New indolin-2-ones, possessing sunitinib scaffold as HDAC inhibitors and anti-cancer agents with potential VEGFR inhibition activity; design, synthesis and biological evaluation.

New series of indolin-2-ones possessing sunitinib scaffold and a hydroxamic acid moiety were designed and synthesized as inhibitors of HDAC, demonstrating significant anti-cancer properties with potential VEGFR inhibition, using sunitinib and vorinostat as the lead compounds. The newly synthesized compounds incorporate the sunitinib framework along with functional groups derived from vorinostat, thus they can be named the rigid analogs of vorinostat. The cytotoxic effects of these compounds were assessed against two cancer cell lines, HCT116 (human colon cancer) and HT29 (human colon adenocarcinoma), as well as NIH (a normal fibroblast cell line). A majority of the compounds displayed notable cytotoxicity towards HT-29 and HCT-116, with IC50 values ranging from 1.78 to 38.54 µM notably, compound 13c exhibited the highest anti-proliferative effect against HT-29, with an IC50 of 1.78 µM, comparable to or exceeding that of the reference drugs, sunitinib and vorinostat. This compound reduced the expression levels of VEGFR-2 and phosphorylated VEGFR-2 (pVEGFR-2) by approximately 80 % and inhibited the HDAC1 enzyme (IC50 = 1.07 µM), indicating its anticancer activity through the targeting of these enzymes. Further cellular mechanism investigations revealed that compound 13c induced substantial apoptosis in HCT-116 cells, with a total apoptotic cell percentage of 41.1 % in treated cells (2.59 µM), compared to negative control (3.68 %)). The CAM assay also indicated that 13c possesses antiangiogenic property similar to that of sunitinib. Additionally, a molecular docking simulation supported the initial design strategy and suggested a common mode of interaction of compound 13c at the binding sites of VEGFR-2 and HDAC1. These findings suggested that 13c could be as a promising lead targeting VEGFR-2 and HDAC1. Therefore, it deserved further investigation for cancer treatment.