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Saidbakhrom Saidjalolov Dr. Zainab Edoo Dr. Matthieu Fonvielle Louis Mayer Dr. Laura Iannazzo Dr. Michel Arthur Prof. Dr. Mélanie Etheve-Quelquejeu Dr. Emmanuelle Braud 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(10):3542-3551
The carbapenem class of β-lactams has been optimized against Gram-negative bacteria producing extended-spectrum β-lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d -transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β-lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido-carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems. 相似文献
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This study aims to measure the oxidative status of LDL from human plasma (n=26) as assessed by biomarkers for lipid peroxidation, total hydroxyoctadecadienoic acid (tHODE), 7alpha- and 7beta-hydroxycholesterol (t7-OHCh), and 8-iso-prostaglandin F(2alpha) (t8-iso-PGF(2alpha)) after subfractionation of LDL with an anion-exchange HPLC (AE-HPLC). LDL was separated and quantified by AE-HPLC as LDL-1, LDL-2, and LDL-3 in the order of the anionic charge of the LDL particles. The concentrations of tHODE, t7-OHCh, and t8-iso-PGF(2alpha) in both plasma and LDL subfractions were assessed after reduction and saponification. In this method, the free and ester forms of hydroperoxides, ketones, and hydroxides of linoleic acid and cholesterol are measured as tHODE and t7-OHCh, respectively. It was found that tHODE significantly correlated with the proportion of LDL-2 and LDL-3 as well as with the concentration of malondialdehyde-modified LDL in plasma. Further, by the analyses of LDL subfractions, the concentrations of tHODE, t8-iso-PGF(2alpha), and t7-OHCh in LDL-3 were found to be significantly higher than those in LDL-1 and LDL-2. These results clearly indicate that the extent of oxidation increases in the order of LDL-1相似文献
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Leveraging γ‐Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells 下载免费PDF全文
Dr. Subha Bakthavatsalam Dr. Mark L. Sleeper Azim Dharani Dr. Daniel J. George Dr. Tian Zhang Katherine J. Franz 《Angewandte Chemie (International ed. in English)》2018,57(39):12780-12784
A prodrug approach is presented to direct copper‐dependent cytotoxicity to prostate cancer cells. The prochelator GGTDTC requires activation by γ‐glutamyl transferase (GGT) to release the metal chelator diethyldithiocarbamate from a linker that masks its thiol reactivity and metal binding properties. In vitro studies demonstrated successful masking of copper binding as well as clean liberation of the chelator by GGT. GGTDTC was stable to non‐specific degradation when incubated with a series of prostate cancer and normal cell lines, with selective release of diethyldithiocarbamate only occurring in cells with measurable GGT activity. The antiproliferative efficacy of the prochelator correlated with cellular GGT activity, with 24 h inhibitory concentrations ranging from 800 nm in prostate cancer lines 22Rv1 and LNCaP to over 15 μm in normal prostate PWR‐1E cells. These findings underscore a new strategy to leverage the amplified copper metabolism of prostate cancer by conditional activation of a metal‐binding pharmacophore. 相似文献
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Bunta Watanabe Tatsuya Morikita Yukiko Tabuchi Ryoto Kobayashi Chunjie Li Masakazu Yamamoto Takao Koeduka Jun Hiratake 《Tetrahedron letters》2017,58(38):3700-3703
A previously reported synthetic route to 2-amino-4-{[3-(carboxymethyl)phenoxy](methoxy)phosphoryl}butanoic acid (GGsTop), a potent, highly selective, non-toxic, and irreversible inhibitor of γ-glutamyl transpeptidase (GGT) was substantially improved. This route furnishes GGsTop in four steps with an overall yield of 32% from inexpensive starting materials, i.e., the yield is increased approximately sixfold relative to the previous protocol. The synthesis and inhibitory activity evaluation of potential hydrolysis products of GGsTop clearly demonstrated that GGsTop is the active inhibitor, and the conceivable hydrolysis products barely affect the activity of human GGT. 相似文献
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《Analytical letters》2012,45(16):1863-1876
Abstract The electrochemical activity determination of γ-glutamyl-transpeptidase is described using the electrogenic L-γ-glutamyl paraaminodiphenylamide substrate. In order to correlate the results with classical measurements involving chromogenic substrates, linear calibration curves for the amperometric detection of the released free amine, the kinetics of the catalysis and the enzyme level in one plasma sample have been compared to photometric experiments effectuated in parallel runs, in the same conditions, with L-y-glutamyl paranitroanilide as the substrate. Results show that this new technique applies successfully to such evaluations. 相似文献
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Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized 13C‐Labeled Molecular Probe 下载免费PDF全文
Dr. Tatsuya Nishihara Dr. Hikari A. I. Yoshihara Dr. Hiroshi Nonaka Dr. Yoichi Takakusagi Dr. Fuminori Hyodo Prof. Dr. Kazuhiro Ichikawa Emine Can Dr. Jessica A. M. Bastiaansen Dr. Yuhei Takado Prof. Dr. Arnaud Comment Prof. Dr. Shinsuke Sando 《Angewandte Chemie (International ed. in English)》2016,55(36):10626-10629
The γ‐glutamyl transpeptidase (GGT) enzyme plays a central role in glutathione homeostasis. Direct detection of GGT activity could provide critical information for the diagnosis of several pathologies. We propose a new molecular probe, γ‐Glu‐[1‐13C]Gly, for monitoring GGT activity in vivo by hyperpolarized (HP) 13C magnetic resonance (MR). The properties of γ‐Glu‐[1‐13C]Gly are suitable for in vivo HP 13C metabolic analysis since the chemical shift between γ‐Glu‐[1‐13C]Gly and its metabolic product, [1‐13C]Gly, is large (4.3 ppm) and the T1 of both compounds is relatively long (30 s and 45 s, respectively, in H2O at 9.4 T). We also demonstrate that γ‐Glu‐[1‐13C]Gly is highly sensitive to in vivo modulation of GGT activity induced by the inhibitor acivicin. 相似文献
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