Identification of inhibitors of heparin-growth factor interactions from combinatorial libraries of four-component condensation reactions

Chemical libraries based on four-component condensation (4CC) reactions of isocyanides were constructed to identify compounds capable of blocking hepa rin binding to vascular endothelial growth factor (VEGF) and basic fibrobla st growth factor (bFGF). The reaction products in the synthesized libraries contain heparin mimetic functional groups such as carbohydrates, sulfonate s, carboxylates, and hydroxy groups. These libraries have been screened for the inhibition of heparin binding to growth factors such as VEGF and bFGF. Single point screening at 5.0 muM of the 18,720 reaction products generate d 26 candidates. The IC(50)s of these 26 compounds were determined using HP LC-purified products and 20 of the 26 showed significant inhibition of hepa rin binding to VEGF and/or bFGF. Eighteen of the 20 confirmed active compou nds have a linear extended structure. Structures identified in this library revealed an initial relationship of structure and activity, thus providing direction for further investigation of this type of heparin mimetic librar ies. (C) 2001 Published by Elsevier Science Ltd.