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排序方式: 共有290条查询结果,搜索用时 15 毫秒
1.
Samuel K Yin W Stearns RA Tang YS Chaudhary AG Jewell JP Lanza T Lin LS Hagmann WK Evans DC Kumar S 《Journal of mass spectrometry : JMS》2003,38(2):211-221
Metabolic activation of drug candidates to electrophilic reactive metabolites that can covalently modify cellular macromolecules may result in acute and/or idiosyncratic immune system-mediated toxicities in humans. This presents a significant potential liability for the future development of these compounds as safe therapeutic agents. We present here an example of an approach where sites of metabolic activation within a new drug candidate series were rapidly identified using online liquid chromatography/multi-stage mass spectrometry on an ion trap mass spectrometer. This was accomplished by trapping the reactive intermediates formed upon incubation of compounds with rat and human liver microsomes as their corresponding glutathione conjugates and mass spectral characterization of these thiol adducts. Based on the structures of the GSH adducts identified, potential sites and mechanisms of bioactivation within the chemical structure were proposed. These metabolism studies were interfaced with iterative structural modifications of the chemical series in order to block these bioactivation sites within the molecule. This strategy led to a significant reduction in the propensity of the compounds to undergo metabolic activation as evidenced by reductions in the irreversible binding of radioactivity to liver microsomal material upon incubation of tritium-labeled compounds with this in vitro system. With the efficiency and throughput achievable with such an approach, it appears feasible to identify and address the metabolic activation potential of new drug leads during routine metabolite identification studies in an early drug discovery setting. 相似文献
2.
E. V. Zhernosek S. V. Kvach L. A. Eroshevskaya E. N. Kalinichenko A. I. Zinchenko 《Chemistry of Natural Compounds》2006,42(2):208-211
Previously undescribed conjugates of 2′,3′-dideoxyuridine-5′-monophosphate-(L)-methoxytryptophylphosphoramidate (5) and 2′,3′-dideoxycytidine-5′-monophosphate-(L)-methoxytryptophylphosphoramidate (7) were isolated by a chemical enzymatic method in order to study their pharmacological properties and to prepare new medicinal
preparations based on them.
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Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 173–175, March–April, 2006. 相似文献
3.
Kuuranne T Kotiaho T Pedersen-Bjergaard S Einar Rasmussen K Leinonen A Westwood S Kostiainen R 《Journal of mass spectrometry : JMS》2003,38(1):16-26
Anabolic androgenic steroids (AAS) are metabolized extensively in the human body, resulting mainly in the formation of glucuronide conjugates. Current detection methods for AAS are based on gas chromatographic/mass spectrometric (GC/MS) analysis of the hydrolyzed steroid aglycones. These analyses require laborious sample preparation steps and are therefore time consuming. Our interest was to develop a rapid and straightforward method for intact steroid glucuronides in biological samples, using liquid-phase microextraction (LPME) sample clean-up and concentration method combined with liquid chromatographic/tandem mass spectrometric (LC/MS/MS) analysis. The applicability of LPME was optimized for 13 steroid glucuronides, and compared with conventional liquid-liquid extraction (LLE) and solid-phase extraction (SPE) procedures. An LC/MS/MS method was developed for the quantitative detection of AAS glucuronides, using a deuterium-labeled steroid glucuronide as the internal standard. LPME, owing to its high specificity, was shown to be better suited than conventional LLE and SPE for the clean-up of urinary AAS glucuronides. The LPME/LC/MS/MS method was fast and reliable, offering acceptable reproducibility and linearity with detection limits in the range 2-20 ng ml(-1) for most of the selected AAS glucuronides. The method was successfully applied to in vitro metabolic studies, and also tested with an authentic forensic urine sample. For a urine matrix the method still has some unsolved problems with specificity, which should be overcome before the method can be reliably used for doping analysis, but still offering additional and complementary data for current GC/MS analyses. 相似文献
4.
