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Design, Synthesis, and Evaluation of Novel Mutual Prodrugs (Hybrid Drugs) of All-trans-Retinoic Acid and Histone Deacetylase Inhibitors with Enhanced Anticancer Activities in Breast and Prostate Cancer Cells in Vitro

Supporting Info

Lalji K. Gediya^†^§, Aakanksha Khandelwal^†^§, Jyoti Patel^†, Aashvini Belosay^†, Gauri Sabnis^†, Jhalak Mehta^†, Puranik Purushottamachar^† and Vincent C. O. Njar*^†

Department of Pharmacology & Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201-1559, The University of Maryland Marlene and Stewart Greenebaum Cancer Center, School of Medicine, Baltimore, Maryland 21201-1559

J. Med. Chem., 2008, 51 (13), pp 3895–3904

DOI: 10.1021/jm8001839

Publication Date (Web): June 11, 2008

†

University of Maryland School of Medicine, Baltimore.

These authors contributed equally to this work.

Present Address: Laboratory of Cancer Biology and Genetics, National Institutes of Health, Bethesda, Maryland.

Present Address: Department of Food Science and Human Nutrition, University of Illinois, 905 South Goodwin Avenue, Urbana−Champaign, Illinois 61801.

* To whom correspondence should be addressed. Phone: (410) 706 5885. Fax: (410) 706 0032. E-mail: vnjar001@umaryland.edu.

Abstract

Novel mutual prodrugs (MPs) of ATRA (all-trans-retinoic acid) and HDIs (histone deacetylase inhibitors) (10, 13, 17−19) connected via glycine acyloxyalkyl carbamate linker (AC linker) or through a benzyl ester linker (1,6-elimination linker) were rationally designed and synthesized. Most of our novel MPs were potent inhibitors of growth of several hormone-insensitive/drug resistant breast cancer cell lines and the hormone-insensitive PC-3 prostate cancer cell line. The novel MPs exhibited differential antiproliferative potencies in both MDA-MB-231 and PC-3 cell lines. Whereas 19 (VNLG/124) [4-(butanoyloxymethyl)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI₅₀ of 10 nM was the most potent MP versus the MDA-MB-231 cells, 13 (VNLG/66) [{N-[N-{2-[4-{[3-pyridylmethoxy)carbonyamino]methyl}phenyl) carbonylamino]phenyl} carbamoylcarbamoyloxy}methyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI₅₀ = 40 nM was the most potent versus the PC-3 cells. MP 19 exhibited the most benefit because its GI₅₀ of 10 nM versus MDA-MB-231 cells was remarkably 1085-fold lower than that of parent ATRA and over 100000-fold lower than butyric acid (BA).