Co-reporter:Paul Schmid;Matthias Maier;Hendrik Pfeiffer;Anja Belz;Lucas Henry;Alexandra Friedrich;Fabian Schönfeld;Katharina Edkins
Dalton Transactions 2017 vol. 46(Issue 39) pp:13386-13396
Publication Date(Web):2017/10/10
DOI:10.1039/C7DT03096G
Two isostructural and isoelectronic group VI azide complexes of the general formula [M(η3-allyl)(N3)(bpy)(CO)2] with M = Mo, W and bpy = 2,2′-bipyridine were prepared and fully characterized, including X-ray structure analysis. Both reacted smoothly with electron-poor alkynes such as dimethyl acetylenedicarboxylate (DMAD) and 4,4,4-trifluoro-2-butynoic acid ethyl ester in a catalyst-free room-temperature iClick [3 + 2] cycloaddition reaction. Reaction with phenyl(trifluoromethyl)acetylene, on the other hand, did not lead to any product formation. X-ray structures of the four triazolate complexes isolated showed the monodentate ligand to be N2-coordinated in all cases, which requires a 1,2-shift of the nitrogen from the terminal azide to the triazolate cycloaddition product. On the other hand, a 19F NMR spectroscopic study of the reaction of the fluorinated alkyne with the tungsten azide complex at 27 °C allowed detection of the N1-coordinated intermediate. With this method, the second-order rate constant was determined as (7.3 ± 0.1) × 10−2 M−1 s−1, which compares favorably with that of first-generation compounds such as difluorocyclooctyne (DIFO) used in the strain-promoted azide–alkyne cycloaddition (SPAAC). In contrast, the reaction of the molybdenum analogue was too fast to be studied with NMR methods. Alternatively, solution IR studies revealed pseudo-first order rate constants of 0.4 to 6.5 × 10−3 s−1, which increased in the order of Mo > W and F3C–CC–COOEt > DMAD.
Co-reporter:F. Wittkamp, C. Nagel, P. Lauterjung, B. Mallick, U. Schatzschneider and U.-P. Apfel
Dalton Transactions 2016 vol. 45(Issue 25) pp:10271-10279
Publication Date(Web):23 May 2016
DOI:10.1039/C6DT01209D
Here we present the syntheses and structural, spectroscopic, as well as electrochemical properties of four dinitrosyl iron complexes (DNICs) based on silicon- and carbon-derived di- and tripodal phosphines. Whereas CH3C(CH2PPh2)3 and Ph2Si(CH2PPh2)2 coordinate iron in a η2 – binding mode, CH3Si(CH2PPh2)3 undergoes cleavage of one Si–C bond to afford [Fe(NO)2(P(CH3)Ph2)2] at elevated temperatures. The complexes were characterized by IR spectroelectrochemistry as well as UV-vis measurements. The oxidized {Fe(NO)2}9 compounds were obtained by oxidation with (NH4)2[Ce(NO3)6] and their properties evaluated with Mössbauer and IR spectroscopy. Stability experiments on the complexes suggest that they are capable of releasing their NO-ligands in the oxidized {Fe(NO)2}9 but not in the reduced {Fe(NO)2}10 form. A detailed DFT analysis is provided in order to understand the electronic configurations and the complexes’ ability to release NO.
Co-reporter:U Schatzschneider
British Journal of Pharmacology 2015 Volume 172( Issue 6) pp:1638-1650
Publication Date(Web):
DOI:10.1111/bph.12688
Carbon monoxide (CO) is an endogenous small signalling molecule in the human body, produced by the action of haem oxygenase on haem. Since it is very difficult to apply safely as a gas, solid storage and delivery forms for CO are now explored. Most of these CO-releasing molecules (CORMs) are based on the inactivation of the CO by coordinating it to a transition metal centre in a prodrug approach. After a brief look at the potential cellular target structures of CO, an overview of the design principles and activation mechanisms for CO release from a metal coordination sphere is given. Endogenous and exogenous triggers discussed include ligand exchange reactions with medium, enzymatically-induced CO release and photoactivated liberation of CO. Furthermore, the attachment of CORMs to hard and soft nanomaterials to confer additional target specificity to such systems is critically assessed. A survey of analytical methods for the study of the stoichiometry and kinetics of CO release, as well as the tracking of CO in living systems by using fluorescent probes, concludes this review. CORMs are very valuable tools for studying CO bioactivity and might lead to new drug candidates; however, in the design of future generations of CORMs, particular attention has to be paid to their drug-likeness and the tuning of the peripheral ‘drug sphere’ for specific biomedical applications. Further progress in this field will thus critically depend on a close interaction between synthetic chemists and researchers exploring the physiological effects and therapeutic applications of CO.
