Discovery of novel artemisinin-sulfonamidehybrids as potential carbonicanhydraseIX inhibitors with improved antiproliferative activities.

Abstract

A series of artemisinin-sulfonamide hybrids (1-16) have been designed and synthesized by using molecular hybridization approach and investigated for the inhibitory activity of four human (h) carbonic anhydrases (CAs, EC 4.2.1.1), hCA I, II, IX and XII. The results indicated most of the target compounds showed better CA IX and CA XII inhibitory activity than the starting segment sulfanilamide. Among all the compounds, compound 3 (IC50: 5 nM) showed the best CA IX inhibitory efficacy. The p-aminobenzenesulfonamide derivatives showed significant antiproliferative activities against MDA-MB-231 breast cancer cell line and HT-29 colon cancer cell line under hypoxic conditions where CA IX and CA XII are overexpressed and most of them showed no apparent cytotoxic effects toward MCF-10A normal mammary epithelial cell. Among these derivatives, compound 3 displayed the most potent antiproliferative activities (IC50: 0.65 μM) against HT-29 cell line under hypoxia and low cytotoxicity (IC50: 78.0 μM) toward normal cell line. Meanwhile, compound 3 was found to efficiently decrease the hypoxia-induced extracellular acidification in both cancer cells. Molecular docking studies of compounds 3, 4, 5 and 9 revealed the proper interactions between the hybrid molecules and the active site of CA IX. All the results proved the effectiveness of the hybridization approach to develop novel artemisinin-sulfonamide compounds targeting CA IX for cancer treatment.

• Authors: Ran An, Bin Lin, Shuang Zhao, Chun Cao, Yuanxin Wang, Xue Cheng, Yichuang Liu, Mengbi Guo, Hang Xu, Yitong Wang, Zhuang Hou, Chun Guo
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 104 Pg. 104347 (11 2020) ISSN: 1090-2120 [Electronic] United States
• PMID: 33142414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• Artemisinins
• Carbonic Anhydrase Inhibitors
• Sulfonamides
• artemisinin
• CA9 protein, human
• Carbonic Anhydrase IX

Topics

• Antigens, Neoplasm (metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Artemisinins (chemistry, pharmacology)
• Carbonic Anhydrase IX (antagonists & inhibitors, metabolism)
• Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• Hydrogen-Ion Concentration
• Molecular Docking Simulation
• Molecular Structure
• Structure-Activity Relationship
• Sulfonamides (chemistry, pharmacology)