Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Quimque, Mark Tristan J., Magsipoc, Ryan Joseph Y., Llames, Lloyd Christian J., Flores, Angeli Izza G., Garcia, Katherine Yasmin M., Ratzenböck, Andreas, Hussain, Hidayat, Macabeo, Allan Patrick G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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
Descripción
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.