Co-reporter:Xiao Zhou, Xiaoye Su, Pravin Pathak, Ryan Vik, Brittany Vinciguerra, Lyle Isaacs, and Janarthanan Jayawickramarajah
Journal of the American Chemical Society October 4, 2017 Volume 139(Issue 39) pp:13916-13916
Publication Date(Web):September 7, 2017
DOI:10.1021/jacs.7b07977
Host–guest complexes are emerging as powerful components in functional systems with applications ranging from materials to biomedicine. In particular, CB7 based host–guest complexes have received much attention for the controlled release of drugs due to the remarkable ability of CB7 toward binding input molecules in water with high affinity leading to displacement of CB7 from included pharmacophores (or from drug loaded porous particles). However, the release of bound guests from CB7 in response to endogenous biological molecules remains limited since the input biomolecule needs to have the appropriate chemical structure to bind tightly into the CB7 cavity. Herein we describe a synthetic transducer based on self-assembling DNA–small molecule chimeras (DCs) that is capable of converting a chosen biological input, adenosine triphosphate (ATP; that does not directly bind to the CB7 host), into functional displacement of a protein inhibitor that is bound within the CB7 host. Our system—which features the first example of a covalent CB-DNA conjugate—is highly modular and can be adapted to enable responsiveness to other biologically/clinically relevant stimuli via its split DNA aptamer architecture.
Co-reporter:Soumen K. Samanta;Kimberly G. Brady
Chemical Communications 2017 vol. 53(Issue 18) pp:2756-2759
Publication Date(Web):2017/02/28
DOI:10.1039/C6CC10328F
Self-assembly of rigid-rod dipyridine ligand 1 with M(en)(NO3)2 (M = Pd, Pt) affords triangular (3, 5) and square (4, 6) supramolecular coordination complexes (SCCs). The binding affinity of 1 toward CB[n]-type containers results in the formation of triangular [4]molecular necklaces ([4]MNs, 7–10) by either one-pot or post complexation approaches as evidenced by 1H NMR, diffusion ordered spectroscopy, and ESI-MS.
Co-reporter:Wenqi Liu;Soumen K. Samanta;Bradley D. Smith
Chemical Society Reviews 2017 vol. 46(Issue 9) pp:2391-2403
Publication Date(Web):2017/05/09
DOI:10.1039/C7CS00011A
Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. However, biotin/(strept)avidin self-assembly has several well-recognized drawbacks that limit performance in certain technical areas and there is a need for synthetic mimics that can either become superior replacements or operational partners with bio-orthogonal recognition properties. The goal of this tutorial review is to describe the recent progress in making high affinity synthetic association partners that operate in water or biological media. The review starts with a background summary of biotin/(strept)avidin self-assembly and the current design rules for creating synthetic mimics. A series of case studies are presented that describe recent success using synthetic derivatives of cyclodextrins, cucurbiturils, and various organic cyclophanes such as calixarenes, deep cavitands, pillararenes, and tetralactams. In some cases, two complementary partners associate to produce a nanoscale complex and in other cases a ditopic host molecule is used to link two partners. The article concludes with a short discussion of future directions and likely challenges.
Co-reporter:Soumen K. Samanta, Damien Moncelet, Volker Briken, and Lyle Isaacs
Journal of the American Chemical Society 2016 Volume 138(Issue 43) pp:14488-14496
Publication Date(Web):October 10, 2016
DOI:10.1021/jacs.6b09504
Self-assembly of ligand 1 and Pd(NO3)2 delivers Fujita-type metal–organic polyhedron (MOP) 3 which bears 24 covalently attached methyl viologen units on its external surface, as evidenced by 1H NMR, diffusion-ordered spectroscopy NMR, electrospray mass spectrometry, transmission electron microscopy, and atomic force microscopy measurements. MOP 3 undergoes noncovalent complexation with cucurbit[n]urils to yield MOPs 4–6 with diameter ≈5–6 nm. MOP 5 can be fully loaded with doxorubicin (DOX) prodrug 2 via hetero–ternary complex formation to yield 7. The MOPs exhibit excellent stability toward neutral to slightly acidic pH in 10 mM sodium phosphate buffer, mitigating the concern of disassembly during circulation. The results of MTS assays show that MOP 7 is 10-fold more cytotoxic toward HeLa cells than equimolar quantities of DOX prodrug 2. The enhanced cytotoxicity can be traced to a combination of enhanced cellular uptake of 7 and DOX release as demonstrated by flow cytometry and confocal fluorescence microscopy. The confluence of properties imparted by the polycationic MOP architecture and plug-and-play CB[n] complexation provides a potent new platform for drug delivery application.
Co-reporter:Gaya Hettiarachchi; Soumen K. Samanta; Shane Falcinelli; Ben Zhang; Damien Moncelet; Lyle Isaacs;Volker Briken
Molecular Pharmaceutics 2016 Volume 13(Issue 3) pp:809-818
Publication Date(Web):January 12, 2016
DOI:10.1021/acs.molpharmaceut.5b00723
Approximately, 40–70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.
Co-reporter:Dr. Xiaoyong Lu ;Dr. Lyle Isaacs
Angewandte Chemie International Edition 2016 Volume 55( Issue 28) pp:8076-8080
Publication Date(Web):
DOI:10.1002/anie.201602671
Abstract
The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. 1H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host–hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution.
Co-reporter:Dr. Xiaoyong Lu ;Dr. Lyle Isaacs
Angewandte Chemie 2016 Volume 128( Issue 28) pp:8208-8212
Publication Date(Web):
DOI:10.1002/ange.201602671
Abstract
The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. 1H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host–hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution.
Co-reporter:Đani Škalamera, Liping Cao, Lyle Isaacs, Robert Glaser, Kata Mlinarić-Majerski
Tetrahedron 2016 Volume 72(Issue 12) pp:1541-1546
Publication Date(Web):24 March 2016
DOI:10.1016/j.tet.2016.02.002
A series of naphthalene-1,5- and 2,6-diamines and their N-methyl derivatives were synthesized and characterized. 1H NMR spectroscopy showed that an aqueous solution of naphthalene-2,6-di(NMe3I) (2) underwent considerable demethylation over a 24 h period after its initial preparation. Exchange of the iodide nucleophilic anion by the triflate non-nucleophilic counter-ion afforded a stable quaternary aminium salt. H/D α-position exchange in D2O solutions of naphthalene-2,6-di(NH2MeCl) (3·HCl) and naphthalene-2,6-di(NHMe2Cl) (4·HCl) with acidic +NH protons was observed, but not in those of naphthalene-2,6-di(NMe3I) or triflate (2 or 5). Exhaustive per-N-methylation of naphthalene-1,5-di(NMe2) (7) afforded only the mixed naphthalene-1-NMe3I-5-NHMe2I quaternary aminium-tertiary ammonium salt due to severe 1,8-type peri-strain.
