Purushottamachar Puranik - 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.

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  Publication Details (including relevant citation   information):

 
    J Med Chem. 2008 Jul     10;51(13):3895-904. Epub 2008 Jun 11  

  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(2 E,4 E,6 E,8   E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-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-{[3-pyridylmethoxy)carbonyamino]methyl}phenyl)   carbonylamino]phenyl} carbamoylcarbamoyloxy}methyl(2 E,4 E,6 E,8   E)-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).

 

 
   
      PMID: 18543902    
 

  Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/18543902

 

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