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ACS Med Chem Lett. 2012 Feb 28;3(4):268-272.

Ribonuclease-Activated Cancer Prodrug.

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Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.


Cancer chemotherapeutic agents often have a narrow therapeutic index that challenges the maintenance of a safe and effective dose. Consistent plasma concentrations of a drug can be obtained by using a timed-release prodrug strategy. We reasoned that a ribonucleoside 3'-phosphate could serve as a pro-moiety that also increases the hydrophilicity of a cancer chemotherapeutic agent. Herein, we report an efficient route for the synthesis of the prodrug uridine 3'-(4-hydroxytamoxifen phosphate) (UpHT). UpHT demonstrates timed-released activation kinetics with a half-life of approximately 4 h at the approximate plasma concentration of human pancreatic ribonuclease (RNase 1). MCF-7 breast cancer cells treated with UpHT showed decreased proliferation upon co-incubation with RNase 1, consistent with the release of the active drug-4-hydroxytamoxifen. These data demonstrate the utility of a human plasma enzyme as a useful activator of a prodrug.

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