Otimiza??o do prot?tipo LDQMC-014: uma acridinona inibidora da polimeriza??o de Tubulina

• Autor(a) principal: Fonseca, Marina Brand?o da
• Data de Publicação: 2020
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
• Texto Completo: https://tede.ufrrj.br/jspui/handle/jspui/6290
• topic: Rea??o multicomponente; c?ncer; Tubulina; Multicomponent reaction; cancer; Qu?mica

Today, cancer is one of the most deadly diseases in the world. Breast cancer is the fifth most lethal, and its triple negative subtype has the highest mortality rate. There is no specific treatment for the triple negative subtype, and the high rates of disease recurrence and metastasis make it necessary to search for new forms of treatment. A multicomponent reaction is a type of reaction for chemical synthesis, where three or more reagents react to form a single product with a high degree of chemical diversity, and the Hantzsch reaction is one of the first reactions of this type reported. In the present work, a series of molecules were synthesized, using as a basis the Hantzsch reaction and structures analogous to natural products such as Colchicine and Podophyllotoxin, aiming at the optimization of the LDQMC-014 (7-(3,4,5-trimethoxyphenyl)-9,10,11,12-tetrahydrobenzo[c]acridin-8(7H)-one) prototype, whose results in previous works demonstrate good cytotoxic activity in vitro, with a profile of inhibition of Tubulin polymerization (target widely validated as anticancer). Varied yields were obtained with confirmation of the structures by carbon and hydrogen NMR. Once the LDQMC-014 compound obtained satisfactory results, it was sought to optimize the synthesis results. Systematic changes were made in the synthesis parameters, which promoted an increase of more than 78 % in the reaction yield. The enantiomers of LDQMC-014 were separated by chiral chromatography, which provided good enantiomeric separation, which subsequently allowed the determination of the absolute configuration of the asymmetric center present by circular dichroism. Once the enantiomers were isolated, their biological evaluations were performed in order to determine their activity, as well as a molecular modeling study to predict the interaction of the isolated enantiomers with the Tubulin protein. That enantiomers interact differently with the protein in both the in silico and the in vitro tests. The molecular modeling study was extended to all intended acridinones to predict a possible interaction with the Tubulin protein. A cell migration test (Wound Healing) was performed for some of the obtained acridinones, which determined the inhibition profile of cell migration, a desired characteristic in metastasis cases.