Planejamento in silico e síntese de derivados da β-lapachona como candidatos a agentes antimelanoma

Abstract

Melanoma accounts for 3% of cancer diagnoses, however, it has a high mortality rate due to its rapid evolution. It is characterized by the disordered growth of melanocytes and among its risk factors are exposure to UV rays or genetic predisposition. Treatment basically consists of tumor removal and chemotherapy. Thus, the search for new therapies with fewer adverse effects and with longer patient survival is constant. Lapachol, a naphthoquinone first isolated from sawdust of Ipê-roxo (Tabebuia avellanedae), together with its derivatives, has activity against several cancer strains, and has been the subject of many studies in this field. Computational methods make it possible to study the improvement of chemical structures that are candidates for drugs in a more agile way, saving resources in the selection of molecules that will be synthesized and tested, in addition to increasing the chances of success of the study. In this context, this research aimed to evaluate β-lapachone derivatives, obtained from lapachol, as antimelanoma agents, through in silico and in vitro analyses The derivatives were designed based on the literature and subjected to molecular docking analysis, in silico pharmacokinetic and toxicological predictions, synthesis, structural characterization and cytotoxicity analysis. A total of 137 derivatives were evaluated by docking against the enzymes Metalloproteinases of Matrix-2 and - 9; BRAFV600E. Of these, eight were selected and synthesized from 2.52 g of lapachol extracted from Ipê-roxo sawdust. The derivatives were purified by column chromatography and their chemical structure confirmed by 1H NMR (CDCl3; 500 MHz). Then its cytotoxicity was evaluated initially by the Artemia salina test and, later, against MRC-5 human fibroblasts. Of the derivatives synthesized with yields ranging from 24% (11) to 88% (7), seven are unprecedented in the literature. The docking results suggest that these molecules may be potential inhibitors of molecular targets of malignant tumors, due to the binding affinity for the selected proteins. In the test against A. salina, derivatives 3 and 8 presented LC50 of 67.36 and 314.86 μg/mL. respectively, and the others showed no significant toxicity. On the other hand, in the test against MRC-5 cells, all derivatives reduced cell viability below 20% after 48 hours at a concentration of 100 μM, and derivatives 5, 7, 8 and 11 had an IC50 of 48.54, 46 .96, 45.65 and 55.24 μM, respectively, after 72 hours. The observed results indicate the substances developed in this work as promising candidates for future investigations with more specific analyzes of their antimelanoma potential, especially molecule 8, due to its lower IC50 value for normal MRC-5 cells and higher lethality for Artemia salina. Another future perspective may be associated with the choice of formulations that improve their solubility characteristics, to increase their bioavailability.