Síntese de enaminonaftoquinonas com atividade antiproliferativa e sua aplicação no estudo da reação de Povarov

Abstract

2-Amino-1,4-naphthoquinones, also called enamine naphthoquinone, can be formed by a nucleophilic substitution reaction of 1,4-naphthoquinones substituted by halides or any other feasible leaving group, and by oxidative conjugate addition to the 1, 4- naphthoquinone 43. They are compounds of wide biological interest due, among other reasons, to their synthetic versatility. Therefore, in the present work, ten enamine naphthoquinones were synthesized with yields ranging from 43 to 76%, by a nucleophilic substitution reaction. The compounds were evaluated for their antiproliferative activity in vitro by the MTT assay against four types of human cancer cell lines: HCT116, PC3, HL60 and SNB19. Enamine naphthoquinone 108 and 113, consisting of picolylamine and quinoline, respectively, were the most active (IC50 < 24 µM for all cell lines), like the values obtained for the control drugs (doxorubicin e 5- fluorouracil). In silico evaluations were also carried out, which allowed the development of a qualitative structure-activity relationship where the electrostatic characteristics, particularly the C2–C3 internuclear repulsion and the total molecular dipole moment, are related to the biological response. Molecular anchorage simulations indicate that synthetic compounds have the potential to act as inhibitors of topoisomerase II and thymidylate synthase enzymes. In addition, enamine naphthoquinone 105 was used as a nucleophile to obtain tetrahydroquinolines from the study of the Povarov reaction in naphthoquinone systems, using its classical version, that is, an aromatic amine, an aliphatic or aromatic aldehyde and an activated olefin. In this context, many efforts have been made to synthesize substituted tetrahydroquinoline derivatives and among the different reactions for the formation of the tetrahydroquinoline ring, the Povarov reaction proves to be attractive. However, a low nucleophilicity was observed against the first step of the mechanism (Mannich reaction), as shown in a computational study. Alternatively, the reaction was rationalized using 5-amino-1,4-naphthoquinone 280 as the reaction amine, leading to the formation of tetrahydroquinoline 295, characterized by NMR spectroscopy. In this sense, the Povarov adduct was obtained in a naphthoquinone system in an unprecedented way.