Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents

• DOI: 10.1016/j.ejmech.2018.10.068
• Publication Date: 2018-11-02T18:12:43Z
• Authors: Wagdy M. Eldehna; Mahmoud F. Abo-As...; Alessio Nocentini; Radwan S. El-Haggar; Silvia Bua; Alessandro Bonardi; Sara T. Al-Rashood; Ghada S. Hassan; Paola Gratteri; Hatem A. Abdel-Aziz; Claudiu T. Supuran
• Keywords: Isatin; 0301 basic medicine; Sulfonamides; Binding Sites; Phenylurea Compounds; Anticancer activity; Selective hCA IX and XII inhibitors; SLC-0111 hybrids; Tail approach; VEGFR-2 inhibitors; Antineoplastic Agents; Apoptosis; Binding Sites; Carbonic Anhydrase IX; Carbonic Anhydrase Inhibitors; Catalytic Domain; Cell Cycle; Cell Line, Tumor; Humans; Hydrophobic and Hydrophilic Interactions; Isatin; Molecular Docking Simulation; Phenylurea Compounds; Protein Binding; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Cell Cycle; Antineoplastic Agents; Apoptosis; Vascular Endothelial Growth Factor Receptor-2; Molecular Docking Simulation; 03 medical and health sciences; Catalytic Domain; Cell Line, Tumor; Humans; Carbonic Anhydrase IX; Carbonic Anhydrase Inhibitors; Hydrophobic and Hydrophilic Interactions; Protein Binding

Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7-86.1 nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192-239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC50 = 7.43 ± 0.28 and 12.90 ± 0.34 μM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents.