Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs

Bioorg Med Chem. 2012 May 1;20(9):3094-9. doi: 10.1016/j.bmc.2012.02.045.

Rahul S Nandurdikar ¹, Anna E Maciag, Ryan J Holland, Zhao Cao, Paul J Shami, Lucy M Anderson, Larry K Keefer, Joseph E Saavedra

Affiliations

Affiliation

1 Drug Design Section, Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA. nandurdikarr@mail.nih.gov

PMID: 22480849 DOI: 10.1016/j.bmc.2012.02.045

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.

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