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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

Supporting Info

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, and Vincent C. O. Njar*^†

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201-1559, Program in Toxicology, University of Maryland School of Medicine, 10 South Pine Street, MSTF 7-34F, Baltimore, Maryland 21201-1559, Biostatistics Division, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland 21201-1559, Accelrys, 9685 Scranton Road, San Diego, California 92121, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, and Department of Biochemistry and Fels Institute of Cancer Research & Molecular Biology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, Pennsylvania 19140

J. Med. Chem., 2004, 47 (27), pp 6716–6729

DOI: 10.1021/jm0401457

Publication Date (Web): November 26, 2004

†

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine.

‡

These authors contributed equally to this work.

Program in Toxicology, University of Maryland School of Medicine.

University of Maryland Greenebaum Cancer Center.

Accelrys.

Temple University School of Pharmacy.

Temple University School of Medicine.

Corresponding author. Phone: (410) 706 5885. Fax: (410) 706 0032. E-mail: vnjar001@umaryland.edu.

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 IC₅₀ value of 0.009 nM, which is 666,667 times more potent than the well-known RAMBA, liarozole (Liazal, IC₅₀ = 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 supression (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.