Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation

Mohamed A Said; Wagdy M Eldehna; Alessio Nocentini; Samar H Fahim; Alessandro Bonardi; Abdullah A Elgazar; Vladimír Kryštof; Dalia H Soliman; Hatem A Abdel-Aziz; Paola Gratteri; Sahar M Abou-Seri; Claudiu T Supuran

doi:10.1016/j.ejmech.2019.112019

Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation

Eur J Med Chem. 2020 Mar 1:189:112019. doi: 10.1016/j.ejmech.2019.112019. Epub 2020 Jan 2.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
³ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
⁵ Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
⁶ Laboratory of Growth Regulators, Palacky University & Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 78371, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinská 5, 77900, Olomouc, Czech Republic.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al Azhar University, Cairo, P.O. Box 11471, Egypt.
⁸ Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
⁹ Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
¹⁰ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt. Electronic address: sahar.shaarawy@pharma.cu.edu.eg.
¹¹ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 31972394
DOI: 10.1016/j.ejmech.2019.112019

Abstract

In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with K_Is ranges 6-67.6 and 10.1-88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC₅₀ = 6.4, 8.0 and 11.6 μM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.

Keywords: CAN508; CDK inhibitors; Imidazopyrazoles; Molecular docking; Pyrazolopyrimidines; carbonic anhydrase inhibitors.

Publication types

Evaluation Study

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Azo Compounds / chemistry*
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / chemistry*
Cell Proliferation
Drug Design*
Drug Screening Assays, Antitumor
Humans
In Vitro Techniques
Molecular Docking Simulation
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / pathology
Pyrazoles / chemistry*
Structure-Activity Relationship
Sulfonamides / chemistry

Substances

Antineoplastic Agents
Azo Compounds
CAN 508
Carbonic Anhydrase Inhibitors
Pyrazoles
Sulfonamides
Carbonic Anhydrases