Science of Synthesis

Wever, R.; Babich, L.; Hartog, A. F., Science of Synthesis: Biocatalysis in Organic Synthesis, (2015) 1, 223.

Organic phosphates, in particular nucleoside phosphates, are important pharmaceuticals; however, the high charge due to the phosphate group prevents penetration of cells, limiting the ability of these compounds to reach intracellular targets. Therefore, they are chemically modified to so-called prodrugs which have no or poor biological activity;[‌9‌,‌10‌] in vivo the prodrugs undergo transformation to release the active drug,[‌11‌] which is subsequently further phosphorylated by cellular kinases to the active triphosphate form. Alternatively, to increase the solubility of drugs that are orally administered, phosphate derivatives are synthesized[‌12‌] with an increased aqueous solubility.[‌13‌] Prednisolone sodium phosphate is a classic example of a phosphate prodrug. The phosphate moiety is linked directly to a free hydroxy group on prednisolone. The prodrug is much more water-soluble than prednisolone and the oral liquid formulation is used as an immunosuppressant in allergic and inflammatory conditions.[‌14‌] Furthermore, the phosphate group masks the unpalatable taste of prednisolone tablets. Amprenavir, an HIV protease inhibitor, has been converted into a phosphate ester, the prodrug fosamprenavir, which is tenfold more water-soluble.[‌13‌,‌14‌] In vivo phosphatases, such as alkaline phosphatase, hydrolyze the phosphate group, releasing the active parent drug molecule.

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References