Open AccessPolyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity
Author(s) -
Mark Tristan J. Quimque,
Ryan Joseph Y. Magsipoc,
Lloyd Christian J. Llames,
Angeli Izza G. Flores,
Katherine Yasmin M. Garcia,
Andreas Ratzenböck,
Hidayat Hussain,
Allan Patrick G. Macabeo
Publication year - 2022
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.2c05544
Subject(s) - chemistry , stereochemistry , pharmacophore , docking (animal) , circular dichroism , enzyme , computational chemistry , biochemistry , nursing , medicine
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 (1 S ,2 S ,3 R ,6 R ) 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.