Iodoquinazolinones bearing benzenesulfonamide as human carbonic anhydrase I, II, IX and XII inhibitors: Synthesis, biological evaluation and radiosensitizing activity.

Abstract

In the present work, we report the design and synthesis of a set of iodinated quinazolinones carrying benzenesulfonamide moiety as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The target compounds showed promising inhibitory activity against the four examined human (h) CA isoforms; I, II, IX and XII. Compounds 4-18 displayed variable inhibition constants, ranging as follows: 7.6-782.8 nM for hCA I, 34.4-412.1 nM for hCA II, 29.1-2225.3 nM for hCA IX and 8.8-429.4 nM for hCA XII. Compound 9, the most potent against the tumor-specific CA IX/CA XII (KI = 29.1 and 8.8 nM) gives the possibility to evaluate its cytotoxicity and selectivity in vitro against HepG-2, HCT-116 and MCF-7 cancer cell lines. Compound 9 showed significant cytotoxicity against the tumor cell lines (IC50 = 1.78, 1.94 and 3.07 μM, respectively) and relatively lower toxicity against WI38 normal cell line. The radiosensitizing activity of compound 9 was evaluated and displayed an increase in the radiation-induced cell death in cancer cells after receiving a single dose of 8 Gy gamma radiation. Thus, radiation was able to enhance the antiproliferative activity of compound 9. Molecular docking of 9 into the active site of CA IX and XII revealed the key interactions that could explain its potent activity and selectivity towards these isoforms.

• Authors: Aiten M Soliman, Mostafa M Ghorab, Silvia Bua, Claudiu T Supuran
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 200 Pg. 112449 (Aug 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32485534 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Carbonic Anhydrase Inhibitors
• Isoenzymes
• Radiation-Sensitizing Agents
• Sulfonamides
• benzenesulfonamide
• Carbonic Anhydrases

Topics

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