Co-reporter:Wanning Hu;Jan Hoyer;Ines Neundorf;Preshendren Govender;Gregory S. Smith
European Journal of Inorganic Chemistry 2015 Volume 2015( Issue 9) pp:1505-1510
Publication Date(Web):
DOI:10.1002/ejic.201403060
Abstract
Dendrimers of different generations and core structures [diaminobutane poly(propylenimine) (DAB) G1, G2, G3; poly(amidoamine) (PAMAM) G1] were chosen as carriers for bioactive organometallic half-sandwich complexes of the type CpM(CO)3 (Cp = cyclopentadienyl, M = Mn or Re) to study the influence of these parameters on their biological activity against cancer cells. Structure–activity relationships were determined by variation of the metal center as well as the type, molecular weight, and number of terminal functional groups of the dendrimer conjugates. All conjugates were characterized by IR and NMR spectroscopy as well as HPLC. Their biological activity was determined on MCF-7 human breast cancer cells by the resazurin assay. Interestingly, the most-active compounds were the first-generation dendrimer conjugates. The Mn and Re series showed nearly the same activities. Thus, the cytotoxicity of the dendrimer conjugates does not seem to directly correlate with the type or number of terminal functional groups. Rather, it points to a mechanism of action that is different from that previously observed for peptide conjugates with similar CpM(CO)3 functional groups.
Co-reporter:Peter V. Simpson, Krzysztof Radacki, Holger Braunschweig, Ulrich Schatzschneider
Journal of Organometallic Chemistry 2015 Volume 782() pp:116-123
Publication Date(Web):15 April 2015
DOI:10.1016/j.jorganchem.2014.12.034
•Four new NHC complexes of rhodium and iridium synthesized and characterized.•X-ray structures of [IrCl(COD)(NHC)], [IrCl(CO)2(NHC)], [Ir(N3)(COD)(NHC)] reported.•First structurally characterized iridium NHC azide complex presented.•[IrCl(CO)2(NHC)] acts as a CO-releasing molecule (CORM).Four NHC complexes of rhodium and iridium of the general structure [RhI(COD)(NHC)], [IrCl(COD)(NHC)], [IrCl(CO)2(NHC)], and [Ir(N3)(COD)(NHC)] (NHC = N-heterocyclic carbene) were synthesised and characterised, including X-ray structure determination for all three iridium compounds. Release of carbon monoxide from [IrCl(CO)2(NHC)] occurred via a rapid bolus of CO on a very short timescale, independent of whether the experiment was performed in the dark or with UV-light illumination, thus establishing the compound as a novel ligand-exchange triggered CO-releasing molecule (CORM). The azide complex represents the first iridium–NHC complex containing an azide ligand.NHC complexes of rhodium and iridium were prepared for applications in bioorganometallic chemistry. The reactivity of [Ir(N3)(COD)(NHC)] towards alkynes in iClick reactions was explored while [IrCl(CO)2(NHC)] was investigated as a CO-releasing molecule. Ligand-exchange triggered CO release occurred rapidly on a short timescale while photoactivation did not have any additional effect.
Co-reporter:Peter V. Simpson, Christoph Nagel, Heike Bruhn, and Ulrich Schatzschneider
Organometallics 2015 Volume 34(Issue 15) pp:3809-3815
Publication Date(Web):July 21, 2015
DOI:10.1021/acs.organomet.5b00458
Five manganese(I) tricarbonyl complexes of the general formula [Mn(CO)3(bpyR,R)(azole)]PF6 with R = H, COOCH3, and azole = ketoconazole (ktz), miconazole (mcz), and clotrimazole (ctz) were synthesized and fully charaterized, including X-ray structure analysis for the ctz compound. The antibacterial activity on a panel of eight Gram-positive and Gram-negative bacterial strains was determined. While there was no effect on the latter microorganisms, the ctz complex showed submicromolar activity on Staphylococcus aureus and S. epidermidis with MIC values of 0.625 μM. Antiparasitic activity was investigated on Leishmania major and Trypanosoma brucei. Coordination of the organic azole drugs to the Mn(CO)3 moiety led to complexes with low micromolar IC50 values, but their potential for antileishmanial therapy is low due to comparable toxicity on mammalian cell lines 293T and J774.1. In contrast, the antitrypanosomal activity is much more promising, and the most potent compound incorparting the ktz ligand has an IC50 value on T. brucei of 0.7 μM with selectivity on parasitic over mammalian cells as expressed by a selectivity index above 10. These results demonstrate that metal coordination of established drugs can significantly improve their biological activity and expand their range of medicinal applications.
