Novel retinoic acid metabolism blocking agents endowed with multiple biological activities are efficient growth inhibitors of human breast and prostate cancer cells in vitro and a human breast tumor xenograft in nude mice.

Abstract

Novel retinoic acid metabolism blocking agents (RAMBAs) have been synthesized and characterized. The synthetic features include introduction of nucleophilic ligands at C-4 of all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid, and modification of terminal carboxylic acid group. Most of our compounds are powerful inhibitors of hamster liver microsomal ATRA metabolism enzyme(s). The most potent compound is methyl (2E,4E,6E,8E)-9-(3-imidazolyl-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (5) with an IC(50) value of 0.009 nM, which is 666,667 times more potent than the well-known RAMBA, liarozole (Liazal, IC(50) = 6000 nM). Quite unexpectedly, there was essentially no difference between the enzyme inhibitory activities of the two enantiomers of compound 5. In MCF-7 cell proliferation assays, the RAMBAs also enhance the ATRA-mediated antiproliferative activity in a concentration dependent manner. The novel atypical RAMBAs, in addition to being highly potent inhibitors of ATRA metabolism in microsomal preparations and in intact human cancer cells (MCF-7, T47D, and LNCaP), also exhibit multiple biological activities, including induction of apoptosis and differentiation, retinoic acid receptor binding, and potent antiproliferative activity on a number of human cancer cells. Following subcutaneous administration to mice bearing human breast MCF-7 tumor xenografts, 6 (VN/14-1, the free carboxylic acid of 5) was well-tolerated and caused significant tumor growth suppression ( approximately 85.2% vs control, p = 0.022). Our RAMBAs represent novel anticancer agents with unique multiple mechanisms of action. The most potent compounds are strong candidates for development as therapeutic agents for the treatment of a variety of cancers.

• Authors: Jyoti B Patel, Carlic K Huynh, Venkatesh D Handratta, Lalji K Gediya, Angela M H Brodie, Olga G Goloubeva, Omoshile O Clement, Ivo P Nanne, Dianne Robert Soprano, Vincent C O Njar
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 27 Pg. 6716-29 (Dec 30 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15615521 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Cytochrome P-450 Enzyme Inhibitors
• Enzyme Inhibitors
• Tretinoin
• Cytochrome P-450 Enzyme System
• Retinoic Acid 4-Hydroxylase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, pathology)
• Cricetinae
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Male
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• Mice, Nude
• Microsomes, Liver (metabolism)
• Neoplasm Transplantation
• Prostatic Neoplasms (drug therapy, pathology)
• Retinoic Acid 4-Hydroxylase
• Stereoisomerism
• Transplantation, Heterologous
• Tretinoin (metabolism)