Document Detail

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    
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.
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
Related Documents :
23362159 - Shape- and nitric oxide flux-dependent bactericidal activity of nitric oxide-releasing ...
8097689 - Role of cytochromes p-450 and flavin-containing monooxygenase in the biotransformation ...
12743769 - Biodegradation of chloronaphthalenes and polycyclic aromatic hydrocarbons by the white-...
4087129 - P-nitrophenyl vinyl ether, a novel substrate for the assay of cytochrome p-450 dependen...
3624229 - Structure-mechanism relationships in hemoproteins. oxygenations catalyzed by chloropero...
23103569 - Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing ch...
24626959 - The chemical origin and catalytic activity of coinage metals: from oxidation to dehydro...
21366059 - Chemical composition of the essential oil of cachrys libanotis from algeria.
20693069 - Prediction of drug-induced immediate hypersensitivity in guinea pigs.
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:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Contribution of mammary epithelial cells to the immune response during early stages of a bacterial i...
Next Document:  The role of continuing bonds in coping with grief: overview and future directions.