Co-reporter:Lucas Henry, Christoph Schneider, Benedict Mützel, Peter V. Simpson, Christoph Nagel, Katharina Fucke and Ulrich Schatzschneider
Chemical Communications 2014 vol. 50(Issue 99) pp:15692-15695
Publication Date(Web):23 Oct 2014
DOI:10.1039/C4CC07892F
The catalyst-free room temperature iClick reaction of an unsymmetrically 2,3-disubstituted oxanorbornadiene (OND) as a “masked” alkyne equivalent with [Mn(N3)(bpyCH3,CH3)(CO)3] leads to isolation of a phenylalanine ester bioconjugate, in which the model amino acid is linked to the metal moiety via a N-2-coordinated triazolate formed in a cycloaddition-retro-Diels–Alder (crDA) reaction sequence, in a novel approach to bioorthogonal coupling reactions based on metal-centered reactivity.
Co-reporter:Sandesh Pai, Maryam Hafftlang, George Atongo, Christoph Nagel, Johanna Niesel, Svetlana Botov, Hans-Günther Schmalz, Benito Yard and Ulrich Schatzschneider
Dalton Transactions 2014 vol. 43(Issue 23) pp:8664-8678
Publication Date(Web):03 Mar 2014
DOI:10.1039/C4DT00254G
Five manganese(I) tricarbonyl complexes of the general formulae [Mn(bpeaNCHC6H4R)(CO)3]PF6 and [Mn(bpeaNHCH2C6H4R)(CO)3]PF6 based on the tridentate bis(pyrazolyl)ethylamine (bpea) ligand, each containing a pendant 4-substituted phenyl group with R = H, I, and CC–H, were synthesized and fully characterized, including X-ray structure analysis for three compounds. All complexes are stable in the dark in aqueous buffer for an extended period of time. However, CO-release could be triggered by illumination at 365 nm, establishing these compounds as novel photoactivatable CO-releasing molecules (PhotoCORMs). The influence of the imine vs. amine group in the ligands on the electronic structure and the photophysical behavior was investigated with the aid of DFT and TDDFT calculations. Solution IR studies on selected compounds allowed identification of intermediates resulting from the photoreaction. Finally, light-induced CO release from a model compound was demonstrated both in PBS buffer and in vitro in human umbilical vein endothelial cells (HUVECs) using COP-1 as a fluorescent switch-on probe.
Co-reporter:Christoph Nagel, Samantha McLean, Robert K. Poole, Holger Braunschweig, Thomas Kramer and Ulrich Schatzschneider
Dalton Transactions 2014 vol. 43(Issue 26) pp:9986-9997
Publication Date(Web):22 May 2014
DOI:10.1039/C3DT51848E
[Mn(CO)3(tpa-κ3N)]Br was prepared as a novel photoactivatable CO-releasing molecule (PhotoCORM) from [MnBr(CO)5] and tris(2-pyridylmethyl)amine (tpa) for the delivery of carbon monoxide to biological systems, with the κ3N binding mode of the tetradentate tpa ligand demonstrated by X-ray crystallography. The title compound is a CORM prodrug stable in solution in the dark for up to 16 h. However, photoactivation at 365 nm leads to CO release from the metal coordination sphere and transfer to haem proteins, as demonstrated by the standard myoglobin assay. Different iCORM intermediates could be detected with solution IR spectroscopy and assigned using DFT vibrational calculations. The antibacterial activity of the complex was studied on Escherichia coli. No effects were observed when the cultures were either kept in the dark in the presence of PhotoCORM or illuminated in the absence of metal complex. However, photoactivation of [Mn(CO)3(tpa-κ3N)]Br at 365 nm led to the appearance of the spectral signatures of CO-coordinated haems in the terminal oxidases of the bacterial electron transport chain in whole-cell UV/Vis absorption spectra. Significant internalization of the PhotoCORM was demonstrated by ICP-MS measurement of the intracellular manganese concentration. In particular when using medium with succinate as the sole carbon source, a very pronounced and concentration-dependent decrease in the E. coli growth rate could be observed upon illumination in the presence of metal complex, which is attributed to the constrained energy metabolism under these conditions and a strong indicator of terminal oxidase inhibition by carbon monoxide delivered from the PhotoCORM.
