title: PABA/NO lead optimization: Improved targeting of cytotoxicity to glutathione S-transferase P1-overexpressing cancer cells.
abstract: 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.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, United States.
authors.forename: Youseung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Chemical Biology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United States.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.affiliation: Chemical Biology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United States.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Center for Biomolecular Science and Engineering, Naval Research Laboratory, Washington, DC 20375, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.affiliation: Chemical Biology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United States. Electronic address: saavedjo@mail.nih.gov.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, United States.
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, United States. Electronic address: hollandrj@mail.nih.gov.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Holland
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D055162:Biocatalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000737:chemistry / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D008968:Molecular Conformation; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity
chemical_list: D009569:Nitric Oxide; D051549:Glutathione S-Transferase pi; D005978:Glutathione; D010129:4-Aminobenzoic Acid
keywords: Antiproliferative; Apoptosis; Arylation; Cytotoxicity; Diazeniumdiolate; Glutathione; Glutathione S-transferase P1 (GSTP1); Nitric oxide (NO); Oxidative stress; PABA/NO