MEDI 313 |
| 2-chlorodeoxyadenosine (2CdA, cladribine) is a potent anticancer and immunosuppressive agent used as the drug of choice for hairy-cell leukaemia but can also be used in other neoplasms. As with most nucleoside drugs, it needs to be phosphorylated into the active triphosphate form. In this work we report the application of the phosphoramidate prodrug approach1 in order to improve cellular penetration and to by-pass the first step of kinase-mediated activation. We describe the synthesis of different “protides” where the phosphate in 5' is masked as a phosphate prodrug, containing an aromatic ester and a protected amino acid. All the final compounds are obtained as mixture of two diasteroisomers, in variable ratio, due to the stereochemistry of the phosphorus centre.2 The results of biological evaluation, in different leukaemia cell lines, provide evidence for an increase in activity for the phosphoramidate analogues, with an average 10-fold enhancement in potency shown by the most active derivates, when compared to the parent nucleoside. 1Cahard, D.; McGuigan, C.; Balzarini, J. Aryloxy Phosphoramidate Triester as Pro-Tide. Mini-Reviews in Medicinal Chemistry 2004, 4, 371-382 2Congiatu, C.; Brancale, A.; Mason, M.; Jiang, W.; McGuigan, C. Novel potential anticancer naphtyl phosphoramidates of BVdU: separation of diasteroisomers and assignment of the absolute configuration of the phosphorus center. J. Med. Chem. 2006, 49, 452-455
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |
