Synthesis, conformation, biodistribution, and in vitro cytotoxicity of daunomycin-branched polypeptide conjugates

F. Hudecz, J. A. Clegg, F. Hudecz, M. J. Embleton, M. Szekerke, R. W. Baldwin

Research output: Contribution to journalArticle

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Abstract

Daunomycin has been attached to various structurally related synthetic branched polypeptides with a polylysine backbone, using its acid-labile cis-aconityl derivative (cAD). Due to the importance of the side-chain structure in α-helix formation and immunological and pharmacological properties of branched polypeptides, we have investigated the conformation, biodistribution, and in vitro cytotoxicity of cAD-carrier conjugates with polypeptides containing amino acid residues of different identity and/or configuration at the side-chain end (XAK type) or at the position next to the polylysine backbone (AXK type), where X = Leu, D-Leu, Pro, Glu, or D-Glu. According to CD studies, polycationic conjugates with hydrophobic Leu in the side chains could assume a highly ordered conformation, while amphoteric conjugates containing Glu proved to be unordered in PBS. The reduction of in vitro cytotoxic activity of cAD by conjugation to carriers and the biodistribution profile of the conjugates were found to be dependent predominantly on the charge properties and on the side-chain sequence of the carrier polypeptide. It was demonstrated that by proper combination of structural elements of the carrier molecule, it is feasible to construct a cAD-branched polypeptide conjugate with significantly prolonged blood survival and with no reduction in in vitro cytotoxicity of the drug.

Original languageEnglish
Pages (from-to)49-57
Number of pages9
JournalBioconjugate Chemistry
Volume3
Issue number1
Publication statusPublished - 1992

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Daunorubicin
Polypeptides
Cytotoxicity
Conformations
Peptides
Derivatives
NSC 153174
Polylysine
Amino acids
Blood
In Vitro Techniques
Pharmacology
Amino Acids
Molecules
Acids
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Hudecz, F., Clegg, J. A., Hudecz, F., Embleton, M. J., Szekerke, M., & Baldwin, R. W. (1992). Synthesis, conformation, biodistribution, and in vitro cytotoxicity of daunomycin-branched polypeptide conjugates. Bioconjugate Chemistry, 3(1), 49-57.

Synthesis, conformation, biodistribution, and in vitro cytotoxicity of daunomycin-branched polypeptide conjugates. / Hudecz, F.; Clegg, J. A.; Hudecz, F.; Embleton, M. J.; Szekerke, M.; Baldwin, R. W.

In: Bioconjugate Chemistry, Vol. 3, No. 1, 1992, p. 49-57.

Research output: Contribution to journalArticle

Hudecz, F, Clegg, JA, Hudecz, F, Embleton, MJ, Szekerke, M & Baldwin, RW 1992, 'Synthesis, conformation, biodistribution, and in vitro cytotoxicity of daunomycin-branched polypeptide conjugates', Bioconjugate Chemistry, vol. 3, no. 1, pp. 49-57.
Hudecz, F. ; Clegg, J. A. ; Hudecz, F. ; Embleton, M. J. ; Szekerke, M. ; Baldwin, R. W. / Synthesis, conformation, biodistribution, and in vitro cytotoxicity of daunomycin-branched polypeptide conjugates. In: Bioconjugate Chemistry. 1992 ; Vol. 3, No. 1. pp. 49-57.
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