Banca de DEFESA: FELIPE VITORIO RIBEIRO
Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.DISCENTE : FELIPE VITORIO RIBEIRO
DATA : 06/03/2020
HORA: 09:30
LOCAL: sala 50
TÍTULO:
Design, Synthesis and Antitumor Evaluation of Substituted Dihydropyrimidinones and Imidazopyridines Derived from Substituted 3-keto-coumarins
PALAVRAS-CHAVES:
Cancer, coumarins, dihydropyrimidinones, imidazopyridines, reaction mechanism, monastrol, novobiocin, Biginelli multicomponent reaction
PÁGINAS: 244
GRANDE ÁREA: Ciências Exatas e da Terra
ÁREA: Química
SUBÁREA: Química Orgânica
ESPECIALIDADE: Síntese Orgânica
RESUMO:
Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues, and can spread to distant places in the body through the blood and lymphatic systems through a process known as metastasis, being considered by the World Health Organization. Health one of the biggest health problems facing humanity in this century. Among the various therapeutic classes for the treatment of cancer are coumarins and imidazopyridines, which are the target of continuous investigations of biological interest due to their pharmaceutical properties and different mechanisms of action. Thus, the present thesis proposes the planning, the synthesis of a series of dihydropyrimidinonic analogues to monastrol (165a-u), the determination of the mechanistic reaction pathway, since its attainment goes through a Biginelli three-component reaction, and its biological evaluation. The planning, synthesis, characterization and antiproliferative evaluation of new imidazopyrines (166a-x) is also a focus of this work. The series described here were planned through molecular hybridization of the dihydropyrimidinone or imidazopyrine nucleus with the coumarin subunit. Both nuclei are proven to be active on tumor cell lines. Therefore, this work aims to study the synthesis process of the planned series, its reaction scope and to evaluate its antiproliferative properties. The series were synthesized through classic reactions of organic chemistry. All series were characterized by physical and chemical methods of analysis. This is the first report proving by EM-ESI and theoretical calculations that the coumarin nucleus and its multicomponent reaction mechanism curiously passes through a Knoevenagel intermediate, which was considered unlikely in the literature. The libraries of new compounds were obtained with low to excellent yields (23-96%), and their final structure was also confirmed by X-ray diffraction studies. Among the dihydropyrimidinones the ones that are most active against the PC-3 tumor cell were those that have a coumarin position 7 diethylamino (IC50 = 3.28 µM) and those with more structural similarity to monastrol (IC50 = 8, 89 µM), most of the tested substances were more active than monastrol (IC50 = 22.02 µM). And among imidazopyridines, this substitution profile is also the most active (IC50 = 2.07 µM for cell B16-F10), being ten times more selective for that cell compared to healthy cells. You can then see a very interesting structure-to-activity analysis and promising compounds in potency and selectivity.
MEMBROS DA BANCA:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interno - 1735975 - CEDRIC STEPHAN GRAEBIN
Interna - 1979542 - RENATA BARBOSA LACERDA
Interna - 1177598 - ROSANE NORA CASTRO
Externo à Instituição - DANIEL PAIS PIRES VIEIRA - IFRJ
Externo à Instituição - BRUNO ALMEIDA COTRIM - IFRJ
Externo à Instituição - LEANDRO SOTER DE MARIZ E MIRANDA - UFRJ