4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI:10.1021/acs.jmedchem.4c01894

Wagdy M Eldehna, Mohamed Fares, Alessandro Bonardi, Moscos Avgenikos, Fady Baselious, Matthias Schmidt, Tarfah Al-Warhi, Hatem A Abdel-Aziz, Robert Rennert, Thomas S Peat, Claudiu T Supuran, Ludger A Wessjohann, Hany S Ibrahim

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引用次数: 0

Abstract

Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases (hCA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas (SH7a-t) were developed and evaluated for their inhibitory activity against hCA IX and XII. They showed promising results (hCA IX: K_I = 15.9-67.6 nM, hCA XII: K_I = 16.7-65.7 nM). Particularly, SH7s demonstrated outstanding activity (K_Is = 15.9 nM for hCA IX and 55.2 nM for hCA XII) and minimal off-target kinase inhibition over a panel of 258 kinases. In NCI anticancer screening, SH7s exhibited broad-spectrum activity with an effective growth inhibition full panel GI₅₀ (MG-MID) value of 3.5 μM and a subpanel GI₅₀ (MG-MID) range of 2.4-6.3 μM. Furthermore, SH7s enhanced the efficacy of Taxol and 5-fluorouracil in cotreatment regimens under hypoxic conditions in HCT-116 colorectal cancer cells, indicating its potential as a promising anticancer agent.

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4-(吡唑基)苯磺酰胺脲类作为大肠癌细胞的碳酸酐酶抑制剂和缺氧介导的化疗增敏剂

肿瘤缺氧会导致化疗耐药性，而碳酸酐酶（hCA IX 和 XII）导致的酸中毒又会加重肿瘤缺氧。靶向这些酶可以缓解酸中毒，从而提高肿瘤对细胞毒性药物的敏感性。本文开发了新型 4-(吡唑基)苯磺酰胺脲类（SH7a-t），并评估了它们对 hCA IX 和 XII 的抑制活性。它们显示出了良好的效果（hCA IX：KI = 15.9-67.6 nM，hCA XII：KI = 16.7-65.7 nM）。特别是，SH7s 在 258 种激酶中表现出卓越的活性（对 hCA IX 的 KI = 15.9 nM，对 hCA XII 的 KI = 55.2 nM）和最小的脱靶激酶抑制作用。在 NCI 抗癌筛选中，SH7s 表现出广谱活性，有效生长抑制全组 GI50（MG-MID）值为 3.5 μM，亚组 GI50（MG-MID）范围为 2.4-6.3 μM。此外，在HCT-116结直肠癌细胞的缺氧条件下，SH7s还能增强紫杉醇和5-氟尿嘧啶协同治疗方案的疗效，这表明它有潜力成为一种有前途的抗癌剂。

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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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.