期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 15, 页码 4980-4988出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.05.020
关键词
Glutathione S-transferase P1 (GSTP1); Glutathione; Nitric oxide (NO); PABA/NO; Diazeniumdiolate; Arylation; Oxidative stress; Antiproliferative; Cytotoxicity; Apoptosis
资金
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
- NIH, National Cancer Institute, Center for Cancer Research
- National Institute on Drug Abuse (NIDA) [Y1-DA1101]
- Naval Research Laboratory
PABA/NO [O-2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate] is a nitric oxide (NO)-releasing arylating agent designed to be selectively activated by reaction with glutathione (GSH) on catalysis by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer cells. PABA/NO has proven active in several cancer models in vitro and in vivo, but its tendency to be metabolized via a variety of pathways, some that generate inactive metabolites and hydrolysis products, limits its potential as a drug. Here we show that a simple replacement of cyano for nitro at the 4 position to give compound 4b ('p-cyano-PABA/NO') has the dual effect of slowing the undesired side reactions while enhancing the proportion of NO release and arylating activity on catalysis by GSTP1. Compound 4b showed increased resistance to hydrolysis and uncatalyzed reaction with GSH, along with a more favorable product distribution in the presence of GSTP1. It also showed significant proapoptotic activity. The data suggest p-cyano-PABA/NO to be a more promising prodrug than PABA/NO, with better selectivity toward cancer cells. Published by Elsevier Ltd.
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