title: Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.
abstract: 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 inducing 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: Chemical Biology Laboratory, Leidos Biomedical Research, Inc. , Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
authors: Anna E
authors: AE
authors: Maciag
authors: Ryan J
authors: RJ
authors: Holland
authors: Youseung
authors: Y
authors: Kim
authors: Vandana
authors: V
authors: Kumari
authors: Christina E
authors: CE
authors: Luthers
authors: Waheed S
authors: WS
authors: Sehareen
authors: Debanjan
authors: D
authors: Biswas
authors: Nicole L
authors: NL
authors: Morris
authors: Xinhua
authors: X
authors: Ji
authors: Lucy M
authors: LM
authors: Anderson
authors: Joseph E
authors: JE
authors: Saavedra
authors: Larry K
authors: LK
authors: Keefer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D015195:Drug Design; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs; D011719:Pyrazines; D009569:Nitric Oxide; D000069286:Bortezomib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D051549:Glutathione S-Transferase pi