Co-reporter:Sesh Pai;Krzysztof Radacki
European Journal of Inorganic Chemistry 2014 Volume 2014( Issue 18) pp:2886-2895
Publication Date(Web):
DOI:10.1002/ejic.201402123
Abstract
In this work, facial tricarbonylmanganese(I) complexes [Mn(bpeaCH2C6H4R)(CO)3]PF6 incorporating a functionalized 2,2-bis(pyrazolyl)ethylamine (bpea) ligand with R = I, C≡CH, and CHO have been explored for their utility in bioorthogonal coupling to carrier peptides bearing N-terminal alkyne, azide, and aminoxy residues. As a model system, the transforming growth factor β-recognizing (TGF-β) peptide sequence R′-Leu-Pro-Leu-Gly-Asn-Ser-His-OH was used in which R′ is the reactive group complementary to the metal complex functionality. The use of catalyst-free oxime ligation gave the most stable conjugate with no degradation observed by HPLC over 96 h even after repeated freeze–thaw cycles. Both the parent complex as well as the functionalized peptide were investigated for photoactivated CO delivery to heme proteins by using the myoglobin assay and found to have essentially identical release properties. This work has established a new strategy for the conjugation of photoactivatable CO-releasing molecules (PhotoCORMs) to biological carrier systems.
Co-reporter:Preshendren Govender, Sandesh Pai, Ulrich Schatzschneider, and Gregory S. Smith
Inorganic Chemistry 2013 Volume 52(Issue 9) pp:5470-5478
Publication Date(Web):April 17, 2013
DOI:10.1021/ic400377k
The first CO-releasing metallodendrimers, based on polypyridyl dendritic scaffolds functionalized with Mn(CO)3 moieties, of the general formula [DAB-PPI-{MnBr(bpyCH3,CH═N)(CO)3}n], where DAB = 1,4-diaminobutane, PPI = poly(propyleneimine), bpy = bipyridyl, and n = 4 for first- or n = 8 for second-generation dendrimers, were synthesized and comprehensively characterized by analytical (HR-ESI mass spectrometry and elemental analysis) and spectroscopic (1H, 13C{1H}-NMR, infrared, and UV/vis spectroscopy) methods. The CO-release properties of these compounds were investigated in pure buffer and using the myoglobin assay. Both metallodendrimer generations are stable in the dark in aqueous buffer for up to 16 h but show photoactivated CO release upon excitation at 410 nm, representing a novel class of macromolecular photoactivatable CO-releasing molecules (PhotoCORMs). No scaling effects were observed since both metallodendrimers release ∼65% of the total number of CO ligands per molecule, regardless of the generation number. In addition, the mononuclear model complex [MnBr(bpyCH3,CH═NCH2CH2CH3)(CO)3] was prepared and comprehensively studied, including DFT/TDDFT calculations. These metallodendrimer-based PhotoCORMs afford new methods of targeted delivery of large amounts of carbon monoxide to cellular systems.
Co-reporter:Caroline Bischof, Tanmaya Joshi, Aakanksha Dimri, Leone Spiccia, and Ulrich Schatzschneider
Inorganic Chemistry 2013 Volume 52(Issue 16) pp:9297-9308
Publication Date(Web):August 6, 2013
DOI:10.1021/ic400746n
A series of ruthenium(II) dicarbonyl complexes of formula [RuCl2(L)(CO)2] (L = bpyCH3,CH3 = 4,4′-dimethyl-2,2′-bipyridine, bpyCH3,CHO = 4′-methyl-2,2′-bipyridine-4-carboxyaldehyde, bpyCH3,COOH = 4′-methyl-2,2′-bipyridine-4-carboxylic acid, CppH = 2-(pyridin-2-yl)pyrimidine-4-carboxylic acid, dppzcH = dipyrido[3,2-a:2′,3′-c]phenazine-11-carboxylic acid), and [RuCl(L)(CO)2]+ (L = tpyCOOH = 6-(2,2′:6′,2″-terpyridine-4′-yloxy)hexanoic acid) has been synthesized. In addition, a high-yield synthesis of a peptide nucleic acid (PNA) monomer containing the 2-(pyridin-2-yl)pyrimidine ligand was also developed, and this compound was used to prepare the first Ru(II) dicarbonyl complex, [RuCl2(Cpp-L-PNA)(CO)2],(Cpp-L-PNA = tert-butyl-N-[2-(N-9-fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoyl]glycinate) attached to a PNA monomer backbone. Such metal-complex PNA–bioconjugates are attracting profound interest for biosensing and biomedical applications. Characterization of all complexes has been undertaken by IR and NMR spectroscopy, mass spectrometry, elemental analysis, and UV–vis spectroscopy. Investigation of the CO-release properties of the Ru(II) complexes in water/dimethyl sulfoxide (49:1) using the myoglobin assay showed that they are stable under physiological conditions in the dark for at least 60 min and most of them even for up to 15 h. In contrast, photoinduced CO release was observed upon illumination at 365 nm, the low-energy shoulder of the main absorption maximum centered around 300 nm, establishing these compounds as a new class of PhotoCORMs. While the two 2,2′-bipyridine complexes release 1 equiv of CO per mole of complex, the terpyridine, 2-(2′-pyridyl)pyrimidine, and dipyrido[3,2-a:2′,3′-c]phenazine complexes are less effective CO releasers. Attachment of the 2-(2′-pyridyl)pyrimidine complex to a PNA backbone as in [RuCl2(Cpp-L-PNA)CO2] did not significantly change the spectroscopic or CO-release properties compared to the parent complex. Thus, a novel class of Ru(II)-based PhotoCORMs has been established which can be coupled to carrier delivery vectors such as PNA to facilitate cellular uptake without loss of the inherent CORM properties of the parent compound.
