CONTRIBUIÇÃO AO ESTUDO QUÍMICO DE ESPÉCIES DE Ocotea OCORRENTES NA REGIÃO CENTRO-OESTE: NEOLIGNANAS BICICLO[3.2.1]OCTÂNICAS E OUTROS CONSTITUINTES DAS FOLHAS E CASCA DO CAULE DE Ocotea aciphylla

Abstract

Since time immemorial, natural products have been used in folk medicine in the treatment of various ailments, including the fight against inflammatory processes. A survey carried out between 1981-2019 showed that about 49% of medicines registered by the Food and Drug Administration (FDA) came from natural products, such as prototypes or in their entirety. Inserted in the Lauraceae family, the genus Ocotea has a rich chemical composition, highlighting the sesquiterpenes, phenylpropanoids, alkaloids, benzopyrones, lignans and neolignans. Neolignans are dimers of C-6/C-3 units (propenylphenols and allylphenols) obtained via oxidative coupling and have a great structural diversity, which provides a promising biological potential, reflected by various biological activities, such as anti-inflammatory and antitumor activities , antimicrobial, anti-T. crossed, among others. Therefore, the objective of this work was to continue the line of research developed in the Chemistry of Natural Bioactive Products laboratory (PRONABio/INQUI/UFMS) aiming at the isolation, characterization and in silico evaluation of neolignans from a specimen of Ocotea aciphylla (Lauraceae). For this, the plant material (stem bark and leaves) was collected in the city of Nova Canaã do Norte/MT and extracted separately with EtOH 95%. Then, the ethanol extracts were individually partitioned with hexane, CH2Cl2 and AcOEt. From the resulting phases, the hexane and CH2Cl2 of the stem bark and leaves were selected for chemical study. Through the combination of chromatographic processes, such as column chromatography on silica gel 60 (70-230 and 230-400 mesh), Sephadex LH-20 and reverse phase high performance liquid chromatography, 28 substances were isolated and purified. For the structural determination of the substances obtained, the techniques of 1H and 13C NMR one- and two-dimensional spectroscopy, high resolution mass spectrometry via electrospray ionization and gas chromatography coupled to mass spectrometry were used. Four sesquiterpenes (spatulenol, germacrene D, torreyol and eudesm-4(15)-ene-1β,6α-diol), a phenylpropanoid (isoelemicin), an acyclic diterpene ((E)-phytol) were obtained from the leaves of O. aciphylla), a mixture of steroids (ꞵ-sitosterol, stigmasterol and campesterol), a polyprenol and nine bicyclo[3.2.1]octanic neolignans, seven of the macrophilin type (aciphyllins A, B, E, GH, neolignan A and nectamazin A) , one of the guianine type (Neolignana O) and one with a skeleton from a rare oxidative coupling (aciphyllin J). From the bark of the stem, two epimeric sesquiterpenes with a ẟ-cadinane skeleton (cubenol and epi-cubenol), a phenylpropanoid (dilapiol), the mixture of steroids also obtained from the leaves, five bicyclo[3.2.1]octanic neolignans (aciphyllins CD, F, I and neolignan D) and three others already obtained from leaves (Aciphyllins A, H and neolignan A). With the exception of neolignans A, D, O and nectamazin A, the ten neolignans called aciphyllins A-J are new. Through spatial chemistry (ChemGPS-NP) PCA was evaluated by correlating the physicochemical properties of PAF antagonist substances with the neolignans obtained, which provided a spatial approximation of neolignans from O. aciphylla with those bioactive for this biological assay model . In addition, the pharmacokinetic and toxicity profiles of neolignans were evaluated, which showed excellent ADME and toxicity results against the analyzed models. Finally, the species O. aciphylla is a rich source of bicyclooctane neolignans, which are compounds that present good pharmacokinetic results in addition to a possible anti-PAF activity in in silico evaluations.