1037543-18-2Relevant academic research and scientific papers
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
Gediya, Lalji K.,Khandelwal, Aakanksha,Patel, Jyoti,Belosay, Aashvini,Sabnis, Gauri,Mehta, Jhalak,Purushottamachar, Puranik,Njar, Vincent C. O.
, p. 3895 - 3904 (2008)
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).
MUTUAL PRODRUGS AND METHODS TO TREAT CANCER
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Page/Page column 39; 44, (2009/01/24)
Mutual prodrugs comprising retinoids and histone deacetylase inhibitors, methods for production of the mutual prodnigs, and methods of treatment comprising administration of the mutual prodrugs. The retinoids include all-trans retinoic acid, 13-cis retinoic acid, and retinoic acid analogs that have a substitution at C-4. Further, the mutual prodrugs of the present invention can be used as therapeutic agents for the treatment of cancer and dermatological diseases and conditions. Pharmaceutical compositions comprising the mutual prodrugs.