Co-reporter:Peter V. Simpson;Claudia Schmidt;Ingo Ott;Heike Bruhn
European Journal of Inorganic Chemistry 2013 Volume 2013( Issue 32) pp:5547-5554
Publication Date(Web):
DOI:10.1002/ejic.201300820
Abstract
Four new N-heterocyclic carbene (NHC) rhodium and iridium complexes decorated with anionic or cationic pendant groups to increase their water solubility and biological activity have been synthesised and characterised. The lipophilicity of the complexes was determined and the complexes that contained cationic phosphonium groups can be considered delocalised lipophilic cations (DLCs). All complexes were tested for their antibacterial, antiparasitic and anticancer activity, with only the phosphonium-functionalised complexes showing moderate to high activity, whereas the exchange of metal from rhodium to iridium had a negligible effect. Most promising was the activity on Trypanosoma brucei, with IC50 values in the range of 150–400 nM and a selectivity index (SI) of up to 50. General toxicity on mammalian cell lines was a general problem, though, and needs to be mitigated in future work. Cellular uptake studies clearly confirmed that the cationic phosphonium groups facilitated uptake, which was linked with higher biological activity.
Co-reporter:Hendrik Pfeiffer, Thomas Sowik, Ulrich Schatzschneider
Journal of Organometallic Chemistry 2013 734() pp: 17-24
Publication Date(Web):
DOI:10.1016/j.jorganchem.2012.09.016
Co-reporter:G. Dördelmann, Thomas Meinhardt, Thomas Sowik, Anke Krueger and Ulrich Schatzschneider
Chemical Communications 2012 vol. 48(Issue 94) pp:11528-11530
Publication Date(Web):09 Oct 2012
DOI:10.1039/C2CC36491C
The copper-catalyzed 1,3-dipolar azide–alkyne cycloaddition (CuAAC) was used for the first time to attach a biologically active carbon monoxide delivery agent to modified nanodiamond (ND) as a highly biocompatible carrier. The [Mn(CO)3(tpm)]+ photoactivatable CO-releasing molecule (PhotoCORM) on the surface retained the carbon monoxide release properties of the parent compound as shown with the myoglobin assay.
Co-reporter:Lotta Glans, Wanning Hu, Christian Jöst, Carmen de Kock, Peter J. Smith, Matti Haukka, Heike Bruhn, Ulrich Schatzschneider and Ebbe Nordlander
Dalton Transactions 2012 vol. 41(Issue 21) pp:6443-6450
Publication Date(Web):15 Mar 2012
DOI:10.1039/C2DT30077J
Organometallic analogues of chloroquine show promise as new antimalarial agents capable of overcoming resistance to the parent drug chloroquine. Here, the synthesis and characterization of three new cymantrene (CpMn(CO)3) and cyrhetrene (CpRe(CO)3) 4-aminoquinoline conjugates with either an amine or amide linker are reported. The antimalarial activity of the new organometallic conjugates N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide (3), N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide (4) and N-(7-chloroquinolin-4-yl)-N′-(cymantrenylmethyl)ethane-1,2-diamine (6) was evaluated against a chloroquine-sensitive (CQS) and a chloroquine-resistant strain (CQR) of the malaria parasite Plasmodium falciparum. The cymantrene complex with an amine linker (6) showed good activity against the CQS strain but was inactive against the CQR strain. In contrast, cymantrene and cyrhetrene compounds with an amide linker were active against both the CQS and the CQR strain. In addition, the antibacterial, anti-trypanosomal and anti-leishmanial activity of the compounds was evaluated. Compound 6 showed submicromolar activity against Trypanosoma brucei at a concentration where the toxicity to normal human cells is low. No significant effect was noticed on the exchange of manganese for rhenium in the CpM(CO)3 moiety in any of the biological assays.
