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 beta-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 beta-glucuronidase results in the liberation of the parent drug paclitaxel via gamma or delta 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies
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Antineoplastic Agents, Phytogenic / chemical synthesis*
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / pharmacology*
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Catalysis
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Drug Delivery Systems
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Glucuronates / chemistry*
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Glucuronidase / metabolism
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Humans
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Magnetic Resonance Spectroscopy
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Mass Spectrometry
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Paclitaxel / analogs & derivatives*
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Paclitaxel / chemistry*
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / pharmacology*
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Taxoids*
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Tumor Cells, Cultured
Substances
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Antibodies
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Antineoplastic Agents, Phytogenic
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Glucuronates
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N-(paclitaxel-2'-O-(2-amino)phenylpropionate)-O-(beta-glucuronyl)carbamate
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N-(paclitaxel-2'-O-3,3-dimethyl butanoate)-O-(beta-glucuronyl)carbamate
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Prodrugs
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Taxoids
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Glucuronidase
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Paclitaxel