title: Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs.
abstract: JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.
authors.affiliation: Drug Design Section, Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA. nandurdikarr@mail.nih.gov
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Nandurdikar
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Holland
authors.forename: Zhao
authors.initials: Z
authors.lastname: Cao
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Anderson
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001391:Azo Compounds / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D005978:Glutathione / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D009569:Nitric Oxide / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione