Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Synthesis and Evaluation of Macromolecule-Bound Derivatives of a Peptidyl-1-ß-D-arabinofuranosylcytosine Prodrug

Author(s): Zoltan Balajthy.

Abstract:

Macromolecule-bound Val-Leu-Lys-ara-C (1) prodrugs were synthesized with spacers (-HN-(CH2)x-CO-; x =1,3,5) between the dextran carrier (T-70) and 1, in order to achieve a sustained-release drug delivery system dextran-NH- (CH2)x:1,3,5-CO-Val-Leu-Lys-ara-C (5, 6 and 7). The conjugation increased the stability of 1 in aqueous buffer solutions by three times (t1/2 53.0 h, pH 7.4). The length of spacer also regulated the rate of hydrolysis of the prodrugs in serum. The shortest spacer (-HN-(CH2)-CO-, (2)) in 5 provided the best protection of 1 against the hydrolyzing ability of proteinase- α2-macroglobulin complexes, increasing its half-life approximately 30-fold. The conjugation procedure resulted in a growth arrest ability for macromolecular-bound prodrugs 5, 6 and 7 against L1210 with IC50 of 0.01 μM in vitro, which is significantly lower than that of other ara-C-macromolecule conjugates. 5 and 6 arrested cell growth in a broader range of concentration, between 1 x 10-5-1.0 μM, than ara-C could.

Keywords: Ara-C, prodrug, dextran, macromolecule conjugates

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Article Details

VOLUME: 2
ISSUE: 2
Year: 2008
Page: [83 - 89]
Pages: 7
DOI: 10.2174/187231208784040960
Price: $58