Davide Moi*, Serena Vittorio, Andrea Angeli, Claudiu T. Supuran and Valentina Onnis,
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引用次数: 0
摘要
研究人员设计、合成了一系列由取代的哌嗪/苄胺衍生的 1-(4-磺酰胺基苯甲酰基)哌啶-4-甲酰胺,并对人碳酸酐酶(hCA)进行了测试。以乙酰唑胺(AAZ)作为标准抑制剂,分析了新型磺酰胺类化合物对 hCA I、II、IX 和 XII 的抑制活性。几种磺酰胺类药物在低纳摩尔浓度下均表现出抑制活性,并对细胞质 hCA II 异构体具有选择性,对肿瘤相关的 hCA IX 和 XII 也表现出同样的趋势。苯磺酰胺基羧酰胺 11 和 15 分别是哌嗪基和苄氨基系列中药效最强的。对接和分子动力学研究表明,化合物 11 对肿瘤相关 hCA 异构体的高选择性与其能够参与 hCA IX 和 hCA XII 活性位点内的有利相互作用有关,而在 hCA I 和 hCA II 异构体内则未检测到此类相互作用。
Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors
A series of 1-(4-sulfamoylbenzoyl)piperidine-4-carboxamides deriving from substituted piperazines/benzylamines was designed, synthesized, and tested on human carbonic anhydrase (hCA). The inhibitory activity of the new sulfonamides was analyzed using acetazolamide (AAZ) as a standard inhibitor against hCA I, II, IX, and XII. Several sulfonamides showed both inhibitory activity at low nanomolar concentrations and selectivity against the cytosolic hCA II isoform, and the same trend was observed on the tumor-associated hCA IX and XII. The benzenesulfonamido carboxamides 11 and 15 were the most potent of the piperazino- and benzylamino-based series, respectively. Docking and molecular dynamics studies related the high selectivity of compound 11 toward the tumor-associated hCA isoforms to its capability to participate in favorable interactions within hCA IX and hCA XII active sites, whereas no such interactions were detected within both hCA I and hCA II isoforms.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.