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Nitric Oxide (NO)-Releasing Poly-[ADP-Ribose]-Polymerase-1 (PARP-1) Inhibitors Targeted to Glutathione S-Transferase P1-Overexpressing Cancer Cells.
MedLine Citation:
PMID:  24521039     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
We report the antitumor effects of nitric oxide (NO)-releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N-N(O)=NO- group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 induce cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.
Authors:
Anna E Maciag; Ryan John Holland; Youseung Kim; Vandana Kumari; Christina E Luthers; Waheed Saadiya Sehareen; Debanjan Biswas; Nicole L Morris; Xinhua Ji; Lucy M Anderson; Joseph E Saavedra; Larry K Keefer
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-2-12
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-2-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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