Design, synthesis and biological evaluation of novel carbohydrate-based sulfonamide derivatives as antitumor agents.

Abstract

A series of novel carbohydrate-based sulfonamides were designed and synthesized by the sugar-tail approach. The classical aromatic sulfonamide pharmacophore (ArSO2NH2) was directly linked to a hydrophilic sugar-tail moiety through a rigid 1, 2, 3-triazole linker by the click chemistry reaction. The inhibitory activity against three carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I, hCA II and hCA IX) of all new compounds so designed were investigated in vitro and efficient inhibition against all three CA isoforms, especially the tumor-associated hCA IX, were observed. These glycoconjugate sulfonamide derivatives displayed better inhibitory efficacy in comparison with the starting segments (SA and p-hydroxybenzene sulfonamide). In particular, compound 12g was found to be the most effective and rather selective inhibitor of hCA IX with inhibitory constant (IC50) value of 7 nM, being four times more potent than the clinical used agent acetazolamide (AAZ) (IC50 = 30 nM). Meanwhile, almost all compounds showed moderate antiproliferative activities against two cancer cell lines (HT-29 and MDA-MB-231) in both hypoxic and normoxic conditions while compound 12g also exhibited the most prominent antitumor activity. Furthermore, evident recovery (20-35% reduction of IC50 values) of cytotoxic efficiency of doxorubicin with the combination of compounds 12d, 12g and 22d as CAIs were detected on MDA-MB-231 cell line under hypoxic environment. In addition, docking studies revealed that the sugar-tail fragment of the target compounds participated in interactions with hydrophilic subpocket at the surface of hCA IX active site and supported the CA IX inhibitory activities of carbohydrate-based sulfonamide derivatives.

• Authors: Shuang Hao, Xue Cheng, Xin Wang, Ran An, Hang Xu, Mengbi Guo, Chuanchao Li, Yitong Wang, Zhuang Hou, Chun Guo
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 104 Pg. 104237 (11 2020) ISSN: 1090-2120 [Electronic] United States
• PMID: 32911194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Carbohydrates
• Carbonic Anhydrase Inhibitors
• Isoenzymes
• Sulfonamides
• Carbonic Anhydrases

Topics

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