Oxindole–Coumarin Hybrids With Broad-Spectrum Anticancer Activity: Apoptosis Induction and Selective CA IX/XII Targeting

Abstract

A scaffold hybridization approach was utilized to enhance the antitumor and carbonic anhydrase inhibitory activity of our oxindole and coumarin lead compounds (V and X). Two oxindole-coumarin hybrids 6c and 6e showed broad spectrum of anticancer activity with NCI full panel MG-MIDs of 5.01 and 6.31 µM, respectively. They revealed GI₅₀ of a single digit micromolar concentration against 46 and 39 cell lines, respectively. An apoptosis dependent mechanism is suggested for the potent anticancer activity of compounds 6c and 6e via the increase in the BAX/BCL-2 ratio and enhancement of the expression levels of caspase-9 and the tumor suppressor p53. While this structure hybridization resulted in enhanced antitumor activity, it resulted in moderate CA IX and XII inhibitory activity. The potent anticancer compound 6e was among the most active inhibitors of the tumor associated CA IX and CA XII in this study (K_I = 1.8 and 2.1 μM, respectively). As a result, even compound 6e's moderate CA IX/XII inhibitory activity may have synergistic effects contributing to its increased tumor growth suppression and proapoptotic activity. Moreover, compound 6e revealed a nonsignificant cytotoxicity toward the normal kidney epithelial Vero cell line and was totally inactive against the cytosolic isoforms CA I and CA II (K_I = > 100 μM) which mitigate its side effect as chemotherapeutic agent and enforce its safety profile.