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Polyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity
[Image: see text] Shikimic acid-derived polyoxygenated cyclohexene natural products commonly occurring in several species of the Uvaria represent natural products with promising biological activities. While a number of derivatives have been reported from Uvaria grandiflora (U. grandiflora), further...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9583304/ https://www.ncbi.nlm.nih.gov/pubmed/36278100 http://dx.doi.org/10.1021/acsomega.2c05544 |
Sumario: | [Image: see text] Shikimic acid-derived polyoxygenated cyclohexene natural products commonly occurring in several species of the Uvaria represent natural products with promising biological activities. While a number of derivatives have been reported from Uvaria grandiflora (U. grandiflora), further studies are needed to discover additional bioactive congeners, particularly derivatives with multi-protein target inhibitory properties implicated in diseases such as diabetes and obesity. In this paper, isolation and identification of a new highly oxygenated cyclohexene, uvagrandol (1), along with the known compound (-)-zeylenone (2) from the DCM sub-extract of U. grandiflora following in vitro and in silico assessment of their enzyme inhibitory properties against α-glucosidase, dipeptidyl peptidase IV, porcine lipase, and human recombinant monoacylglycerol lipase are reported. The structure of 1 was elucidated using 1D and 2D NMR data analysis. The absolute configuration of 1 was established by quantum chemical calculations via the Gauge-Independent Atomic Orbital (GIAO) NMR method followed by TDDFT-Electronic Circular Dichroism (ECD) calculations. The structures of the eight possible stereoisomers were optimized by means of DFT calculations (B3LYP/6-31+G[d,p] in vacuum), and then their isotropic shielding tensors were obtained using the GIAO method at mPW1PW91/6-31G(d,p) in chloroform. Through DP4+, the isomer of configuration (1S,2S,3R,6R) for 1 was predicted with 96.3% probability. Compounds 1 and 2 significantly inhibited the four target enzymes in vitro. Binding studies through molecular docking simulations showed strong binding affinities for (-)-zeylenone (2), thus validating the in vitro results. Our findings suggest the potential of polyoxygenated cyclohexenes, in particular (-)-zeylenone (2), in anti-diabetic and anti-obesity drug discovery. |
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