Text in English / Specially prepared 2-amino-5-bromo-3-iodoacetophenone and 5-bromo-2-hydroxy-3 iodoacetophenone were subjected to Claisen-Schmidt aldol condensation with benzaldehyde derivatives followed by sequential and/or one-pot palladium catalyzed Sonogashira cross coupling and heteroannulation of the 3-alkynylated intermediates to afford indole-chalcones and benzofuran-chalcones, respectively. The indole-chalcones derivatives were, in turn, subjected to trifluoroacetic anhydride in tetrahydrofuran under reflux to afford the corresponding 3-trifluoroacetyl substituted indole-chalcone derivatives. The coupling constant values (Jtrans) of about 16.0 Hz for the chalcone derivatives corresponding to the vinylic protons confirmed the trans geometry of the α,β-unsaturated carbonyl framework in all the cases. Their trans geometry of the chalcone derivatives was further confirmed by single crystal X-ray diffraction (XRD) analyses. Further structural elaboration of the ambident electrophilic α,β unsaturated carbonyl (chalcone) moiety of the indole-chalcones and the analogous benzofuran chalcones with 2-aminothiophenol afforded novel benzothiezapine-appended indole and benzofuran hybrids, respectively. Sonogashira cross-coupling of 5-bromo-2-hydroxy-3 iodoacetophenone with terminal acetylenes followed by heteroannulation of the intermediate 3-alkynylated 5-bromo-2-hydroxyacetophenones afforded the corresponding 7-acetyl-2-aryl-5-bromobenzofurans in a single-pot operation. The oximes derived from the 7-acetyl–substituted 2-aryl-5-bromobenzofurans were subjected to Beckmann rearrangement with triflic acid in acetonitrile under reflux. We isolated the corresponding 7-amino-2-aryl-5 bromobenzofuran derivatives formed from hydrolysis in situ of the intermediate 7-acetamide 2-aryl-5-bromobenzofurans. Amino-dechlorination of the 4-chloroquinazoline derivatives with the 7-aminobenzofurans afforded novel benzofuran 4-aminoquinazoline hybrids. The prepared compounds were characterized using a combination of nuclear magnetic resonance (1H-NMR & 13C-NMR including 19F-NMR), infrared (IR) and mass spectroscopic techniques complemented with single crystal X-ray diffraction (XRD) analyses and/or density functional (DFT) method. The benzofuran-chalcone 203a–y derivatives were evaluated for anti-growth effect against the breast cancer (MCF-7) cell line by the MTT cell viability assay. Their mode of cancer cell death (apoptosis versus necrosis) was detected by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The most cytotoxic compounds 203i and 203o were also evaluated for potential to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. The experimental results were complemented with theoretical data from molecular docking into ATP binding site of the EGFR and colchicine binding site of tubulin, respectively. The benzofuran–4-aminoquinazoline hybrids 215a–j, on the other hand, were evaluated for antiproliferative propeties in vitro against the human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (C3A) cell lines. The benzofuran-aminoquinazoline hybrids were also evaluated for potential to induce apoptosis and for their capability to inhibit EGFR-TK phosphorylation complemented with molecular docking (in silico) into the ATP binding site of EGFR. Mechanistic studies demonstrated that the benzofuran-appended aminoquinazoline hybrids 215d and 215j induced apoptosis via activation of caspase-3 pathway. Moreover, compounds 215d and 215j exhibited significant and moderate inhibitory effects against EGFR (IC50 = 29.3 nM and 61.5 nM, respectively) when compared to Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 215 into EGFR-TK active site suggested that they bind to the region of EGFR like Gefitinib does. / Chemistry / D. Phil. (Chemistry)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work reports on the optical properties of chalcones molecules in solution, using methanol as solvent. For the characterization of the linear optical properties, were obtained absorbance spectra. While for the characterization of the nonlinear optical properties, it has been used techniques hyper-Rayleigh scattering and Z-scan. Using hyper-Rayleigh scattering technique, were determined the first hyperpolarizabilities of the molecules studied. With the Z-scan technique, we could obtain the two-photon absorption spectra at several wavelengths in the range of 480 to 790 nm. From the two-photon absorption spectra were possible to determine the coefficients of two-photon absorption and their respective cross section. The results help to understand the effects of substituents added to the basic structure of chalcones in both linear optical properties as nonlinear. / Neste trabalho, estudamos as propriedades ópticas de moléculas de chalconas em solução, usando o metanol como solvente. Para a caracterização das propriedades ópticas lineares foram determinados os espectros de absorção. Na caracterização das propriedades ópticas não lineares foram utilizadas as técnicas de espalhamento hiper-Rayleigh e de varredura-Z. Utilizando a técnica de espalhamento hiper-Rayleigh foram determinadas as primeiras hiperpolarizabilidades das moléculas estudadas. Com a técnica de varredura-Z conseguimos obter os espectros de absorção de dois fótons em vários comprimentos de onda no intervalo dos 480 aos 790 nm. A partir dos espectros de absorção de dois fótons foi possível determinar o coeficiente da absorção de dois fótons e sua respectiva seção de choque. Os resultados ajudam a compreender os efeitos de substituintes, adicionados à estrutura básica das chalconas, tanto nas propriedades ópticas lineares quanto não lineares.