期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 57, 期 39, 页码 12780-12784出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201807582
关键词
cancer; copper; dithiocarbamate; prochelators; -glutamyl transpeptidase
资金
- National Science Foundation (NSF) [CHE-1152054]
- Duke Cancer Institute P30 Cancer Center Support Grant [NIH CA014236]
- Foerster-Bernstein postdoctoral fellowship
- NATIONAL CANCER INSTITUTE [P30CA014236] Funding Source: NIH RePORTER
A prodrug approach is presented to direct copper-dependent cytotoxicity to prostate cancer cells. The prochelator GGTDTC requires activation by -glutamyl transferase (GGT) to release the metal chelator diethyldithiocarbamate from a linker that masks its thiol reactivity and metal binding properties. In vitro studies demonstrated successful masking of copper binding as well as clean liberation of the chelator by GGT. GGTDTC was stable to non-specific degradation when incubated with a series of prostate cancer and normal cell lines, with selective release of diethyldithiocarbamate only occurring in cells with measurable GGT activity. The antiproliferative efficacy of the prochelator correlated with cellular GGT activity, with 24h inhibitory concentrations ranging from 800nm in prostate cancer lines 22Rv1 and LNCaP to over 15m in normal prostate PWR-1E cells. These findings underscore a new strategy to leverage the amplified copper metabolism of prostate cancer by conditional activation of a metal-binding pharmacophore.
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