Design, synthesis, and molecular modeling of quinoline-based derivatives as anti-breast cancer agents targeting EGFR/AKT signaling pathway

Two series of quinoline-thiazole and quinoline-thiazolidinone hybrids were designed, synthesized, and evaluated for their in vitro antitumor activity on MCF-7 breast cancer cell line. In comparison with lapatinib (IC50 = 4.69 mu M), compounds 4b and 6b exhibited the best antiproliferative activity with IC50 values of 33.19 and 5.35 mu M, respectively. Although compound 6b showed higher cytotoxicity, compound 4b exhibited better inhibitory activity toward the epidermal growth factor receptor (EGFR) pathway than compound 6b as represented by the significant reduction in the EGFR kinase activity and the levels of phosho-EGFR and phosho-AKT when compared to lapatinib as a reference standard. Moreover, compound 4b was capable of down-regulating the anti-apoptotic genes Bcl-2 and survivin and up-regulating the level of the pro-apoptotic gene BAX. Molecular modeling study was carried out to predict the binding interactions of both compounds into the target kinase. Finally, the physicochemical properties were investigated in silico as well.

Automated summary

Two series of quinoline-thiazole and quinoline-thiazolidinone hybrids were synthesized and evaluated for their in vitro antitumor activity. Compound 4b and 6b showed better antiproliferative activity than lapatinib, with compound 4b also exhibiting better inhibitory activity towards the EGFR pathway. Compound 4b was capable of down-regulating anti-apoptotic genes and up-regulating a pro-apoptotic gene.