Co-reporter:Matthew J. Webber;Lavanya S. Thapa;Brittany Vinciguerra;Abel B. Cortinas;Eric A. Appel;Siddharth Jhunjhunwala;Robert Langer;Daniel G. Anderson
PNAS 2016 Volume 113 (Issue 50 ) pp:14189-14194
Publication Date(Web):2016-12-13
DOI:10.1073/pnas.1616639113
The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved
modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice
by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the
body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a
platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host–guest interactions
to endow proteins with prosthetic functionality. Specifically, a series of cucurbit[7]uril (CB[7])–PEG conjugates are shown
to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity
interaction between CB[7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering
of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached
PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving
protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality
to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy.
Co-reporter:Xiaoyong Lu and Lyle Isaacs
Organic Letters 2015 Volume 17(Issue 16) pp:4038-4041
Publication Date(Web):August 7, 2015
DOI:10.1021/acs.orglett.5b01948
Enantiomerically pure acyclic cucurbit[n]uril containers 1 and 2 were synthesized by the condensation of enantiomerically pure aromatic sidewalls 3b and 4b with glycoluril tetramer 5. Containers 1 and 2 are C2-symmetric, feature four arms of the same handedness, and bind to a variety of guests (6–15) in aqueous solution including aliphatic and aromatic ammonium ions, amino acids, dyes, and viologens. The binding constants of hosts 1Ac and 1OH toward selected chiral ammonium ions were measured by 1H NMR and UV/vis spectroscopy.
Co-reporter:David Sigwalt, Sarah Ahlbrand, Mingming Zhang, Brittany Vinciguerra, Volker Briken, and Lyle Isaacs
Organic Letters 2015 Volume 17(Issue 23) pp:5914-5917
Publication Date(Web):November 23, 2015
DOI:10.1021/acs.orglett.5b03145
The synthesis of acyclic cucurbit[n]uril dendrimers G1–G3 that bear four dendrons on their aromatic sidewalls via thiolate SN2 chemistry is reported. G1–G3 are polycationic and can bind to pEGFP plasmid DNA as shown by dynamic light scattering (DLS), gel electrophoresis, and scanning electron microscopy (SEM). The gene delivery ability of G1–G3 is presented.
Co-reporter:Yuri V. Fedorov, Sergey V. Tkachenko, Ekaterina Yu. Chernikova, Ivan A. Godovikov, Olga A. Fedorova and Lyle Isaacs
Chemical Communications 2015 vol. 51(Issue 7) pp:1349-1352
Publication Date(Web):01 Dec 2014
DOI:10.1039/C4CC08474H
We report that three-component systems comprising styryl dyes (1 or 2) and two hosts (hydroxypropyl-β-cyclodextrin (HP-β-CD) and cucurbit[7]uril (CB[7])) undergo photoinduced transformation and translocation of the styryl guest from the cavity of HP-β-CD to CB[7]. We find that the protonation of guest trans-1 or the addition of Ba2+ as competitor for CB[7] triggers dissociation of the container–guest complexes.
Co-reporter:Yang Yu, Jie Li, Mingming Zhang, Liping Cao and Lyle Isaacs
Chemical Communications 2015 vol. 51(Issue 18) pp:3762-3765
Publication Date(Web):27 Jan 2015
DOI:10.1039/C5CC00236B
Hydrophobic monofunctionalized cucurbit[7]uril derivatives (1 and 2) were synthesized by clicking CB[7]-azide with propargylated alkylamines. Compounds 1 and 2 form self-inclusion complexes that are transformed into vesicle-type assemblies by addition of guests (3–5) as confirmed by 1H and DOSY NMR, SEM, TEM, and fluorescence spectroscopy.
Co-reporter:Mingming Zhang, David Sigwalt and Lyle Isaacs
Chemical Communications 2015 vol. 51(Issue 78) pp:14620-14623
Publication Date(Web):13 Aug 2015
DOI:10.1039/C5CC05803A
We report the synthesis of mono- and difunctionalized acyclic cucurbit[n]uril-type containers (1HA, 1HDA, 2HDA) which bear hexylammonium and hexanediammonium arms. The intra- and intermolecular assembly processes of 1HA, 1HDA, 2HDA as well as the ability of CB[n] to trigger allosteric host–guest binding toward guests 9–11 are presented.
Co-reporter:Brittany Vinciguerra, Peter Y. Zavalij, and Lyle Isaacs
Organic Letters 2015 Volume 17(Issue 20) pp:5068-5071
Publication Date(Web):September 25, 2015
DOI:10.1021/acs.orglett.5b02558
A building block approach to the synthesis of Me4CB[8] and Cy2CB[8] by condensation of glycoluril hexamer 1 with bis(cyclic ethers) 2 is reported. X-ray crystallography demonstrates that the equatorial substitution results in an ellipsoidal cavity. Me4CB[8] and Cy2CB[8] display enhanced aqueous solubility and retain the ability to bind to guests (3–9) typical of unsubstituted CB[8]. The higher inherent solubility of Me4CB[8] allowed it to be used as a solubilizing excipient for insoluble drugs.
Co-reporter:Jungang Wang, Miao Wang, Jiachen Xiang, Liping Cao, Anxin Wu and Lyle Isaacs
CrystEngComm 2015 vol. 17(Issue 12) pp:2486-2495
Publication Date(Web):19 Feb 2015
DOI:10.1039/C4CE02447H
In order to investigate the self-association of asymmetric glycoluril clips, compounds 1–7 with a common p-dimethoxy-o-xylylene ring sidewall were synthesized and their structures were analyzed by X-ray crystallography. As expected, the clip molecules formed dimers promoted by π–π interactions between their aromatic sidewalls. Interestingly, the nature of the substituents on the differentially substituted sidewall caused appreciable differences in the observed dimerization motifs in the crystalline state. For example, 1 and 2 adopted the out–out dimeric motif with its diaromatic-vinyl-o-xylylene rings bound in the cleft of the neighboring molecular clip by π–π stacking interactions. In contrast, compounds 3–7 adopted the in–in dimeric motif in the solid state, in which the p-dimethoxy-o-xylylene rings were sandwiched by the adjacent clip driven by π–π and OCH3⋯OC H-bonding interactions. X-ray crystallographic analysis of compounds 1–7 indicates that the conformational preferences induced by the linking group between the o-xylylene sidewalls and the terminal aromatic rings plays a critical role in determining which mode of dimerization (in–in versus out–out) and three dimensional packing predominates. The ability to control the selective dimerization of asymmetric glycoluril derived molecular clips via π–π interactions promises to expand the use of these building blocks to design complex and functional solid state architectures.
