Síntese de Biginelli aplicada ao desenvolvimento de novas cumarino-Diidropirimidinonas com potencial uso no diagnóstico e tratamento de cânceres associados à HSP 90

Abstract

Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues and can be spread to distant locations in the body through blood and lymph systems through a process known as metastasis, been considered by the World Health Organization as one of the biggest health problems facing humanity at this century. Hsp90 (Heat Shock Proteins – 90kD) is considered today as one possible therapeutic target in cancer treatment. This enzyme has an important role in the development of tumor cells processes because it is stable, and is present in all organelles, corresponding to 1-2% of the cellular protein content, reaching to 6% stress in stress level. Thus, this work proposes the design and synthesis of a series of novobiocin (24) analogs, and it is known as inhibitor of this enzyme. The molecules described herein belong to the class of dihydropyrimidin-2(1H)-one and was designed by molecular hybridization of this core with coumarin subunit of novobiocin, both compounds have proved activity on tumor cell lines. Therefore this work aims to study the process of synthesis of diidropirimidin-2(1H)-ones planned as inhibitors of Hsp90, its reaction scope and evaluate their fluorescence properties as possible cellular markers. The series was synthesized by multicomponent Biginelli reaction, using ureas (50a-b), aromatic aldehydes (Ar a-n), coumarin beta-ketoesters previously synthesized (105a-b) and HCl as catalyst. All compounds were characterized by physical and chemical methods of analysis. This is the first report of Biginelli adducts bearing a coumarin nucleus in the β-ketoester moiety and their MCR mechanism seems to pass through a Knoevenagel intermediate, which was considered as unlikely before. A chemical library of dihydropyrimidin-2(1H)-one was obtained with low to excellent yields (25-99%), with its final structure confirmed also by studies of X-ray diffraction. Photophysical analyses of representative compounds in different solvents show good Stokes shifts in water that are associated to a postulated ICT process which, along with the determination of their pKa, make these compounds a good start point for new chemical and biological probes as well as useful pH indicators.