Synthesis and cytotoxic activity of a series of bile acid derivatives

Ksenija Kuhajda,Vesna Kojic,Evgenija Djurendic,Gordana Bogdanovic,Katarina Penov-Gasi,Marija Sakac,Stanko Cvjeticanin

doi:10.2298/hemind0904313k

Ksenija Kuhajda, Vesna Kojic + Show 5 more

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https://doi.org/10.2298/hemind0904313k

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Abstract

The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized. The conjugation reaction was carried out in ethyl acetate in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) and triethylamine. Under the same experimental conditions, the conjugation reaction involving ethyl 6-aminohexanoate resulted in formation of a conjugate 9 only in the case of deoxycholic acid (3) in addition to the unexpected ethyl ester 10. In the case of the other bile acids (cholic (1), hyodeoxycholic (4) and 12-ketocholic (5) acids) only an unexpected ester formation took place giving esters 6, 12, and 14. Cytotoxic activity against four tumor cell lines (human breast adenocarcinoma ER-, MDA-MB-231; breast adenocarcinoma ER+, MCF-7; cervix epiteloid carcinoma, HeLa S-3; and prostate cancer, PC-3) was evaluated. Conjugate 8 showed strong activity against HeLa S-3 and conjugate 11 for PC-3. Ethyl ester of 12-ketocholic acid 14 showed very strong antiproliferative activity against MCF-7 and HeLa S-3.

Highlights

The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized
In the past several years, it has been reported that synthetic bile acid derivatives induced apoptosis in several human cancer cells [2], including heaptocellular carcinoma cells [3,4], breast carcinoma cells [5,6], leukemic T cells [7], prostate cancer cells [8], colon cancer cells [9], osteosarcoma cells [10], and cervical carcinoma cells [11]
In view of all the above, the aim of this work was to investigate the possibility of the synthesis of some new conjugates of selected bile acids with natural amino acids of the different carbon chain length and examine their effect on the mechanism of formation of the conjugates of 11-aminoundecanoic and 6-aminoundecanoic acid

Summary

Introduction

The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized. Ethyl ester of 12-ketocholic acid 14 showed very strong antiproliferative activity against MCF-7 and HeLa S-3. The synthesis and growth inhibition studies against the MCF-7 human breast cancer and SKOV-3 ovarian carcinoma cell lines of derivatives of lithocholic acid and cholic acid in which quinoline-3-carboxylate and acridine-9-carboxylate are substituted at 3 and/or the 24 position are reported [12], along with weak activity against the MCF-7 and SKOV-3 lines was exhibited. A series of new conjugates and unexpectedly obtained ethyl esters of bile acids, as well as the starting substances, were tested as potential cytotoxic agents against human tumor cells MDA-MB-231, MCF-7, HeLa S-3, PC-3, and against healthy MRC-5 cells.

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