Co-reporter:Laura Gilberg, Ben Zhang, Peter Y. Zavalij, Vladimir Sindelar and Lyle Isaacs
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 13) pp:4041-4050
Publication Date(Web):23 Feb 2015
DOI:10.1039/C5OB00184F
We present the synthesis of a series of six new glycoluril derived molecular clips and acyclic CB[n]-type molecular containers (1–3) that all feature SO3− solubilizing groups but differ in the number of glycoluril rings between the two terminal dialkoxyaromatic sidewalls. We report the X-ray crystal structure of 3b which shows that its dialkoxynaphthalene sidewalls actively define a hydrophobic cavity with high potential to engage in π–π interactions with insoluble aromatic guests. Compounds 1–3 possess very good solubility characteristics (≥38 mM) and undergo only very weak self-association (Ks < 92 M−1) in water. The weak self-association is attributed to unfavorable SO3−⋯SO3− electrostatic interactions in the putative dimers 12–42. Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, β-estradiol, and ziprasidone). We find that the containers 3a and 3b which feature three glycoluril rings between the terminal dialkoxy-o-xylylene and dialkoxynaphthalene sidewalls are less efficient solubilizing agents than 4a and 4b because of their smaller hydrophobic cavities. Containers 1 and 2 behave as molecular clip type receptors and therefore possess the ability to bind to and thereby solubilize aromatic drugs like camptothecin, ziprasidone, and PBS-1086.
Co-reporter:Liping Cao, Đani Škalamera, Peter Y. Zavalij, Jiří Hostaš, Pavel Hobza, Kata Mlinarić-Majerski, Robert Glaser and Lyle Isaacs
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 22) pp:6249-6254
Publication Date(Web):12 May 2015
DOI:10.1039/C5OB00784D
We report the binding constants of CB[7] toward a series of naphthalene diammonium and 4,4′-dipiperidinium derivatives and compare the results with those obtained previously for CB[7]·3b by 1H NMR and X-ray crystallography. The nature of binding in the host·guest complexes was investigated using quantum mechanical tools.
Co-reporter:Lyle Isaacs
Accounts of Chemical Research 2014 Volume 47(Issue 7) pp:2052-2062
Publication Date(Web):May 2, 2014
DOI:10.1021/ar500075g
Many guests display large pKa shifts within their CB[n]–guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB[7] toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB[7] from gold nanoparticles passivated with hexanediammonium ion·CB[7] complexes and thereby trigger cytotoxicity. CB[7] derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems.
Co-reporter:Mingming Zhang, Liping Cao and Lyle Isaacs
Chemical Communications 2014 vol. 50(Issue 94) pp:14756-14759
Publication Date(Web):15 Oct 2014
DOI:10.1039/C4CC07268E
We report the synthesis of cucurbit[6]uril–cucurbit[7]uril heterodimer (1) by click chemistry of monofunctionalized CB[6] and CB[7] derivatives. Combinations of 1 with hydrophobic guest 4b or hydrophilic polymeric guests 5b and 5c deliver hydrophobic or amphiphilic supramolecular block copolymers which form supramolecular networks (6) and supramolecular micelles (7), respectively, in the solid state.
Co-reporter:Ben Zhang
Journal of Medicinal Chemistry 2014 Volume 57(Issue 22) pp:9554-9563
Publication Date(Web):November 4, 2014
DOI:10.1021/jm501276u
We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a–1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M–1). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a–1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a–1e, lower concentrations of 1a–1e are required to achieve identical [drug].
Co-reporter:Ben Zhang, Peter Y. Zavalij and Lyle Isaacs
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 15) pp:2413-2422
Publication Date(Web):21 Feb 2014
DOI:10.1039/C3OB42603C
We report the synthesis and X-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3−, OH, NH3+). The X-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by π–π interactions, H-bonds and ion–dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct 1H NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pKa of 6-aminocoumarin 7 (pKa = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pKa = 4.9; 2h: pKa = 4.1; 2f, pKa = 3.4) which reflect in part the relevance of direct ion–ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17α-ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents.
Co-reporter:Marina &x160;ekutor;Kre&x161;imir Mol&x10d;anov;Liping Cao;Robert Glaser;Kata Mlinari&x107;-Majerski
European Journal of Organic Chemistry 2014 Volume 2014( Issue 12) pp:2533-2542
Publication Date(Web):
DOI:10.1002/ejoc.201301844
Abstract
New bisprimary and bisquaternary diamantane-1,6- and -4,9-diammonium/diaminium salts were synthesized, and characterized by NMR spectroscopy and X-ray crystallography. The impetus for these syntheses were previously reported X-ray crystallographic investigations of adamantane mono- and bisquaternary ammonium ions [3,5-diMeAda-1-NH3 or Ada-1,3-di(NMe3)] complexed with cucurbit[n]uril (n = 7, 8). The crystal structures were analyzed to ascertain possible structural hypotheses for high binding affinity guests bound within various diameter pumpkin-shaped hosts. Although Diam-4,9-di(NMe3I) 5 could be readily prepared from the bisprimary precursor, corresponding Diam-1,6-di(NMe3I) 14 could not be obtained even under strong reaction conditions. Stereochemical analysis of this situation suggests very severe steric non-bonding cis-1,3-diaxial type H···H interactions between the “axial”-type NMe3 group and neighboring “axial” proton neighbors. These same interactions are found in Ada-2,6-di(NMe3I) analogues, but they are alleviated in this smaller polycyclic skeleton through tilting the axial C(methylene)–NMe3 bond away from its axial neighbors. However, similar structural relief for Diam-1,6-di(NMe3I) is not possible, because the C(methine)–NMe3 bond therein is ligated to the diamondoid's rigid skeleton.
Co-reporter:Tsuyoshi Minami ; Nina A. Esipenko ; Ali Akdeniz ; Ben Zhang ; Lyle Isaacs ;Pavel Anzenbacher ; Jr.
Journal of the American Chemical Society 2013 Volume 135(Issue 40) pp:15238-15243
Publication Date(Web):September 3, 2013
DOI:10.1021/ja407722a
A supramolecular sensor array composed of two fluorescent cucurbit[n]uril-type receptors (probe 1 and probe 2) displaying complementary selectivities was tested for its ability to detect and quantify drug-related amines. The fluorimetric titration of the individual probes showed highly variable and cross-reactive analyte-dependent changes in fluorescence. An excellent ability to recognize a variety of analytes was demonstrated in qualitative as well as quantitative assays. Importantly, a successful quantitative analysis of several analytes of interest was achieved in mixtures and in human urine. The throughput and sensitivity surpass those of the current state-of-the-art methods that usually require analyte solid-phase extraction (SPE). These results open up the opportunity for new applications of cucurbit[n]uril-type receptors in sensing and pave the way for the development of simple high-throughput assays for various drugs in the near future.
Co-reporter:Dr. Liping Cao;Gaya Hettiarachchi;Dr. Volker Briken;Dr. Lyle Isaacs
Angewandte Chemie International Edition 2013 Volume 52( Issue 46) pp:12033-12037
Publication Date(Web):
DOI:10.1002/anie.201305061
Co-reporter:Dr. James B. Wittenberg;Dr. Peter Y. Zavalij ;Dr. Lyle Isaacs
Angewandte Chemie International Edition 2013 Volume 52( Issue 13) pp:3690-3694
Publication Date(Web):
DOI:10.1002/anie.201300404
Co-reporter:Dr. James B. Wittenberg;Dr. Peter Y. Zavalij ;Dr. Lyle Isaacs
Angewandte Chemie 2013 Volume 125( Issue 13) pp:3778-3782
Publication Date(Web):
DOI:10.1002/ange.201300404
Co-reporter:Tsuyoshi Minami ; Nina A. Esipenko ; Ben Zhang ; Maria E. Kozelkova ; Lyle Isaacs ; Ryuhei Nishiyabu ; Yuji Kubo ;Pavel Anzenbacher ; Jr.
