Síntese de derivados desidratados do diterpeno cafestol e docking molecular direcionado a alvos envolvidos no aumento de colesterol

Abstract

Cafestol, an ent-kaurane furanoditerpene from the lipid fraction of coffee beans (Coffea sp.), is a potent hypercholesterolemic agent resulting from the agonist action on the farnesoid X receptor (FXR) and the inhibition of cholesterol-7-α-hydroxylase (CYP7A1), two proteins involved in the regulation and biosynthesis of bile acids. During the roasting of coffee beans, cafestol undergoes thermal degradation, yielding the derivatives 15,16-dehydrocafestol and its regioisomers 13,16-dehydrocafestol and cafestal (tautomer of 16,17-dehydrocafestol). The formation of these substances is dependent on the intensity of roasting; consequently, deeply roasted beans, typically consumed in Brazil, present high concentrations of these dehydrated derivatives. Regarding these compounds, whose isolation from coffee beans is not simple by conventional chromatographic techniques, little information is known about their biological activities. Therefore, this dissertation aimed to synthesize the dehydrated products of cafestol present in roasted coffee beans and to preliminarily evaluate the potential binding modes of the roasting derivatives with the FXR receptor and the human CYP7A1 enzyme in molecular docking simulations. After the development of a three-step synthetic route and characterization of the products by mass spectrometry and one- and two-dimensional nuclear magnetic resonance, the products cafestal and 15,16-dehydrocafestol were identified. In the molecular docking simulations, cafestol and its derivatives showed similar affinities (kcal/mol) and types of interaction with amino acid residues in the different complexes with FXR and CYP7A1. By combining these in silico data with a new alternative to obtain these compounds, the evaluation of the hypercholesterolemic activity becomes favorable in the future.