Anticancer activity of the synthetic kusunokinin analogues on human cancer cell lines

Abstract

The series of racemic kusunokinin derivatives were synthesized and their cytotoxic activities and cell viability on cancer cells including breast cancer (MCF-7, MDA-MB468), colon cancer (HT-29), cholangiocarcinoma (KKU-M213) and ovarian cancer (A2780) cells were investigated. The results showed that compounds 6aa, 6da, and 6de exhibited growth inhibition against breast cancer (MDA-MB468), cholangiocarcinoma (KKU-M213), colon cancer (HT-29), and ovarian cancer (A2780) cells with IC50 values (μM) 13.77 ± 0.38, 7.94 ± 0.45, and 4.22 ± 0.13 (MDA-MB468); 4.21 ± 0.21, 0.97 ± 0.03, and 0.09 ± 0.02 (KKU-M213); 22.66 ± 0.23, and 15.62 ± 0.06 (HT-29); 13.11 ± 0.37, 11.51 ± 0.43, and 1.87 ± 0.01 (A2780); respectively. Interestingly, a positive control, doxorubicin, showed less cytotoxicity than 6da and 6de on cholangiocarcinoma KKU-M213 and ovarian cancer A2780 cells. Moreover, these three synthetic compounds also exhibited less toxicity than doxorubicin on the normal cells, MMNK-1, Vero and L-929. The binding possibility towards CSF1R, 6de (−11.59 kcal/mol) and trans-(−)-kusunokinin (−11.75 kcal/mol) were similar in both docking energies and docking poses. 6de interacted with Trp550 via π-π stacking in the similar manner with trans-(−)-kusunokinin and trans-(+)-kusunokinin.