Journal of the American Chemical Society 2012 Volume 134(Issue 49) pp:20021-20024
Publication Date(Web):November 29, 2012
DOI:10.1021/ja3102192
A supramolecular assay based on two fluorescent cucurbit[n]uril probes enables the recognition and quantification of nitrosamines, including cancer-associated nitrosamines, compounds that are difficult to recognize. The cross-reactive sensor leverages weak interactions and competition among the probe, metal, and guest, yielding high information density in the signal output (variance) and enabling the recognition of structurally similar guests.
Co-reporter:Cai Shen ; Da Ma ; Brendan Meany ; Lyle Isaacs ;YuHuang Wang
Journal of the American Chemical Society 2012 Volume 134(Issue 17) pp:7254-7257
Publication Date(Web):April 18, 2012
DOI:10.1021/ja301462e
Making single-walled carbon nanotubes (SWNTs) soluble in water is a challenging first step to use their remarkable electronic and optical properties in a variety of applications. We report that acyclic cucurbit[n]uril molecular containers 1 and 2 selectively solubilize small-diameter and low chiral angle SWNTs. The selectivity is tunable by increasing the concentration of the molecular containers or by adjusting the ionic strength of the solution. Even at a concentration 1000 times lower than typically required for surfactants, the molecular containers render SWNTs soluble in water. Molecular mechanics simulations suggest that these C-shaped acyclic molecules complex the SWNTs such that a large portion of nanotube sidewalls are exposed to the external environment. These “naked” nanotubes fluoresce upon patching the exposed surface with sodium dodecylbenzene sulfonate.
Co-reporter:Ekaterina Chernikova, Daria Berdnikova, Yuri Fedorov, Olga Fedorova, Alexander Peregudov and Lyle Isaacs
Chemical Communications 2012 vol. 48(Issue 58) pp:7256-7258
Publication Date(Web):18 Jun 2012
DOI:10.1039/C2CC33243D
A novel supramolecular assembly comprising CB[7], styrylpyridinium dye (1) and Hg2+ forms in aqueous solution based on the hydrophobic effect and metal–ligand and ion–dipole interactions. The binding of Hg2+ to 1·CB[7] displays positive cooperativity relative to 1 itself.
Co-reporter:Liping Cao and Lyle Isaacs
Organic Letters 2012 Volume 14(Issue 12) pp:3072-3075
Publication Date(Web):2017-2-22
DOI:10.1021/ol3011425
The building block synthesis of a derivative of CB[6] that bears a reactive propargyloxy group and its functionalization by click chemistry to yield 1 which contains a covalently attached isobutylammonium group is presented. Compound 1 undergoes self-assembly to yield a cyclic [c2] daisy chain assembly (12) in water. The behavior of 12 in response to various stimuli (e.g., guests and CB[n] receptors) is described.
Co-reporter:Dr. Da Ma;Ben Zhang;Dr. Ulrike Hoffmann;Dr. Martina Grosse Sundrup;Dr. Matthias Eikermann; Lyle Isaacs
Angewandte Chemie International Edition 2012 Volume 51( Issue 45) pp:11358-11362
Publication Date(Web):
DOI:10.1002/anie.201206031
Co-reporter:Derick Lucas ; Tsuyoshi Minami ; Greg Iannuzzi ; Liping Cao ; James B. Wittenberg ; Pavel Anzenbacher ; Jr.
Journal of the American Chemical Society 2011 Volume 133(Issue 44) pp:17966-17976
Publication Date(Web):October 4, 2011
DOI:10.1021/ja208229d
We report that the p-xylylenediammonium ion (11) acts as a template in the cucurbit[n]uril forming reaction that biases the reaction toward the production of methylene bridged glycoluril hexamer (6C) and bis-nor-seco-CB[10]. Hexamer 6C is readily available on the gram scale by a one step synthetic procedure that avoids chromatography. Hexamer 6C undergoes macrocylization with (substituted) phthalaldehydes 12, 14, 15, and 18—in 9 M H2SO4 or concd HCl at room temperature to deliver monofunctionalized CB[6] derivatives 13, 16, 17, and 19—that are poised for further functionalization reactions. The kinetics of the macrocyclization reaction between hexamer and formaldehyde or phthalaldehyde depends on the presence and identity of ammonium ions as templates. p-Xylylenediammonium ion (11) which barely fits inside CB[6] sized cavities acts as a negative template which slows down transformation of 6C and paraformaldehyde into CB[6]. In contrast, 11 and hexanediammonium ion (20) act as a positive template that promotes the macrocyclization reaction between 6C and 12 to deliver (±)-21 as a key intermediate along the mechanistic pathway to CB[6] derivatives. Naphthalene-CB[6] derivative 19 which contains both fluorophore and ureidyl C═O metal-ion (e.g., Eu3+) binding sites forms the basis for a fluorescence turn-on assay for suitable ammonium ions (e.g., hexanediammonium ion and histamine).
Co-reporter:Li-Ping Cao, Jun-Gang Wang, Jiao-Yang Ding, An-Xin Wu and Lyle Isaacs
Chemical Communications 2011 vol. 47(Issue 30) pp:8548-8550
Publication Date(Web):01 Jul 2011
DOI:10.1039/C1CC13288A
We report herein a five-component self-sorted system comprising molecular clips that form heterodimers 1·4 and 8·11, and homodimer 14·14 in C6D5CD3/CDCl3. The three component self-sorting mixture comprising 1·1, 8·8, and 14·14 undergoes triggered reassembly self-sorting upon addition of 4·4 and 11·11.
Co-reporter:James B. Wittenberg, Matthew G. Costales, Peter Y. Zavalij and Lyle Isaacs
Chemical Communications 2011 vol. 47(Issue 33) pp:9420-9422
Publication Date(Web):20 Jul 2011
DOI:10.1039/C1CC13358F
This paper describes the synthesis of host 1 by the double bridging reaction of bis-ns-CB[10] with 2 under acidic conditions. Host 1 functions as a double cavity host for aliphatic and aromatic ammonium ions (3–17) in water. Conducting the bridging reaction in the presence of guest 4 delivers [3]rotaxane 1·42 by a clipping process.
