title: Synthesis and functional evaluation of a peptide derivative of 1-beta-D-arabinofuranosylcytosine.
abstract: We have synthesized a peptidyl prodrug derivative of 1-beta-D-arabinofuranosylcytosine (1) designed to be a selective substrate of plasmin. D-Val-Leu-Lys-ara-C (2) was obtained by coupling the protected peptide Cbz-D-Val-Leu-(N6-Cbz)Lys-OH and ara-C (1) by a water-soluble carbodiimide (EDCI), followed by the removal of the Cbz groups by using catalytic hydrogenolysis over Pd/C. The kinetic constant of hydrolysis of 2 in the presence of plasmin demonstrated effective release of 1. The amino group of 1, which is sensitive to the removal by cytidine deaminase, is protected in 2 by the formation of the amide bond resulting in a prolonged half-life of 2 in biological milieu. The antiproliferative efficiency of 2 against L1210 leukemic cells was significantly higher than that of 1. The activity of 2 was abolished in the presence of serine proteinase inhibitor, (4-amidinopheny)methanesulfonyl fluoride. These data indicate that 2 is a prodrug form of 1 in systems generating plasmin.
authors.affiliation: Department of Biochemistry, Medical University of Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Balajthy
authors.forename: J
authors.initials: J
authors.lastname: Aradi
authors.forename: I T
authors.initials: IT
authors.lastname: Kiss
authors.forename: P
authors.initials: P
authors.lastname: Elödi
mesh_terms: D000818:Animals; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D010455:Peptides; D011355:Prodrugs; D003561:Cytarabine