Co-reporter:Anna-Maria Pütz, Ulrich Schatzschneider and Eva Rentschler
Physical Chemistry Chemical Physics 2012 vol. 14(Issue 5) pp:1649-1653
Publication Date(Web):20 Dec 2011
DOI:10.1039/C2CP23063A
The stability of the α-nitronyl nitroxide radical unit under acidic conditions is investigated by an integrated experimental UV/Vis spectroscopy and TDDFT study. In the field of molecular magnetism, α-nitronyl nitroxide radicals are important as purely organic spin carriers due to their synthetic versatility. Here, the existence of an intermediate of the protonated α-nitronyl nitroxide radical unit is demonstrated for the first time and a proposed disproportionation reaction is confirmed.
Co-reporter:Wanning Hu;Katrin Splith;Ines Neundorf
JBIC Journal of Biological Inorganic Chemistry 2012 Volume 17( Issue 2) pp:175-185
Publication Date(Web):2012 February
DOI:10.1007/s00775-011-0840-5
Organometallic complexes conjugated to cell-penetrating peptides (CPPs) are promising systems for diagnostic imaging and therapeutic applications in human medicine. Recently, we reported on the synthesis of cymantrene(CpMn(CO)3)–CPP conjugates with biological activity on different cancer cell lines. However, the precise mechanism of cytotoxicity remained elusive in these studies. To investigate the role of the metal center and the linker between the CpM(CO)3 moiety and the peptide, a number of derivatives with manganese replaced by rhenium and the keto linker originally used substituted by a methylene group were prepared and fully characterized by 1H NMR spectroscopy, infrared spectroscopy, electrospray ionization mass spectrometry, and elemental analysis as well as X-ray structure determination. The organometal–peptide conjugates as well as carboxyfluorescein-labeled derivatives thereof were prepared by solid-phase peptide synthesis, purified by high-performance liquid chromatography, and analyzed by mass spectrometry. Fluorescence microscopy studies of MCF-7 human breast cancer cells revealed an efficient cellular uptake and pronounced nuclear localization of the bioconjugates with the methylene linker compared with systems with the keto group. In addition, the latter also showed a higher cytotoxicity. In contrast, the variation of the metal center from manganese to rhenium had a negligible effect. The structure–activity relationships determined in the present work will aid in the further tuning of the biological activity of organometal–peptide conjugates.
Co-reporter:Gregor Dördelmann ; Hendrik Pfeiffer ; Alexander Birkner
Inorganic Chemistry 2011 Volume 50(Issue 10) pp:4362-4367
Publication Date(Web):April 20, 2011
DOI:10.1021/ic1024197
Silicium dioxide nanoparticles of about 20 nm diameter containing azido groups at the surface were prepared by emulsion copolymerization of trimethoxymethylsilane and (3-azidopropyl)triethoxysilane and studied by transmission electron microscopy (TEM). A photoactivatable CO-releasing molecule (PhotoCORM) based on [Mn(CO)3(tpm)]+ (tpm = tris(pyrazolyl)methane) containing an alkyne-functionalized tpm ligand was covalently linked to the silicium dioxide nanoparticles via the copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC “click” reaction). The surface functionalization of the particles with azido groups and manganese CORMs was analyzed by UV–vis, IR, 1H and 13C CP-MAS NMR spectroscopies as well as energy-dispersive X-ray spectroscopy (EDX). The myoglobin assay was used to demonstrate that the CORM-functionalized nanoparticles have photoinducible CO-release properties very similar to the free complex. In the future, such functionalized silicium dioxide nanoparticles might be utilized as delivery agents for CORMs in solid tumors.
Co-reporter:Ulrich Schatzschneider
Inorganica Chimica Acta 2011 Volume 374(Issue 1) pp:19-23
Publication Date(Web):1 August 2011
DOI:10.1016/j.ica.2011.02.068
Carbon monoxide is now well-established as a small-molecule biological effector in the human body. Metal–carbonyl complexes are a promising way to achieve safe and controlled delivery of CO for therapeutic applications and thus, such CO releasing molecules (CORMs) have achieved significant attention in the last 10 years. In most CORMs, the liberation of carbon monoxide is triggered by hydrolytic processes in aqueous medium and thus their half-life under physiological conditions determines their potential therapeutic utility. To overcome such limitations, photo-induced CO release from dark-stable metal–carbonyl complex prodrugs is an interesting alternative. Thus, in this review, the current knowledge on PhotoCORMs is summarized and their properties critically evaluated. The main challenge for the future will be to achieve photolytic liberation of carbon monoxide by near-IR excitation in the phototherapeutic window of the cell. Different ways how this goal might be achieved are discussed.Graphical abstractPhotoinduced CO release from metal carbonyl complexes acting as PhotoCORMs allows precise spatial and temporal control of the biological activity of this small-molecule messenger. The present review summarizes current developments and methods to study PhotoCORMs as well as future perspectives of this highly active field of research.Highlights► Carbon monoxide is an important small-molecule messenger in the human body. ► CO releasing molecules (CORMs) allow safe delivery of carbon monoxide. ► Photoinduced liberation of CO allows precise control of its biological activity. ► Review of light-activatable metal–carbonyl complexes as PhotoCORMs.