Co-reporter:Lyle Isaacs
Israel Journal of Chemistry 2011 Volume 51( Issue 5-6) pp:578-591
Publication Date(Web):
DOI:10.1002/ijch.201100022
Abstract
This article begins by describing the synthesis and recognition properties of the cucurbit[n]uril homologues CB[5], CB[6], CB[7], CB[8], and CB[10]. Subsequently, we describe the state-of-the-art in understanding the mechanism of CB[n] formation. We describe the experiments that establish that glycoluril (1 H) undergoes condensation with formaldehyde by a combination of chain-growth and step-growth polymerization processes. Chain-growth processes deliver methylene bridged glycoluril oligomers 2 C–8 C as intermediates that may undergo macrocyclization to nor-seco-CB[n] when the oligomer is long enough (5 C–8 C) and subsequently form CB[n]. Step-growth processes allow oligomers to condense to give longer oligomers connected by a single CH2-bridge that undergo macrocyclization to deliver (±)-bis-nor-seco-CB[6] and bis-nor-seco-CB[10]. Lastly, we describe some of the exciting new recognition processes of the newly formed members of the CB[n] family. For example, bis-nor-seco-CB[10] undergoes homotropic allostery during ternary complex formation, (±)-bis-nor-seco-CB[6] exhibits moderately diastereoselective recognition processes (d.r. up to 88 : 12) with chiral ammonium ions in water, and nor-seco-CB[6] functions as an aldehyde reactive CB[n] synthon that can control the folding of alkanediammonium ions into a backfolded conformation in water.
Co-reporter:Soumyadip Ghosh
Journal of the American Chemical Society 2010 Volume 132(Issue 12) pp:4445-4454
Publication Date(Web):March 8, 2010
DOI:10.1021/ja910915k
We report the synthesis of two-faced inhibitors 1−5 that contain both enzyme inhibitor and cucurbit[n]uril binding domains. The enzyme binding domains of 1−5 bind to the active sites of bovine carbonic anhydrase (BCA) or acetylcholinesterase (AChE) and inhibit their catalytic activities. Addition of CB[7] to BCA•1 and BCA•2 results in the transient formation of the BCA•1•CB[7] and BCA•2•CB[7] ternary complexes that undergo rapid dissociation to form free catalytically active BCA along with CB[7]•1 and CB[7]•2. The on−off cycle can be performed repetitively by the sequential addition of competitive guest 8 and CB[7]. The detailed origins of this on−off switching of the catalytic activity of BCA is delineated by the combined inference of UV/vis catalytic assays, fluorescence displacement assays, 1H NMR, along with measurement of the fundamental values of Ka, kon, and koff for the various complexes involved. In contrast, addition of CB[7] to AChE•44 and AChE•54 results in the formation of thermodynamically stable ternary complexes AChE•44•CB[7]4 and AChE•54•CB[7]4 that are catalytically inactive. We highlight some of the advantages and disadvantages of the strategy, based on the direct competition between two receptors (e.g., enzyme and CB[7]) for a common inhibitor, used in this paper to control enzyme catalytic activity compared to the strategy employed by Nature involving the binding of an allosteric small molecule remote from the enzyme active site.
Co-reporter:Li-Ping Cao, Xiang-Gao Meng, Jiao-Yang Ding, Yun-Feng Chen, Meng Gao, Yan-Dong Wu, Yi-Tao Li, An-Xin Wu and Lyle Isaacs
Chemical Communications 2010 vol. 46(Issue 25) pp:4508-4510
Publication Date(Web):19 May 2010
DOI:10.1039/C0CC00677G
A noncovalent macrocycle-within-noncovalent macrocycle assembly is formed from twelve molecules of (±)-1 and twelve molecules of MeOH in the solid state. The H-bonded (MeOH)12 cyclododecamer assumes a crown-shaped geometry that has not previously been predicted theoretically or found experimentally.
Co-reporter:Neng-Fang She ; Meng Gao ; Xiang-Gao Meng ; Guang-Fu Yang ; Johannes A. A. W. Elemans ; An-Xin Wu
Journal of the American Chemical Society 2009 Volume 131(Issue 33) pp:11695-11697
Publication Date(Web):July 31, 2009
DOI:10.1021/ja904920r
A programmed assembly process produces rhombic grid networks from compounds L1−L4 in the crystal by π−π stacking interactions that generate a bimolecular grid synthon, which undergoes further NH···N hydrogen-bond-mediated assembly.
Co-reporter:Nengfang She, Meng Gao, Liping Cao, Anxin Wu and Lyle Isaacs
Organic Letters 2009 Volume 11(Issue 12) pp:2603-2606
Publication Date(Web):May 18, 2009
DOI:10.1021/ol900858d
We report the synthesis, X-ray crystal structure, and photophysics of a fluorescent molecular clip (1). Binding studies of 1 toward phenols 2a−j were carried out using fluorescence, 1H NMR, and IR spectroscopy, which revealed a high affinity and selectivity for 4-nitrophenol (2a) due to formation of the 1·2a complex driven by H-bonding and π−π stacking interactions.
Co-reporter:Regan Nally, Lyle Isaacs
Tetrahedron 2009 65(35) pp: 7249-7258
Publication Date(Web):
DOI:10.1016/j.tet.2009.02.055
Co-reporter:Jing Wu Dr.
Chemistry - A European Journal 2009 Volume 15( Issue 43) pp:11675-11680
Publication Date(Web):
DOI:10.1002/chem.200901522
Abstract
Complexation of yellow diaminoazobenzenes 1 and 3 inside cucurbit[7]uril (CB[7]) results in the formation of purple-colored CB[7]⋅cis-1⋅2 H+ and CB[7]⋅cis-3⋅2 H+ complexes, respectively. The high binding affinity and selectivity displayed by CB[7] toward 1 and 3 pays the >10 kcal mol−1 thermodynamic cost for this isomerization. We investigated the behavior of these complexes as a function of pH and observed large pKa shifts and high pH responsiveness, which are characteristic of cucurbit[n]uril molecular containers. The remarkable yellow to purple color change was utilized in the construction of an indicator displacement assay for biologically active amines 4–10. This indicator displacement assay is capable of quantifying the pseudoephedrine (5) content in Sudafed tablets over the 5–350 μM range.
Co-reporter:Olga A. Fedorova, Ekaterina Yu. Chernikova, Yuri V. Fedorov, Elena N. Gulakova, Aleksander S. Peregudov, Konstantin A. Lyssenko, Gediminas Jonusauskas and Lyle Isaacs
The Journal of Physical Chemistry B 2009 Volume 113(Issue 30) pp:10149-10158
Publication Date(Web):July 6, 2009
DOI:10.1021/jp903289q
In this paper, we report the interaction of the CB[7] molecular container with crown ether styryl and (bis)styryl dyes 1−6. The interaction of monostyryl dyes (1 and 2) with CB[7] results in the formation of 1:1 complexes where the CB[7] molecule is located on the region of the guest encompassing the pyridinium ring, C═C double bond, and a portion of the aryl ring of benzocrown ethers 1 and 2. For (bis)styryl dyes (3−5), the formation of two types of complexes with composition dye·CB[7]·dye and CB[7]·dye·CB[7] was confirmed by a combination of optical and electrospray ionization mass spectroscopy (ESI-MS) methods. In the case of (bis)styryl dye (6), both 2:1 and 1:1 compositions 6·CB[7]·6 and CB[7]·6 were formed. Complex formation is accompanied by substantial changes in the optical characteristics of the dyes and formation of long-lived excimer species. We tested the stimuli responsiveness of this system in response to metal ions. We find that the metal ions prefer to bind to the electrostatically negative ureidyl C═O portals of the CB[7] rather than with the crown ether moiety of the styryl dyes.
