title: Synthesis and biological activity of beta-glucuronyl carbamate-based prodrugs of paclitaxel as potential candidates for ADEPT.
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.
authors.affiliation: Department of Organic Chemistry, University of Nijmegen, The Netherlands.
authors.forename: D B
authors.initials: DB
authors.lastname: de Bont
authors.forename: R G
authors.initials: RG
authors.lastname: Leenders
authors.forename: H J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: I
authors.initials: I
authors.lastname: van der Meulen-Muileman
authors.forename: H W
authors.initials: HW
authors.lastname: Scheeren
mesh_terms: D000906:Antibodies; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D016503:Drug Delivery Systems; D005965:Glucuronates / Q000737:chemistry*; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043823:Taxoids; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; C105916:N-(paclitaxel-2'-O-(2-amino)phenylpropionate)-O-(beta-glucuronyl)carbamate; C105915:N-(paclitaxel-2'-O-3,3-dimethyl butanoate)-O-(beta-glucuronyl)carbamate; D011355:Prodrugs; D043823:Taxoids; D005966:Glucuronidase; D017239:Paclitaxel