新型 2,4-二氯-5-氨基磺酰基苯甲酸肟酯：作为潜在人体碳酸酐酶抑制剂的首次研究

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-23 DOI:10.1021/acsmedchemlett.4c00206

Jaydeo T. Kilbile, Suryakant B. Sapkal, Gioele Renzi, Ilaria D’Agostino, Luigi Cutarella, Mattia Mori, Barbara De Filippis, Imadul Islam, Maria Luisa Massardi, Elena Somenza, Roberto Ronca, Yasinalli Tamboli*, Fabrizio Carta* and Claudiu T. Supuran,

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引用次数: 0

摘要

在这项研究中，我们合成了一个含有希夫碱的 2,4-二氯-5-氨基磺酰基苯甲酸（lasamide）肟酯衍生物重点库，并在体外测试了它们抑制细胞质人碳酸酐酶（hCA）I 和 II 以及跨膜和肿瘤相关的 IX 和 XII 异构体的能力。因此，我们对有可能用作 CA 抑制剂（CAIs）的 Lasamide 衍生物有了初步的了解。我们特别关注了衍生物 11，它对 hCA IX 和 XII 的选择性高于细胞同工酶。我们进行了一项硅学研究，以评估 11 在 hCA IX 和 XII 中的结合模式。此外，抗增殖试验也突显了有前景的衍生物。这项研究获得的数据目前正用于开发针对肿瘤相关同工酶的性能更好的化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

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.