Co-reporter:Neng-Fang She, Xiang-Gao Meng, Meng Gao, An-Xin Wu and Lyle Isaacs
Chemical Communications 2008 (Issue 27) pp:3133-3135
Publication Date(Web):04 Apr 2008
DOI:10.1039/B800785C
Glycoluril derivative 1—whose bulky Ph–CC– substituents prevent formation of H-bonded tapes—undergoes solvent dependent assembly in the crystal; a tetrameric molecular bowl is formed by R44(24) H-bonding interactions from CH2Cl2 whereas DMF results in H-bond dimerization followed by oligomerization via C–H⋯π interactions.
Co-reporter:Jason M. Nichols, Yu Liu, Peter Zavalij, Lyle Isaacs, Michael P. Doyle
Inorganica Chimica Acta 2008 Volume 361(Issue 11) pp:3309-3314
Publication Date(Web):27 July 2008
DOI:10.1016/j.ica.2007.12.001
1,6-Bis-(N-benzyl)-diphenylglycoluril (1,6-BPGlyc) was used as a ligand in the synthesis of a dinuclear rhodium(II) paddlewheel complex. The ligand exchange reaction from Rh2(OAc)4 was remarkably selective for the formation of Rh2(1,6-BPGlyc)2(OAc)2 with a cis-(1,3) ligand arrangement in 46% isolated yield. The bis-substitution pattern and diastereoselective ligand exchange is attributed to the steric bulk of the glycoluril backbone that prevents further ligand substitution. Rh2(1,6-BPGlyc)2(OAc)2 catalyzes cyclopropanation reactions via decomposition of diazoacetates with reactivities and selectivities that were comparable to those of dirhodium(II) tetrakis-μ-carboxamidates.1,6-Bis-(N-benzyl)-diphenylglycoluril (1,6-BPGlyc) is a new bridging carboxamidate ligand for dirhodium(II) structures. The formation of a bis-glycoluril-bis-acetate dirhodium(II) complex is reported.
Co-reporter:Simin Liu Dr.;AtindraD. Shukla Dr.;Suresh Gadde Dr.;BrianD. Wagner Dr.;AngelE. Kaifer Dr. Dr.
Angewandte Chemie International Edition 2008 Volume 47( Issue 14) pp:2657-2660
Publication Date(Web):
DOI:10.1002/anie.200705346
Co-reporter:Hyunuk Kim;Mikhail V. Rekharsky;Tadashi Mori;Simin Liu;Angel E. Kaifer;David Sobransingh;Cheng Yang;Kimoon Kim;Wei Chen;N. Selvapalam;Michael K. Gilson;Sarvin Moghaddam;Young Ho Ko;Yoshihisa Inoue
PNAS 2007 Volume 104 (Issue 52 ) pp:20737-20742
Publication Date(Web):2007-12-26
DOI:10.1073/pnas.0706407105
The molecular host cucurbit[7]uril forms an extremely stable inclusion complex with the dicationic ferrocene derivative bis(trimethylammoniomethyl)ferrocene
in aqueous solution. The equilibrium association constant for this host-guest pair is 3 × 1015 M−1 (K
d = 3 × 10−16 M), equivalent to that exhibited by the avidin–biotin pair. Although purely synthetic systems with larger association constants
have been reported, the present one is unique because it does not rely on polyvalency. Instead, it achieves its extreme affinity
by overcoming the compensatory enthalpy–entropy relationship usually observed in supramolecular complexes. Its disproportionately
low entropic cost is traced to extensive host desolvation and to the rigidity of both the host and the guest.
Co-reporter:Wei-Hao Huang;Peter Y. Zavalij Dr. Dr.
Angewandte Chemie 2007 Volume 119(Issue 39) pp:
Publication Date(Web):13 AUG 2007
DOI:10.1002/ange.200702189
Zupackender Wirt: Isolierung, Charakterisierung und Erkennungseigenschaften des ersten chiralen Cucurbit[n]urils, des (±)-Bis-nor-seco-CB[6], werden beschrieben. (±)-Bis-ns-CB[6] wechselwirkt in diastereoselektiven Erkennungsereignissen mit Gästen, die stereogene Zentren enthalten, einschließlich Aminosäuren, Aminoalkoholen und meso-Verbindungen.
Co-reporter:Wei-Hao Huang;Peter Y. Zavalij Dr. Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 39) pp:
Publication Date(Web):13 AUG 2007
DOI:10.1002/anie.200702189
Picky host: The isolation, characterization, and recognition properties of the first chiral cucurbit[n]uril—(±)-bis-nor-seco-CB[6]—are reported. The (±)-bis-ns-CB[6] undergoes diastereoselective recognition events with guests that contain stereogenic centers including amino acids, amino alcohols, and meso compounds.
Co-reporter:Jason Lagona;Pritam Mukhopadhyay Dr.;Sriparna Chakrabarti Dr. Dr.
Angewandte Chemie International Edition 2005 Volume 44(Issue 31) pp:
Publication Date(Web):29 JUL 2005
DOI:10.1002/anie.200460675
In 1981, the macrocyclic methylene-bridged glycoluril hexamer (CB[6]) was dubbed “cucurbituril” by Mock and co-workers because of its resemblance to the most prominent member of the cucurbitaceae family of plants—the pumpkin. In the intervening years, the fundamental binding properties of CB[6]—high affinity, highly selective, and constrictive binding interactions—have been delineated by the pioneering work of the research groups of Mock, Kim, and Buschmann, and has led to their applications in waste-water remediation, as artificial enzymes, and as molecular switches. More recently, the cucurbit[n]uril family has grown to include homologues (CB[5]–CB[10]), derivatives, congeners, and analogues whose sizes span and exceed the range available with the α-, β-, and γ-cyclodextrins. Their shapes, solubility, and chemical functionality may now be tailored by synthetic chemistry to play a central role in molecular recognition, self-assembly, and nanotechnology. This Review focuses on the synthesis, recognition properties, and applications of these unique macrocycles.
Co-reporter:Jason Lagona;Pritam Mukhopadhyay Dr.;Sriparna Chakrabarti Dr. Dr.
