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

  • Eur J Med Chem. 2020 Aug 15;200:112449. doi: 10.1016/j.ejmech.2020.112449.
Aiten M Soliman  1 ,  Mostafa M Ghorab  2 ,  Silvia Bua  3 ,  Claudiu T Supuran  4
Affiliations
  • 1. Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City P.O. Box 29, Cairo, 11765, Egypt.
  • 2. Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City P.O. Box 29, Cairo, 11765, Egypt. Electronic address: [email protected].
  • 3. University of Florence, NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.
  • 4. University of Florence, NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy. Electronic address: [email protected].
PMID: 32485534 DOI: 10.1016/j.ejmech.2020.112449
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.

Keywords
Benzenesulfonamide; Carbonic anhydrase inhibitors; Cytotoxicity; Docking; Quinazolinone.
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