Synthesis of chemoreversible prodrugs of ara-C with variable time-release profiles. Biological evaluation of their apoptotic activity.

Abstract

N4-Dipeptidyl slow-release forms of the anticancer drug ara-C were prepared by acylation of the lithiated nucleotide with 4,4-dialkyloxazolinones. An azapeptide prodrug of ara-C was obtained by condensation of an amino acid hydrazide with an activated nucleotide urea. The use of unnatural amino acid residues at N4 prevented nonspecific proteolytic cleavage in biological medium. Ara-C prodrugs 10, 15, 17, and 19 released active drug with half-lives from a few minutes to several days, respectively. Activation via intramolecular N4-deacylation did not require enzymatic intervention but was strictly dependent on the structure of the peptide chain. The prodrugs 10, 15, and 17 produced similar growth inhibition as ara-C in cultured murine leukemia cells while the azapeptide prodrug 19 was less potent reflecting the slow release of active drug with this compound. All four prodrugs retained the ability to induce apoptosis in human HL-60 leukemia cells with kinetics dictated by the rate of intramolecular N4-deacylation. This the first demonstration for the control of apoptotic cell death by the modulation of drug release from prodrugs.

• Authors: P Wipf, W Li, C M Adeyeye, J M Rusnak, J S Lazo
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 4 Issue 10 Pg. 1585-96 (Oct 1996) ISSN: 0968-0896 [Print] England
• PMID: 8931928 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Delayed-Action Preparations
• Prodrugs
• Cytarabine

Topics

• Animals
• Apoptosis
• Chromatography, High Pressure Liquid
• Cytarabine (chemistry)
• Delayed-Action Preparations (chemical synthesis)
• Half-Life
• Humans
• Magnetic Resonance Spectroscopy
• Mice
• Prodrugs (administration & dosage, chemical synthesis, pharmacokinetics)
• Tumor Cells, Cultured