles containing the oligoethylene glycol fragments. Similar dyes with acyclic oligoelythene glycol substituents in the same position were used to compare the efficiencies of the intra- and inter-molecular aza-BODIPY forming reactions, and the characteristics of the products. All the fluors with oligoethylene glycol fragments, i.e. cyclic or acyclic, localized in the endoplasmic reticulum of a fibroblast cell line (WEHI-13VAR), the human pancreatic cancer cell line (PANC-1, rough ER predominates) and human liver cancer cell line (HepG2, smooth ER prevalent). These fluors are potentially useful for near IR (λmax emis at 730 nm) ER staining probes.
Co-reporter:Anyanee Kamkaew, Siang Hui Lim, Hong Boon Lee, Lik Voon Kiew, Lip Yong Chung and Kevin Burgess
Chemical Society Reviews 2013 - vol. 42(Issue 1) pp:NaN88-88
Publication Date(Web):2012/09/26
DOI:10.1039/C2CS35216H
BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with 3O2. In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.
(2Z)-2-BUTEN-2-YLBENZENE
Ethenylcyclopropane
Acetamide,N-2-propen-1-yl-
3-(Ethylamino)phenol
(R)-2-Methylbutanol
Benzeneethanol, α-phenyl-
Thymidine5'-(tetrahydrogen triphosphate), 3'-deoxy-
Benzene, 1,1'-(1,2-ethenediyl)bis-
1-acetyl-2-sulfanylideneimidazolidin-4-one
dipotassium oxalate