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4-(吡唑基)苯磺酰胺脲类作为碳酸酐酶抑制剂和低氧介导的结直肠癌细胞化疗增敏剂。

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

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia Street, Alexandria 21648, Egypt.

出版信息

J Med Chem. 2024 Nov 28;67(22):20438-20454. doi: 10.1021/acs.jmedchem.4c01894. Epub 2024 Nov 17.

DOI:10.1021/acs.jmedchem.4c01894
PMID:39550697
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11613454/
Abstract

Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases (CA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas () were developed and evaluated for their inhibitory activity against CA IX and XII. They showed promising results (CA IX: = 15.9-67.6 nM, CA XII: = 16.7-65.7 nM). Particularly, demonstrated outstanding activity (s = 15.9 nM for CA IX and 55.2 nM for CA XII) and minimal off-target kinase inhibition over a panel of 258 kinases. In NCI anticancer screening, exhibited broad-spectrum activity with an effective growth inhibition full panel GI (MG-MID) value of 3.5 μM and a subpanel GI (MG-MID) range of 2.4-6.3 μM. Furthermore, 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.

摘要

肿瘤中的缺氧会导致化疗耐药，而碳酸酐酶（CAIX 和 CAXII）驱动的酸中毒会使情况恶化。针对这些酶可以减轻酸中毒，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)苯磺酰胺脲类化合物 ()，并评估了它们对 CAIX 和 CAXII 的抑制活性。结果表明，它们具有较好的抑制活性（CAIX： = 15.9-67.6 nM，CAXII： = 16.7-65.7 nM）。特别是化合物 表现出突出的活性（CAIX 的 s = 15.9 nM，CAXII 的 s = 55.2 nM），对 258 种激酶的靶外激酶抑制作用最小。在 NCI 抗癌筛选中， 表现出广谱活性，全谱 GI（MG-MID）值为 3.5 μM，亚谱 GI（MG-MID）值为 2.4-6.3 μM。此外， 在 HCT-116 结直肠癌细胞缺氧条件下与紫杉醇和 5-氟尿嘧啶联合治疗时，增强了它们的疗效，表明其具有作为有前途的抗癌药物的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/4e5888d73a67/jm4c01894_0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/06fccc68f6d7/jm4c01894_0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/4e5888d73a67/jm4c01894_0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/5fe4e18438bb/jm4c01894_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/784d40d0ae5c/jm4c01894_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/6d215e1bc156/jm4c01894_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/e4292e11cfe0/jm4c01894_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/06fccc68f6d7/jm4c01894_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/bdd6b291fa69/jm4c01894_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f749/11613454/4e5888d73a67/jm4c01894_0007.jpg

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