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J Med Chem. 2011 Oct 13;54(19):6647-56. doi: 10.1021/jm200521a. Epub 2011 Sep 9.

Bisphosphonamidate clodronate prodrug exhibits potent anticancer activity in non-small-cell lung cancer cells.

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  • 1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, WBSB 305, Baltimore, Maryland 21201, United States.


Bisphoshonates are used clinically to treat disorders of calcium metabolism, hypercalcemia and osteoporosis, and malignant bone disease. Although these agents are commonly used in cancer patients and have potential direct anticancer effects, their use for the treatment of extraskeletal disease is limited as a result of poor cellular uptake. We have designed and synthesized bisphosphonamidate prodrugs that undergo intracellular activation to release the corresponding bisphosphonate and require only two enzymatic activation events to unmask multiple negative charges. We demonstrate efficient bisphosphonamidate activation and significant enhancement in anticancer activity of two bisphosphonamidate prodrugs in vitro compared to the parent bisphosphonate. These data suggest a novel approach to optimizing the anticancer activities of commonly used bisphosphonates.

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