Design, Synthesis, and Evaluation of Duocarmycin O-Amino Phenol Prodrugs Subject to Tunable Reductive Activation
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- 作者：James P. Lajiness ; William M. Robertson ; Irene Dunwiddie ; Melinda A. Broward ; George A. Vielhauer ; Scott J. Weir ; Dale L. Boger
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：November 11, 2010
- 年：2010
- 卷：53
- 期：21
- 页码：7731-7738
- 全文大小：901K
- 年卷期：v.53,no.21(November 11, 2010)
- ISSN：1520-4804
文摘
A series of N-acyl O-amino derivatives of seco-CBI-indole2 are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments which carry an intrinsically higher concentration of “reducing” nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N−O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs, even enlisting subtle variations in the electronic and steric environment around the weak N−O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.