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

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.

Synthesis and anticancer activity of new benzensulfonamides incorporating s-triazines as cyclic linkers for inhibition of carbonic anhydrase IX.

Limited presence of hCA IX in normal physiological tissues and their overexpression only in solid hypoxic tumors made this isoform excellent possible target for developing new anticancer agents. We reported designing and synthesis of two novel series of benzenesulfonamides derivatives as hCA IX inhibitors bearing rigid cyclic linkers (1,3,5-dihydrotriazine in series A and 1,3,5-triazine in series B) in replace of traditional linear linkers. Also, novel cyanoethenyl spacer was assembled next to the 1,3,5-triazine linker in series B. Target compounds of series (A) and (B) were screened against four hCA isoforms. Human CA IX efficiently inhibited in series (A) by compound 5a (KI = 134.8 nM). Meanwhile, in series (B) the most active inhibitor was 12i (KI = 38.8 nM). US-NCI protocol was followed to evaluate the anticancer activity of target compounds against panel of sixty cancer cell lines. Compound 12d, exposed the best activity towards breast cancer (MDA-MB-468) with GI% = 62%. The most active analogues, 12d and 12i were further screened for in vitro cytotoxic activity under hypoxic condition against breast cancer (MDA-MB-468) (IC50 = 3.99 ± 0.21 and 1.48 ± 0.08 µM, respectively) and leukemia (CCRF-CM) cell line (IC50 = 4.51 ± 0.24 and 9.83 ± 0.52 µM, respectively). In addition, 12d arrested breast cancer MDA-MB-468 cell cycle in G0-G1 and S phases and induced its apoptosis which indicated by increasing the level of cleaved caspases 3 and 9. Molecular docking was performed for selected analogues to understand their biological alterations. This study revealed that insertion of 1,3,5-triazines as cyclic linkers enhanced the significant anticancer and hCA IX inhibition activity of benzenesulfonamides.