Co-reporter:Sandesh Pai, Maryam Hafftlang, George Atongo, Christoph Nagel, Johanna Niesel, Svetlana Botov, Hans-Günther Schmalz, Benito Yard and Ulrich Schatzschneider
Dalton Transactions 2014 - vol. 43(Issue 23) pp:NaN8678-8678
Publication Date(Web):2014/03/03
DOI:10.1039/C4DT00254G
Five manganese(I) tricarbonyl complexes of the general formulae [Mn(bpeaNCHC6H4R)(CO)3]PF6 and [Mn(bpeaNHCH2C6H4R)(CO)3]PF6 based on the tridentate bis(pyrazolyl)ethylamine (bpea) ligand, each containing a pendant 4-substituted phenyl group with R = H, I, and CC–H, were synthesized and fully characterized, including X-ray structure analysis for three compounds. All complexes are stable in the dark in aqueous buffer for an extended period of time. However, CO-release could be triggered by illumination at 365 nm, establishing these compounds as novel photoactivatable CO-releasing molecules (PhotoCORMs). The influence of the imine vs. amine group in the ligands on the electronic structure and the photophysical behavior was investigated with the aid of DFT and TDDFT calculations. Solution IR studies on selected compounds allowed identification of intermediates resulting from the photoreaction. Finally, light-induced CO release from a model compound was demonstrated both in PBS buffer and in vitro in human umbilical vein endothelial cells (HUVECs) using COP-1 as a fluorescent switch-on probe.
Co-reporter:F. Wittkamp, C. Nagel, P. Lauterjung, B. Mallick, U. Schatzschneider and U.-P. Apfel
Dalton Transactions 2016 - vol. 45(Issue 25) pp:NaN10279-10279
Publication Date(Web):2016/05/23
DOI:10.1039/C6DT01209D
Here we present the syntheses and structural, spectroscopic, as well as electrochemical properties of four dinitrosyl iron complexes (DNICs) based on silicon- and carbon-derived di- and tripodal phosphines. Whereas CH3C(CH2PPh2)3 and Ph2Si(CH2PPh2)2 coordinate iron in a η2 – binding mode, CH3Si(CH2PPh2)3 undergoes cleavage of one Si–C bond to afford [Fe(NO)2(P(CH3)Ph2)2] at elevated temperatures. The complexes were characterized by IR spectroelectrochemistry as well as UV-vis measurements. The oxidized {Fe(NO)2}9 compounds were obtained by oxidation with (NH4)2[Ce(NO3)6] and their properties evaluated with Mössbauer and IR spectroscopy. Stability experiments on the complexes suggest that they are capable of releasing their NO-ligands in the oxidized {Fe(NO)2}9 but not in the reduced {Fe(NO)2}10 form. A detailed DFT analysis is provided in order to understand the electronic configurations and the complexes’ ability to release NO.
Co-reporter:Lotta Glans, Wanning Hu, Christian Jöst, Carmen de Kock, Peter J. Smith, Matti Haukka, Heike Bruhn, Ulrich Schatzschneider and Ebbe Nordlander
Dalton Transactions 2012 - vol. 41(Issue 21) pp:NaN6450-6450
Publication Date(Web):2012/03/15
DOI:10.1039/C2DT30077J
Organometallic analogues of chloroquine show promise as new antimalarial agents capable of overcoming resistance to the parent drug chloroquine. Here, the synthesis and characterization of three new cymantrene (CpMn(CO)3) and cyrhetrene (CpRe(CO)3) 4-aminoquinoline conjugates with either an amine or amide linker are reported. The antimalarial activity of the new organometallic conjugates N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide (3), N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide (4) and N-(7-chloroquinolin-4-yl)-N′-(cymantrenylmethyl)ethane-1,2-diamine (6) was evaluated against a chloroquine-sensitive (CQS) and a chloroquine-resistant strain (CQR) of the malaria parasite Plasmodium falciparum. The cymantrene complex with an amine linker (6) showed good activity against the CQS strain but was inactive against the CQR strain. In contrast, cymantrene and cyrhetrene compounds with an amide linker were active against both the CQS and the CQR strain. In addition, the antibacterial, anti-trypanosomal and anti-leishmanial activity of the compounds was evaluated. Compound 6 showed submicromolar activity against Trypanosoma brucei at a concentration where the toxicity to normal human cells is low. No significant effect was noticed on the exchange of manganese for rhenium in the CpM(CO)3 moiety in any of the biological assays.
Co-reporter:Christoph Nagel, Samantha McLean, Robert K. Poole, Holger Braunschweig, Thomas Kramer and Ulrich Schatzschneider
Dalton Transactions 2014 - vol. 43(Issue 26) pp:NaN9997-9997
Publication Date(Web):2014/05/22
DOI:10.1039/C3DT51848E
[Mn(CO)3(tpa-κ3N)]Br was prepared as a novel photoactivatable CO-releasing molecule (PhotoCORM) from [MnBr(CO)5] and tris(2-pyridylmethyl)amine (tpa) for the delivery of carbon monoxide to biological systems, with the κ3N binding mode of the tetradentate tpa ligand demonstrated by X-ray crystallography. The title compound is a CORM prodrug stable in solution in the dark for up to 16 h. However, photoactivation at 365 nm leads to CO release from the metal coordination sphere and transfer to haem proteins, as demonstrated by the standard myoglobin assay. Different iCORM intermediates could be detected with solution IR spectroscopy and assigned using DFT vibrational calculations. The antibacterial activity of the complex was studied on Escherichia coli. No effects were observed when the cultures were either kept in the dark in the presence of PhotoCORM or illuminated in the absence of metal complex. However, photoactivation of [Mn(CO)3(tpa-κ3N)]Br at 365 nm led to the appearance of the spectral signatures of CO-coordinated haems in the terminal oxidases of the bacterial electron transport chain in whole-cell UV/Vis absorption spectra. Significant internalization of the PhotoCORM was demonstrated by ICP-MS measurement of the intracellular manganese concentration. In particular when using medium with succinate as the sole carbon source, a very pronounced and concentration-dependent decrease in the E. coli growth rate could be observed upon illumination in the presence of metal complex, which is attributed to the constrained energy metabolism under these conditions and a strong indicator of terminal oxidase inhibition by carbon monoxide delivered from the PhotoCORM.
Co-reporter:Anna-Maria Pütz, Ulrich Schatzschneider and Eva Rentschler
Physical Chemistry Chemical Physics 2012 - vol. 14(Issue 5) pp:NaN1653-1653
Publication Date(Web):2011/12/20
DOI:10.1039/C2CP23063A
The stability of the α-nitronyl nitroxide radical unit under acidic conditions is investigated by an integrated experimental UV/Vis spectroscopy and TDDFT study. In the field of molecular magnetism, α-nitronyl nitroxide radicals are important as purely organic spin carriers due to their synthetic versatility. Here, the existence of an intermediate of the protonated α-nitronyl nitroxide radical unit is demonstrated for the first time and a proposed disproportionation reaction is confirmed.
Co-reporter:Lucas Henry, Christoph Schneider, Benedict Mützel, Peter V. Simpson, Christoph Nagel, Katharina Fucke and Ulrich Schatzschneider
Chemical Communications 2014 - vol. 50(Issue 99) pp:NaN15695-15695
Publication Date(Web):2014/10/23
DOI:10.1039/C4CC07892F
The catalyst-free room temperature iClick reaction of an unsymmetrically 2,3-disubstituted oxanorbornadiene (OND) as a “masked” alkyne equivalent with [Mn(N3)(bpyCH3,CH3)(CO)3] leads to isolation of a phenylalanine ester bioconjugate, in which the model amino acid is linked to the metal moiety via a N-2-coordinated triazolate formed in a cycloaddition-retro-Diels–Alder (crDA) reaction sequence, in a novel approach to bioorthogonal coupling reactions based on metal-centered reactivity.
Co-reporter:G. Dördelmann, Thomas Meinhardt, Thomas Sowik, Anke Krueger and Ulrich Schatzschneider
Chemical Communications 2012 - vol. 48(Issue 94) pp:NaN11530-11530
Publication Date(Web):2012/10/09
DOI:10.1039/C2CC36491C
The copper-catalyzed 1,3-dipolar azide–alkyne cycloaddition (CuAAC) was used for the first time to attach a biologically active carbon monoxide delivery agent to modified nanodiamond (ND) as a highly biocompatible carrier. The [Mn(CO)3(tpm)]+ photoactivatable CO-releasing molecule (PhotoCORM) on the surface retained the carbon monoxide release properties of the parent compound as shown with the myoglobin assay.
