Synthesis and Functional Evaluation of a Peptide Derivative of 1-β-D-Arabinofuranosylcytosine

Zoltán Balajthy, János Aradi, Ildikó T. Kiss, Pál Elödi

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We have synthesized a peptidyl prodrug derivative of 1-β-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-n-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.

Original languageEnglish
Pages (from-to)3344-3349
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - Sep 1 1992


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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