Novos compostos heterocíclicos antitumorais e anti-angiogénicos: síntese, modelação molecular, screennig de inibição enzimática e estudos em linhas celulares tumorais e endoteliais com receptores membranares de tirosina cinase como alvos

In this project, based on recent reports on thienopyrimidines and thienopyridines as TKIs of EGFR, PDGFR and VEGFR-2, we propose the synthesis of new bi(hetero)aryls, di(hetero)-arylamines, -arylethers and -arylacetylenes derivatives of methyl 3-aminothieno[3,2-b]pyridines-2-carboxylates by C-C, C-N and C-O Pd and/or Cu-catalyzed couplings. Arylureas or thioureas side-chains will be included from arylamino substituents. New carbonylated thienopyridines will be also prepared by Pd-catalyzed methods. The organometallic synthesis of functionalized heterocyclic compounds and their characterization are the expertises of the PI and this work will be done at the CQ/UM. To evaluate the EGFR, PDGFR and/or VEGFR-2 TK inhibition activity of the new compounds, receptor specific enzymatic assays will be conducted at the CIM/ESA/IPB. These assays measure the ability of each purified receptor in the presence of the new compounds, to catalyse the transfer of a phosphate group from ATP to tyrosine residues in a synthetic peptide. Molecular modelling studies, docking and QSAR, will be also performed at the CIMO/ESA/IPB due to the experience on using bioinformatic tools, to promote the rational design of new TKIs more potent and selective among the receptors in study and to build QSAR models of inhibition. Thus, the best compounds will be selected to be studied at the cellular level which will be done at the CFBQ/FM/UP. EC, SMC and tumor cell cultures will be established and treated with each promising compound. The effects on cell toxicity, expression of the membrane receptors and activation of distinct signaling pathways, involved in either angiogenesis and/or tumor progression will be examined.

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