Angewandte Chemie 2005 Volume 117(Issue 31) pp:
Publication Date(Web):29 JUL 2005
DOI:10.1002/ange.200460675
Im Jahre 1981 tauften Mock und Mitarbeiter das makrocyclische methylenverbrückte Glycoluril-Hexamer (CB[6]) auf den Namen “Cucurbituril” – da ihre Form einem Kürbis ähnelt, dem bekanntesten Mitglied der Cucurbitaceae-Familie in der Pflanzenwelt. In den folgenden Jahren wurden die grundlegenden Bindungseigenschaften von CB[6] – die hohe Affinität und Selektivität sowie der Einschluss von Gästen – in bahnbrechenden Arbeiten der Gruppen von Mock, Kim und Buschmann aufgezeigt; es folgten Anwendungen in der Wasseraufarbeitung, künstlichen Enzymen und molekularen Schaltern. Erst vor kurzem wuchs die Cucurbit[n]uril-Familie um Homologe (CB[5]–CB[10]), Derivate, Verwandte und Analoga, sodass sie nun die Molekülgrößen von α-, β- und γ-Cyclodextrinen umfasst und übersteigt. Auch die Formen, Löslichkeiten und chemischen Funktionalitäten können inzwischen durch spezielle Synthesen den Erfordernissen angepasst werden. Durch diese Eigenschaften sind die Cucurbiturile prädestiniert für eine zentrale Rolle in molekularer Erkennung, Selbstorganisation und Nanotechnologie. Dieser Aufsatz stellt Synthesen, Erkennungseigenschaften und Anwendungen dieser einzigartigen Makrocyclen vor.
Co-reporter:Lyle Isaacs
Advanced Drug Delivery Reviews (15 June 2012) Volume 64(Issue 9) pp:763
Publication Date(Web):15 June 2012
DOI:10.1016/j.addr.2012.04.006
Co-reporter:Brittany Vinciguerra ; Liping Cao ; Joe R. Cannon ; Peter Y. Zavalij ; Catherine Fenselau
Journal of the American Chemical Society () pp:
Publication Date(Web):July 16, 2012
DOI:10.1021/ja3058502
We present a building-block approach toward functionalized CB[7] derivatives by the condensation of methylene-bridged glycoluril hexamer 1 and glycoluril bis(cyclic ethers) 2 and 12. The CB[7] derivatives Me2CB[7] and CyCB[7] are highly soluble in water (264 mM and 181 mM, respectively). As a result of the high intrinsic solubility of Me2CB[7], it is able to solubilize the insoluble benzimidazole drug albendazole. The reaction of hexamer 1 with glycoluril derivative 12, which bears a primary alkyl chloride group, gives CB[7] derivative 18 in 16% isolated yield. Compound 18 reacts with NaN3 to yield azide-substituted CB[7] 19 in 81% yield, which subsequently undergoes click reaction with propargylammonium chloride (21) to yield CB[7] derivative 20 in 95% yield, which bears a covalently attached triazolyl ammonium group along its equator. The results of NMR spectroscopy (1H, variable-temperature, and DOSY) and electrospray mass spectrometry establish that 20 undergoes self-assembly to form a cyclic tetrameric assembly (204) in aqueous solution. CB[7] derivatives bearing reactive functional groups (e.g., N3, Cl) are now available for incorporation into more complex functional systems.
Co-reporter:Wei-Hao Huang ; Peter Y. Zavalij
Organic Letters () pp:
Publication Date(Web):August 5, 2009
DOI:10.1021/ol901539q
In a process reminiscent of RNA folding, acyclic glycoluril decamer (±)-1 undergoes double helical assembly (red/green strands) in water triggered by the neutralization of regions of high electrostatic surface potential by metal cations (Li+, Na+, K+, Ca2+).
Co-reporter:Derick Lucas
Organic Letters () pp:
Publication Date(Web):July 8, 2011
DOI:10.1021/ol201636q
The fragmentation reaction of bis-nor-seco-CB[10] with 3,5-dimethylphenol (3) delivers methylene bridged glycoluril pentamer 5 in 81% yield. The host–guest recognition properties of the previously known tetramer 4 and those of pentamer 5 and hexamer 6 toward cationic guests in water are used to delineate some important features of the binding of acyclic CB[n]-type receptors.
Co-reporter:Yuri V. Fedorov, Sergey V. Tkachenko, Ekaterina Yu. Chernikova, Ivan A. Godovikov, Olga A. Fedorova and Lyle Isaacs
Chemical Communications 2015 - vol. 51(Issue 7) pp:NaN1352-1352
Publication Date(Web):2014/12/01
DOI:10.1039/C4CC08474H
We report that three-component systems comprising styryl dyes (1 or 2) and two hosts (hydroxypropyl-β-cyclodextrin (HP-β-CD) and cucurbit[7]uril (CB[7])) undergo photoinduced transformation and translocation of the styryl guest from the cavity of HP-β-CD to CB[7]. We find that the protonation of guest trans-1 or the addition of Ba2+ as competitor for CB[7] triggers dissociation of the container–guest complexes.
Co-reporter:Yang Yu, Jie Li, Mingming Zhang, Liping Cao and Lyle Isaacs
Chemical Communications 2015 - vol. 51(Issue 18) pp:NaN3765-3765
Publication Date(Web):2015/01/27
DOI:10.1039/C5CC00236B
Hydrophobic monofunctionalized cucurbit[7]uril derivatives (1 and 2) were synthesized by clicking CB[7]-azide with propargylated alkylamines. Compounds 1 and 2 form self-inclusion complexes that are transformed into vesicle-type assemblies by addition of guests (3–5) as confirmed by 1H and DOSY NMR, SEM, TEM, and fluorescence spectroscopy.
Co-reporter:Mingming Zhang, David Sigwalt and Lyle Isaacs
Chemical Communications 2015 - vol. 51(Issue 78) pp:NaN14623-14623
Publication Date(Web):2015/08/13
DOI:10.1039/C5CC05803A
We report the synthesis of mono- and difunctionalized acyclic cucurbit[n]uril-type containers (1HA, 1HDA, 2HDA) which bear hexylammonium and hexanediammonium arms. The intra- and intermolecular assembly processes of 1HA, 1HDA, 2HDA as well as the ability of CB[n] to trigger allosteric host–guest binding toward guests 9–11 are presented.
Co-reporter:Mingming Zhang, Liping Cao and Lyle Isaacs
Chemical Communications 2014 - vol. 50(Issue 94) pp:NaN14759-14759
Publication Date(Web):2014/10/15
DOI:10.1039/C4CC07268E
We report the synthesis of cucurbit[6]uril–cucurbit[7]uril heterodimer (1) by click chemistry of monofunctionalized CB[6] and CB[7] derivatives. Combinations of 1 with hydrophobic guest 4b or hydrophilic polymeric guests 5b and 5c deliver hydrophobic or amphiphilic supramolecular block copolymers which form supramolecular networks (6) and supramolecular micelles (7), respectively, in the solid state.
Co-reporter:James B. Wittenberg, Matthew G. Costales, Peter Y. Zavalij and Lyle Isaacs
Chemical Communications 2011 - vol. 47(Issue 33) pp:NaN9422-9422
Publication Date(Web):2011/07/20
DOI:10.1039/C1CC13358F
This paper describes the synthesis of host 1 by the double bridging reaction of bis-ns-CB[10] with 2 under acidic conditions. Host 1 functions as a double cavity host for aliphatic and aromatic ammonium ions (3–17) in water. Conducting the bridging reaction in the presence of guest 4 delivers [3]rotaxane 1·42 by a clipping process.
