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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.

SUBMITTER: Nandurdikar RS

PROVIDER: S-EPMC3590845 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs.

Nandurdikar Rahul S RS Maciag Anna E AE Holland Ryan J RJ Cao Zhao Z Shami Paul J PJ Anderson Lucy M LM Keefer Larry K LK Saavedra Joseph E JE

Bioorganic & medicinal chemistry 20120309 9

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 activatio ...[more]

PMID: 22480849

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