Synthesis and biological activity of beta-glucuronyl carbamate-based prodrugs of paclitaxel as potential candidates for ADEPT.
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.
de Bont
D B
DB
Department of Organic Chemistry, University of Nijmegen, The Netherlands.
Leenders
R G
RG
Haisma
H J
HJ
van der Meulen-Muileman
I
I
Scheeren
H W
HW
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
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