Derivados do ácido 6alfa,7beta-di-hidroxivouacapan-17beta-óico, isolado de Pterodon polygalaeflorus Benth: obtenção, análise estrutural e estudo da atividade antiproliferativa contra células cancerígenas

Abstract

This work focused on the isolation of the 6,7ß-dihydroxyvouacapan-17beta-oic acid from Pterodon polygalaeflorus Benth fruits, a plant also referred to as sucupira branca. Two lactones derivatives [6-hydroxyvouacapan-7,17-lactone (HVL) and 6-oxovouacapan-7,17-lactone (POL)] were prepared from such plant natural product. Modifications in HVL structure yielded the following furan ring-substituted compounds: 16-(N,N-diethylamino)methylen-6alfa-hydroxyvouacapan-7,17-lactone, 16-(N,N-dipropylamino)methylen-6alfa-hydroxyvouacapan-7,17-lactone, 16-(N,N-diisobutylamino)methylen-6alfa-hydroxyvouacapan-7,17-lactone, 16-(1-pyrrolydino)methylen-6alfa-hydroxyvouacapan-7,17-lactone, 16-(4-morpholino)methylen-6alfa-hydroxyvouacapan-7,17-lactone, and 16-(1-pyperidino)methylen-6alfa-hydroxyvouacapan-7,17-lactone. The first five mentioned compounds are novel in the literature. The furan C16-substitued derivatives were synthesized from Mannich reactions of HVL with iminium salts, which were obtained from also synthesized germinal amines N,N,N,N-tetra alkyl methylenediamine. All compounds were structurally characterized by Infrared (IR) and one and two dimensional Nuclear Magnetic Resonance (1H and 13C NMR) spectroscopy analyses. All synthesized compounds, together with 6-acetoxyvouacapan-7,17-lactone (AVL), were evaluated for the antiproliferative activity against the human cancer cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-ADR/RES (ovarian expressing the resistance phenotype for adriamycin), 786-0 (kidney), NCI-H460 (lung, non-small cells), PC-3 (prostate), OVCAR-03 (ovarian), HT-29 (colon), and K562 (erythromyeloblastoid leukemia). The antiproliferative activities parameters (TGI = concentration of compound that elicits total inhibition of cell growth) of the synthesized compounds were then, for a better understanding of the structure-activity relationship, utilized to a theoretical study about the chemical structure-biological activity relationship by employing DFT/BLYP/6-31G* calculations to obtain orbital energy, orbital population and electronic density parameters.