Synthesis and biological activity of β-glucuronyl carbamate-based prodrugs of paclitaxel as potential candidates for ADEPT

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Abstract

The syntheses of prodrugs of paclitaxel, which can be used in ADEPT in order to target paclitaxel towards tumor cells, are described. The prodrugs 1 and 2a,b consist of a spacer molecule connected via a carbamate linkage to a β-glucuronic acid. The spacer molecule is also connected via an ester linkage to the 2′-OH of paclitaxel. Enzyme-catalyzed hydrolysis of the glucuronic acid moiety by human β-glucuronidase results in the liberation of the parent drug paclitaxel via γ or δ lactam formation with half-lives of 45 min and 2 h (1 and 2b). The prodrugs 1 and 2b are two orders of magnitude less cytotoxic than paclitaxel.

The synthesis of prodrugs 1 and 2a,b is described. Enzyme catalyzed hydrolysis of the glucuronic acid moiety of 1 or 2b results in the liberation of the parent drug paclitaxel via γ or δ lactam formation with half-lives of 45 min and 2 h. The prodrugs 1 and 2b are two orders of magnitude less toxic than paclitaxel.

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Present address: Department of Medicinal Chemistry, Faculty of Pharmacy, Post Office Box 80082, 3508 TB Utrecht, The Netherlands.

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