Synthesis and evaluation of macromolecule-bound derivatives of a peptidyl-1-beta-D-arabinofuranosylcytosine prodrug.
Macromolecule-bound Val-Leu-Lys-ara-C (1) prodrugs were synthesized with spacers (-HN-(CH(2))(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-(CH(2))(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 (t((1/2)) 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-(CH(2))-CO-, (2)) in 5 provided the best protection of 1 against the hydrolyzing ability of proteinase- alpha(2)-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 IC(50) of 0.01 microM 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 microM, than ara-C could.
Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Debrecen, Egyetem tér 1, Hungary. zoli@indi.biochem.dote.hu
Zoltan
Z
Balajthy
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000138:chemical synthesis; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis; D003692:Delayed-Action Preparations; D003911:Dextrans / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis; D000511:alpha-Macroglobulins / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D003911:Dextrans; D004337:Drug Carriers; D011355:Prodrugs; D000511:alpha-Macroglobulins; D003561:Cytarabine