Co-reporter:Ekaterina Chernikova, Daria Berdnikova, Yuri Fedorov, Olga Fedorova, Alexander Peregudov and Lyle Isaacs
Chemical Communications 2012 - vol. 48(Issue 58) pp:NaN7258-7258
Publication Date(Web):2012/06/18
DOI:10.1039/C2CC33243D
A novel supramolecular assembly comprising CB[7], styrylpyridinium dye (1) and Hg2+ forms in aqueous solution based on the hydrophobic effect and metal–ligand and ion–dipole interactions. The binding of Hg2+ to 1·CB[7] displays positive cooperativity relative to 1 itself.
Co-reporter:Li-Ping Cao, Jun-Gang Wang, Jiao-Yang Ding, An-Xin Wu and Lyle Isaacs
Chemical Communications 2011 - vol. 47(Issue 30) pp:NaN8550-8550
Publication Date(Web):2011/07/01
DOI:10.1039/C1CC13288A
We report herein a five-component self-sorted system comprising molecular clips that form heterodimers 1·4 and 8·11, and homodimer 14·14 in C6D5CD3/CDCl3. The three component self-sorting mixture comprising 1·1, 8·8, and 14·14 undergoes triggered reassembly self-sorting upon addition of 4·4 and 11·11.
Co-reporter:Li-Ping Cao, Xiang-Gao Meng, Jiao-Yang Ding, Yun-Feng Chen, Meng Gao, Yan-Dong Wu, Yi-Tao Li, An-Xin Wu and Lyle Isaacs
Chemical Communications 2010 - vol. 46(Issue 25) pp:NaN4510-4510
Publication Date(Web):2010/05/19
DOI:10.1039/C0CC00677G
A noncovalent macrocycle-within-noncovalent macrocycle assembly is formed from twelve molecules of (±)-1 and twelve molecules of MeOH in the solid state. The H-bonded (MeOH)12 cyclododecamer assumes a crown-shaped geometry that has not previously been predicted theoretically or found experimentally.
Co-reporter:Neng-Fang She, Xiang-Gao Meng, Meng Gao, An-Xin Wu and Lyle Isaacs
Chemical Communications 2008(Issue 27) pp:NaN3135-3135
Publication Date(Web):2008/04/04
DOI:10.1039/B800785C
Glycoluril derivative 1—whose bulky Ph–CC– substituents prevent formation of H-bonded tapes—undergoes solvent dependent assembly in the crystal; a tetrameric molecular bowl is formed by R44(24) H-bonding interactions from CH2Cl2 whereas DMF results in H-bond dimerization followed by oligomerization via C–H⋯π interactions.
Co-reporter:Liping Cao, Đani Škalamera, Peter Y. Zavalij, Jiří Hostaš, Pavel Hobza, Kata Mlinarić-Majerski, Robert Glaser and Lyle Isaacs
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 22) pp:NaN6254-6254
Publication Date(Web):2015/05/12
DOI:10.1039/C5OB00784D
We report the binding constants of CB[7] toward a series of naphthalene diammonium and 4,4′-dipiperidinium derivatives and compare the results with those obtained previously for CB[7]·3b by 1H NMR and X-ray crystallography. The nature of binding in the host·guest complexes was investigated using quantum mechanical tools.
Co-reporter:Laura Gilberg, Ben Zhang, Peter Y. Zavalij, Vladimir Sindelar and Lyle Isaacs
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 13) pp:NaN4050-4050
Publication Date(Web):2015/02/23
DOI:10.1039/C5OB00184F
We present the synthesis of a series of six new glycoluril derived molecular clips and acyclic CB[n]-type molecular containers (1–3) that all feature SO3− solubilizing groups but differ in the number of glycoluril rings between the two terminal dialkoxyaromatic sidewalls. We report the X-ray crystal structure of 3b which shows that its dialkoxynaphthalene sidewalls actively define a hydrophobic cavity with high potential to engage in π–π interactions with insoluble aromatic guests. Compounds 1–3 possess very good solubility characteristics (≥38 mM) and undergo only very weak self-association (Ks < 92 M−1) in water. The weak self-association is attributed to unfavorable SO3−⋯SO3− electrostatic interactions in the putative dimers 12–42. Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, β-estradiol, and ziprasidone). We find that the containers 3a and 3b which feature three glycoluril rings between the terminal dialkoxy-o-xylylene and dialkoxynaphthalene sidewalls are less efficient solubilizing agents than 4a and 4b because of their smaller hydrophobic cavities. Containers 1 and 2 behave as molecular clip type receptors and therefore possess the ability to bind to and thereby solubilize aromatic drugs like camptothecin, ziprasidone, and PBS-1086.
Co-reporter:Ben Zhang, Peter Y. Zavalij and Lyle Isaacs
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 15) pp:NaN2422-2422
Publication Date(Web):2014/02/21
DOI:10.1039/C3OB42603C
We report the synthesis and X-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3−, OH, NH3+). The X-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by π–π interactions, H-bonds and ion–dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct 1H NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pKa of 6-aminocoumarin 7 (pKa = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pKa = 4.9; 2h: pKa = 4.1; 2f, pKa = 3.4) which reflect in part the relevance of direct ion–ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17α-ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents.
Co-reporter:Soumen K. Samanta, Kimberly G. Brady and Lyle Isaacs
Chemical Communications 2017 - vol. 53(Issue 18) pp:NaN2759-2759
Publication Date(Web):2017/02/17
DOI:10.1039/C6CC10328F
Self-assembly of rigid-rod dipyridine ligand 1 with M(en)(NO3)2 (M = Pd, Pt) affords triangular (3, 5) and square (4, 6) supramolecular coordination complexes (SCCs). The binding affinity of 1 toward CB[n]-type containers results in the formation of triangular [4]molecular necklaces ([4]MNs, 7–10) by either one-pot or post complexation approaches as evidenced by 1H NMR, diffusion ordered spectroscopy, and ESI-MS.
Co-reporter:Wenqi Liu, Soumen K. Samanta, Bradley D. Smith and Lyle Isaacs
Chemical Society Reviews 2017 - vol. 46(Issue 9) pp:NaN2403-2403
Publication Date(Web):2017/02/13
DOI:10.1039/C7CS00011A
Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. However, biotin/(strept)avidin self-assembly has several well-recognized drawbacks that limit performance in certain technical areas and there is a need for synthetic mimics that can either become superior replacements or operational partners with bio-orthogonal recognition properties. The goal of this tutorial review is to describe the recent progress in making high affinity synthetic association partners that operate in water or biological media. The review starts with a background summary of biotin/(strept)avidin self-assembly and the current design rules for creating synthetic mimics. A series of case studies are presented that describe recent success using synthetic derivatives of cyclodextrins, cucurbiturils, and various organic cyclophanes such as calixarenes, deep cavitands, pillararenes, and tetralactams. In some cases, two complementary partners associate to produce a nanoscale complex and in other cases a ditopic host molecule is used to link two partners. The article concludes with a short discussion of future directions and likely challenges.
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