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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 |
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author | 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. |
author_facet | 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. |
author_sort | Quimque, Mark Tristan J. |
collection | PubMed |
description | [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. |
format | Online Article Text |
id | pubmed-9583304 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-95833042022-10-21 Polyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity 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. ACS Omega [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. American Chemical Society 2022-10-07 /pmc/articles/PMC9583304/ /pubmed/36278100 http://dx.doi.org/10.1021/acsomega.2c05544 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | 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. Polyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity |
title | Polyoxygenated
Cyclohexenes from Uvaria
grandiflora with Multi-Enzyme Targeting Properties
Relevant in Type 2 Diabetes and Obesity |
title_full | Polyoxygenated
Cyclohexenes from Uvaria
grandiflora with Multi-Enzyme Targeting Properties
Relevant in Type 2 Diabetes and Obesity |
title_fullStr | Polyoxygenated
Cyclohexenes from Uvaria
grandiflora with Multi-Enzyme Targeting Properties
Relevant in Type 2 Diabetes and Obesity |
title_full_unstemmed | Polyoxygenated
Cyclohexenes from Uvaria
grandiflora with Multi-Enzyme Targeting Properties
Relevant in Type 2 Diabetes and Obesity |
title_short | Polyoxygenated
Cyclohexenes from Uvaria
grandiflora with Multi-Enzyme Targeting Properties
Relevant in Type 2 Diabetes and Obesity |
title_sort | polyoxygenated
cyclohexenes from uvaria
grandiflora with multi-enzyme targeting properties
relevant in type 2 diabetes and obesity |
url | 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 |
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