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.

[摘要]：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 [4-(butanoyloxymethyl)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimet hylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI50 of 10 nM was [{N-[N-{2-[4-{[3-pyridylmethoxy)carbonyamino]methyl}phenyl) carbonylamino]phenyl} carbamoylcarbamoyloxy}methyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-tri- Me cyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI50 = 40 nM was the most potent vs. the PC-3 cells. MP 19 exhibited the most benefit because its GI50 of 10 nM vs. MDA-MB-231 cells was remarkably 1085-fold lower than that of parent ATRA and over 100000-fold lower than butyric acid (BA).

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