Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs |
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Authors: | Nandurdikar Rahul S Maciag Anna E Holland Ryan J Cao Zhao Shami Paul J Anderson Lucy M Keefer Larry K Saavedra Joseph E |
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Affiliation: | Drug Design Section, Chemical Biology Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA. nandurdikarr@mail.nih.gov |
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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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