Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as H-1 and C-13 NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 mu M against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 mu M and 8.71 mu M, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 mu M and 13.85 mu M, respectively. Interestingly, another compound 6af (IC50 = 2.61 mu M) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 mu M) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.

Automated summary

A library of bile-acid-appended triazolyl aryl ketones was synthesized and evaluated for cytotoxicity against human breast adenocarcinoma and mouse mammary carcinoma cells. Two compounds, 6cf and 6af, showed potent anticancer activity with no toxicity to normal cells, making them potential candidates for the development of anticancer agents.