Polyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity

Abstract

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.

Figure 1

Polyoxygenated cyclohexenes from U. grandiflora.

Figure 2

Homonuclear and heteronuclear correlations in 1.

Figure 3

Structures of eight possible stereoisomers for uvagrandol (1).

Figure 4

Experimental ECD spectrum of uvagrandol (1, black solid curve) compared with ωB97XD/DGDZVP-calculated ECD spectra (red solid curve) for the B3LYP/6-31G(d)-optimized conformers of (1S,2S,3R,6R)-1 and its enantiomer (red dashed curve).

Figure 5

Low-energy conformers (>1%) of (1S,2S,3R,6R)-1 optimized at B3LYP/6-31G(d) (PCM/MeCN).

Figure 6

2D and 3D docking pose of zeylenone (2) against (A) α-glucosidase (PDB ID: 5ZCC); (B) DPP-IV (PDB ID: 2RIP); (C) pancreatic lipase (PDB ID: 1ETH); and (D) MAGL (PDB ID: 3PE6).

Figure 7

BOILED-egg plot and bioavailability radar plots for gastrointestinal tract absorption and brain permeation prediction of compounds 1 and 2.