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

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-(butanoyloxyiiiethyl)phenyl(2E,4E,6E,8E)3,7-dimethyl-9-(2,6,6-trimethylcyelohex- 1-enyl)nona-2,4,6,8-tetraenoate] with a GI(50) of 10 nM was the most potent MP versus the MDA-MB-231 cells, 13 (VNLG/66) [{N-[N-{2-[4-1[3-pyridylmethoxy)carbonyamino]methyl) phenyl) carbonylaminolphenyl} 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 GI(50) = 40 nM was the most potent versus the PC-3 cells. MP 19 exhibited the most benefit because its GI(50) 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).