New antitumor leads from a peptidomimetic library

Letters in Peptide Science - 1999
László Õrfi1, Frigyes Wáczek1, István Kövesdi2, György Mészáros3, Miklós Idei3, Anikó Horvath3, Ferenc Hollósy3, Marianna Mák4, Zsolt Szegedi5, Béla Szende5, György Kéri3
1Institute of Pharmaceutical Chemistry, Semmelweis University of Medicine, Budapest, Hungary
2EGIS Pharmaceuticals Ltd., Budapest, Hungary
3Peptide Biochemistry Research Group, Department of Medical Chemistry, Semmelweis University of Medicine, Budapest, Hungary
4Gedeon Richter Ltd., Budapest, Hungary
51st Institute of Pathology, Semmelweis University of Medicine, Budapest, Hungary

Tóm tắt

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 pp60c−src enzyme. The new structures were based on kown PTK inhibtors 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 pp60c−src PTK showed that the energyminimized 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.

Từ khóa


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