Syntheses of lactam derivatives of chenodeoxycholic acid and in vitro antiproliferative activity

Abstract

With chenodeoxycholic acid as starting material, a series of lactam derivatives of chenodeoxycholic acid was synthesized and their antiproliferative activities against some cancer cells were determined. Among the synthesized derivatives, compounds 6 and 18 displayed distinct antiproliferative activity against PC-3, H-292, SKBR3 and Hey-1B cancer cells, and compounds 10, 17 and 18 showed significant antiproliferative activity against SKBR3 cells. Our results reveal that the position of hydroximino on ring A or B of the parental scaffold dramatically affects the antiproliferative activity of these compounds. The conversion of 7-hydroximino to other substituent or 7-hydroximino to 3-hydroximino in the compounds resulted in a dramatic decrease of the antiproliferative activity, suggesting the importance of 7-hydroximino group for the biological activity of the compounds. The structure/activity correlation generated from the studies provides valuable information for the further design of novel chemotherapeutic drugs.

Keywords

Steroidal lactam / Chenodeoxycholic acid / Antiproliferative activity

References

[1] Czaja M J. Am. J. Physiol. Gastrointest. Liver Physiol., 2003, 284: G875.

[2] Martinez J D, Stratagoules E D, LaRue J M, Powell A A, Gause P R, Craven M P, Marianne B P, Eugene W G, David L E. Nutr. Cancer, 1998, 31: 111.

[3] Faubion W A, Guicciardi M E, Miyoshi H, Bronk S F, Roberts P J, Svingen P A, Kaufmann S K, Gores G J. J. Clin. Invest., 1999, 103: 137.

[4] Sodeman T, Bronk S F, Roberts P J, Miyoshi H, Gores G J. Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 278: G992.

[5] Im E O, Choi Y H, Paik K J, Suh H, Jin Y, Kim K W, Yoo Y H, Kim N D. Cancer Lett., 2001, 163: 83.

[6] Choia Y H, Im E O, Suh H, Jin Y, Yoo Y H, Kim N D. Cancer Lett., 2003, 199: 157.

[7] Brossard D, Kihel L E, Clément M, Sebbahi W, Khalid M, Roussakis C, Rault S. Europ. J. Med. Chem., 2010, 45: 2912.

[8] Rasras A J M, Al-Tel T H, Al-Aboudi A F, Al-Qawasmeh R A. Europ. J. Med. Chem., 2010, 45: 2307.

[9] Siless G E, Knott M E, Derita M G, Zacchino S A, Puricelli L, Palermo J A. Steroids, 2012, 77: 45.

[10] Zhang J L, Wang H, Pi H F, Ruan H L, Zhang P, Wu J Z. Steroids, 2009, 74: 424.

[11] Liang D, Zhou Q, Zhang J L, Gong W, Xu C R, Li B, Wang Y, Li J T. Steroids, 2012, 77: 1381.

[12] Dimitrios T P T. Cancer Lett., 2006, 243: 202.

[13] Natalija M K, Mira S B, Željko, Mirjana D P, Zorica D J, Vladimir D P. Steroids, 2007, 72: 406.

[14] Anna I K, Manolis A F, Evagelia S A, Athanasios P, George N P, Sotiris S N. Bioorg. Med. Chem., 2008, 16: 5207.

[15] Dimitrios T P T, George D G, Catherine K, Athanasios P, Panayiotis K, Charalambos C. Breast Can. Res. Treat., 2006, 97: 17.

[16] Huang Y M, Chen S J, Cui J G, Gan C F, Liu Z P, Wei Y L, Song H C. Steroids, 2011, 76: 690.

[17] Huang Y M, Cui J G, Zhong Z G, Gan C F, Zhang W Y, Song H C. Bioorg. Med. Chem. Lett., 2011, 21: 3641.

[18] Huang Y M, Cui J G, Chen S J, Gan C F, Zhou A M. Steroids, 2011, 76: 1346.

[19] Huang Y M, Cui J G, Zeng Q X, Zeng C, Chen Q, Zhou A M. Steroids, 2012, 77: 829.

[20] Chen S J, Zhang X J, Jia L Y, Cui J G. Chem. Res. Appl., 2010, 22: 848.

[21] Lama R, Zhang L, Naim J M, Williams J, Zhou A, Su B. Bioorg. Med. Chem., 2013, 21: 922.