Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors

Moataz A Shaldam; Hadia Almahli; Andrea Angeli; Rehab Mustafa Badi; Eman F Khaleel; Abdelrahman I Zain-Alabdeen; Zainab M Elsayed; Eslam B Elkaeed; Rofaida Salem; Claudiu T Supuran; Wagdy M Eldehna; Haytham O Tawfik

doi:10.1080/14756366.2023.2203389

Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2203389. doi: 10.1080/14756366.2023.2203389.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
² Department of Chemistry, University of Cambridge, Cambridge, UK.
³ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Italy.
⁴ Department of Medical Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
⁶ Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh Uinversity, Kafrelsheikh, Egypt.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁸ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁹ School of Biotechnology, Badr University in Cairo, Badr City, Egypt.

Abstract

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

Keywords: Synthesis; VEGFR-2 inhibitors; antitumor agents; biological activities; molecular dynamics.

MeSH terms

Antigens, Neoplasm / metabolism
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases* / metabolism
Isatin* / chemistry
Isatin* / pharmacology
Molecular Structure
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology
Vascular Endothelial Growth Factor Receptor-2

Substances

Carbonic Anhydrases
Isatin
Vascular Endothelial Growth Factor Receptor-2
Antineoplastic Agents
Sulfonamides
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase IX
Antigens, Neoplasm

Grants and funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through Large Group Research Project under grant number (RGP2/321/44). The authors extend their appreciation to the Research Center at AlMaarefa University for funding this work.