期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 50, 期 4, 页码 856-864出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm061146x
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资金
- NCI NIH HHS [P30 CA23168, R01 CA34619] Funding Source: Medline
- NIDDK NIH HHS [R01 DK68447] Funding Source: Medline
Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t(1/2) = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar K-i has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.
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