Sonochemical synthesis of rosuvastatin based novel 3-methyleneisoindolin-1-one derivatives as potential anticancer agents

Abstract

The Sonochemical synthesis of a library of 3-methyleneisoindolin-1-one based novel small molecules derived from rosuvastatin designed as potential anticancer agents was undertaken. A Cu-mediated coupling-cyclization strategy was employed to prepare this new class of compounds in a single pot with notable regioselectivity. The use of a terminal alkyne containing the propargylic ether moiety seemed to be responsible for the observed regioselectivity. Evaluation of all these compounds against three cancer cell lines e.g. HCT 116, HepG2 and PA-1 and a non-cancerous HEK cell line resulted in the identification of compound 3b as a promising cytotoxic agent with IC50 of 3.34 ± 0.38 and 1.16 ± 0.20 µM against HCT 116 and PA-1, respectively. In another study 3b showed significant decrease in p-Akt substrates (western blot analysis) indicating its ability to inhibit the p-Akt signal transduction pathway and arresting the growth of PANC-1 cells in vitro. Indeed, 3b showed better cytotoxic effect on PANC-1 cells over rosuvastatin (MTT assay). Notably, the lack of any significant effect of 3b on non-cancerous HEK cell line suggested its potential selectivity towards cancer cells. Further, a reasonable ADME (in silico) was predicted for 3b that showed acceptable stability against rat liver microsomes in vitro. The compound also showed acceptable NOAEL (No Observed Adverse Effect Level ~ 100 µM) for teratogenicity and cardiotoxicity when evaluated for toxicities in Zebrafish embryo. Finally, unlike rosuvastatin the compound 3b did not show any lipid lowering effects in Zebrafish larvae. Overall, as a novel and promising but safer cytotoxic agent 3b could be useful for the potential treatment of colorectal / ovarian and pancreatic cancer.