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-(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).
Department of Pharmacology & Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201-1559, USA.
Lalji K
LK
Gediya
Aakanksha
A
Khandelwal
Jyoti
J
Patel
Aashvini
A
Belosay
Gauri
G
Sabnis
Jhalak
J
Mehta
Puranik
P
Purushottamachar
Vincent C O
VC
Njar
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011355:Prodrugs; D014212:Tretinoin; D006655:Histone Deacetylases