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Synthesis of novel, peptidic kinase inhibitors with cytotoxic activity

Ryszard Ostaszewski 1Wiktor Szymański 1Magdalena Zwolińska 1Izabela Młynarczuk 2

1. Polish Academy of Sciences, Institute of Physical Chemistry, Kasprzaka 44/52, Warszawa 01-224, Poland
2. Medical University of Warsaw, Chałubińskiego 5, Warsaw 02-004, Poland

Abstract

The promising use of small peptides as therapeutics suffers seriously from the problems with farmacokinetics of these compounds. They include: proteolytic instability and high polarity, which prevents small peptides from crossing cell membranes. The synthesis of peptidomimetics aims at the solution of these problems. The changes, which are usually introduced into the structure of the peptide are: N-alkylation of peptide bond [1], introduction of non-coded amino acids [2] and introduction of special functional groups at the terminae of the peptide [3].

A novel method for the preparation of peptidomimetics 7 has been recently developed in our laboratory (Scheme 1) [4]. It uses Passerini multicomponent reaction for the preparation of racemic scaffold rac-4 which is then enantioselectivelly hydrolyzed by hydrolytic enzymes to enantiomerically enriched alcohols 5. These compounds are functionalised towards amines 6, which are used as substrates in the synthesis of peptidomimetics 7.

This methodology was applied for the synthesis of novel, peptidic kinase inhibitors with cytotoxic activity towards tumor cells. Studies on the influence of main structural features of studied compounds on biological activity will be presented. The efforts to determine which enantiomer is responsible for the activity will also be presented.

This work was financially supported by Polish State Committee for Scientific Research, Grant N405 007 31/0544.


[1] Aurelio, L.; Brownlee, R.T.C.; Hughes, A.B. Chem. Rev., 2004, 104, 5823
[2] Huang, Y.; Hang, Y.-B.; Chen, Z.C.; Xu, P.F.Tetrahedron: Asymmetry, 2006, 17, 3152
[3] Marastoni, M.; Baldisserotto, A.; Canella, A.; Gavioli, R.; De Risi, C.; Pollini, G.P.; Tomatis, R. J. Med. Chem., 2004, 47, 1587
[4] W. Szymanski, M. Zwolinska, R. Ostaszewski, Tetrahedron, 2007, 63, 7647

 

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Submitted: 2008-03-13 17:55
Revised:   2009-06-07 00:48