New antitumor leads from a peptidomimetic library

L. Őrfi, Frigyes Wáczek, István Kövesdi, György Mészáros, M. Idei, Anikó Horváth, F. Hollósy, Marianna Mák, Zsolt Szegedi, B. Szende, G. Kéri

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60(c-src) enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18-100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12-14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60(c-src) PTK showed that the energy- minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.

Original languageEnglish
Pages (from-to)325-333
Number of pages9
JournalLetters in Peptide Science
Volume6
Issue number5-6
Publication statusPublished - 1999

Fingerprint

Peptidomimetics
Proto-Oncogene Proteins pp60(c-src)
Protein-Tyrosine Kinases
Protein Kinase Inhibitors
Proteins
Molecular modeling
src-Family Kinases
Substrates
Inhibitory Concentration 50
Libraries
Tumors
Colon
Cell death
Binding sites
Carbon
Binding Sites
Cells
Apoptosis
Peptides
Atoms

Keywords

  • Antiproliferative effect
  • Apoptosis
  • Combinatorial library
  • Isosteric structures
  • Oxaniloyl hydrazides
  • Peptidomimetics
  • Substrate-binding site
  • Tyrosine kinase inhibition

ASJC Scopus subject areas

  • Biochemistry

Cite this

Őrfi, L., Wáczek, F., Kövesdi, I., Mészáros, G., Idei, M., Horváth, A., ... Kéri, G. (1999). New antitumor leads from a peptidomimetic library. Letters in Peptide Science, 6(5-6), 325-333.

New antitumor leads from a peptidomimetic library. / Őrfi, L.; Wáczek, Frigyes; Kövesdi, István; Mészáros, György; Idei, M.; Horváth, Anikó; Hollósy, F.; Mák, Marianna; Szegedi, Zsolt; Szende, B.; Kéri, G.

In: Letters in Peptide Science, Vol. 6, No. 5-6, 1999, p. 325-333.

Research output: Contribution to journalArticle

Őrfi, L, Wáczek, F, Kövesdi, I, Mészáros, G, Idei, M, Horváth, A, Hollósy, F, Mák, M, Szegedi, Z, Szende, B & Kéri, G 1999, 'New antitumor leads from a peptidomimetic library', Letters in Peptide Science, vol. 6, no. 5-6, pp. 325-333.
Őrfi L, Wáczek F, Kövesdi I, Mészáros G, Idei M, Horváth A et al. New antitumor leads from a peptidomimetic library. Letters in Peptide Science. 1999;6(5-6):325-333.
Őrfi, L. ; Wáczek, Frigyes ; Kövesdi, István ; Mészáros, György ; Idei, M. ; Horváth, Anikó ; Hollósy, F. ; Mák, Marianna ; Szegedi, Zsolt ; Szende, B. ; Kéri, G. / New antitumor leads from a peptidomimetic library. In: Letters in Peptide Science. 1999 ; Vol. 6, No. 5-6. pp. 325-333.
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