Oligonucleotides modified by a 2′-deoxy-2′-(N-methoxyamino) ribonucleotide react readily with aldehydes in slightly acidic conditions to yield the corresponding N-(methoxy)oxazolidine-linked oligonucleotide-conjugates. The reaction is reversible and dynamic in slightly acidic conditions, while the products are virtually stable above pH 7, where the reaction is in a ‘‘switched off-state’’. Small molecular examinations have demonstrated that aldehyde constituents affect the cleavage rate of the N-(methoxy)oxazolidine-linkage. This can be utilized to adjust the stability of this pH-responsive cleavable linker for drug delivery applications. In the present study, Fmoc-β-Ala-H was immobilized to a serine-modified ChemMatrix resin and used for the automated assembly of two peptidealdehydes and one aldehyde-modified peptide nucleic acid (PNA). In addition, a triantennary N-acetyl-d-galactosamine-cluster with a β-Ala-H unit has been synthesized. These aldehydes were conjugated via N-(methoxy)oxazolidine-linkage to therapeutically relevant oligonucleotide phosphorothioates and one DNA-aptamer in 19–47% isolated yields. The cleavage rates of the conjugates were studied in slightly acidic conditions. In addition to the diverse set of conjugates synthesized, these experiments and a comparison to published data demonstrate that the simple conversion of Gly-H to β-Ala-H residue resulted in a faster cleavage of the N-(methoxy)oxazolidine-linker at pH 5, being comparable (T0.5 ca 7 h) to hydrazone-based structures. 相似文献
5.
6.
7.
The carbon-13 chemical shifts of seven N-(4-substituted phenyl) piperidine; the corresponding N-oxides, and their thermal rearrangement products were analyzed and assigned. The N-oxidation effect on the carbon-13 chemical shift is discussed, a correlation of N-oxidation effect with substituent constant (σp, σm, σI and σR) has been studied; dual substituent-parameter equation produce better correlation. 相似文献
8.
Dr. Kaveh Matinkhoo Antonio A. W. L. Wong Dr. Chido M. Hambira Brandon Kato Charlie Wei Dr. Christoph Müller Dr. Torsten Hechler Dr. Alexandra Braun Dr. Francesca Gallo Dr. Andreas Pahl Prof. David M. Perrin 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(40):10282-10292
Alpha-amanitin, an extremely toxic bicyclic octapeptide extracted from the death-cap mushroom, Amanita phalloides, is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody-drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans-hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp-analogs to alter the conformational and H-bonding properties of Hyp in amanitin. 相似文献
9.
Oriol Porcar-Tost Bernat Pi-Boleda Jordi García-Anton Ona Illa Rosa M. Ortuño 《Tetrahedron》2018,74(51):7252-7260
Two new conjugates, hcptpyDP and hcptpyTP, of a terpyridine derivative incorporating artificial peptide moieties, have been synthesized and their use in the preparation of metal catalysts and organogelators has been investigated. Ru(II) complexes derived from these ligands showed electrochemical behavior and activity as catalysts in the epoxidation of olefins similar to that of Beller's catalyst. As organogelators, these conjugates were able to gelate a variety of solvents, from toluene to methanol, with satisfactory mgc (minimum gelation concentration) values. The presence of 4′-(4-carboxy)phenylterpyridine (hcptpy) moiety allows tuning the gelling properties and also influences the supramolecular self-assembling mode to produce chiral aggregates with respect to parent peptides DP and TP. In the case of the conjugates, π?π interactions provided by the aromatic moieties cooperate with inter-molecular hydrogen bonding between NH and CO in the amide groups. Further properties of peptide/terpyridine conjugates are under investigation in view of future applications. 相似文献
10.
Nikolaus Krall Dr. Jörg Scheuermann Prof. Dario Neri 《Angewandte Chemie (International ed. in English)》2013,52(5):1384-1402
The targeted delivery of potent cytotoxic agents has emerged as a promising strategy for the treatment of cancer and other serious conditions. Traditionally, antibodies against markers of disease have been used as drug‐delivery vehicles. More recently, lower molecular weight ligands have been proposed for the generation of a novel class of targeted cytotoxics with improved properties. Advances in this field crucially rely on efficient methods for the identification and optimization of organic molecules capable of high‐affinity binding and selective recognition of target proteins. The advent of DNA‐encoded chemical libraries allows the construction and screening of compound collections of unprecedented size. In this Review, we survey developments in the field of small ligand‐based targeted cytotoxics and show how innovative library technologies will help develop the drugs of the future. 相似文献