Autometátese da DL-Kavain e avaliação da atividade mutagênica em células somáticas de Drosophila melanogaster

Abstract

The Kavain molecule is the major component among the cavalactones present in Kava (Piper methysticum G. Forst), exhibits different pharmacological activities, including: anticonvulsive, analgesic, anxiolytic, antiepileptic, antithrombotic, anti-inflammatory and antioxidant. What brings us to the interest of synthesizing compounds from this molecule, which may present an improved activity. The aim of this work was to synthesize these compounds by Self metathesis of olefins, as well as to evaluate the potential effect of Kavain on DNA by means of the mutation and somatic recombination test (SMART) in Drosophila melanogaster. In the bioassay, third-stage larvae derived from a standard (ST) cross and exhibiting high metabolic bioactivation (HB) were treated with different kavain concentrations (32, 64 and 128 μg/mL), alone and in combination with DXR (0.125 mg/mL), at the end of the cycle, the occurrence of mutant spots on the wings was evaluated. The expected products with catalyst: substrate proportion of 1: 1 mol were observed under conditions of 50 ° C for 48 and 96 hours. The conversion of substrate to the formation of stilbene was higher than for formation of bis (4-methoxy-6-vinyl-2H-pyrone), the two products obtained. It is possible that the low yield of the bis (4-methoxy-6-vinyl-2H-pyrone) occurred because of the coordination of the oxygenated groups of the methoxy pyrone part of the Kavain to the metallic center, forming a more stable intermediate and less favorable formation of product. The catalysis of this work was interpreted relating to the characteristics of the catalyst and substrate, mainly electronic and steric. . In ST offspring, kavain showed no mutagenic or recombinogenic effect. In the HB cross, mutagenic activity was observed at kavain concentrations of 64 and 128 μg/mL. When co-administered simultaneously DXR treatment, ST crossing the kavain 32 ug / mL inhibited (75.94%) of the mutagenic activity whereas the DXR 128 ug / ml potentiate DNA damage in 33.04%. Induction (10.28%) and inhibition (53.66%) of DNA damage were observed at the concentrations of 32 and 64 μg / mL, respectively. The mutagenic effect of kavain and the antagonic effects that depend on the concentration and amount of CYP450 complex metabolic enzymes when combined with DXR underscore the importance of toxicogenetic tests before new drugs are approved in order to ensure safe administration to the public.