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

Devesh S Agarwal,Samrat Mazumdar,Kishan S Italiya,Deepak Chitkara,Rajeev Sakhuja

doi:10.3390/molecules26195741

Devesh S Agarwal, Samrat Mazumdar + Show 3 more

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https://doi.org/10.3390/molecules26195741

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Abstract

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM 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 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) 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.

Highlights

From the outset of the proposed work, the synthesis of targeted bile-acid-appended triazolyl aryl ketones commenced with the preparation of cholic acid and deoxycholic acid triazolyl aryl ketones commenced with the preparation of cholic acid and deoxycholic acid propargyl esters (4a,b) and amides (4c,d) by coupling cholic acid (1a)/deoxycholic acid propargyl esters (4a,b) and amides (4c,d) by coupling cholic acid (1a)/deoxycholic acid
We synthesized a series of cholic-acid- and deoxycholic-acid-appended triazolyl aryl ketones in excellent yields via a Cu-catalyzed multi-component approach
All the synthesized conjugates were evaluated for their cytotoxicity against human breast adenocarcinoma (MCF-7) and mouse mammary carcinoma (4T1) cells at 10 μM, which highlighted three conjugates (6af, 6bf, 6cf) displaying interesting anticancer activity with

Summary

Introduction

Cancer treatment procedures, such as hormone and radiation therapy, immunotherapy, combination chemotherapy and surgery, have been implemented to achieve reasonable success in this battle of mankind against cancer [7]

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