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
_version_ 1784813042548080640
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
work_keys_str_mv AT quimquemarktristanj polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT magsipocryanjosephy polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT llameslloydchristianj polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT floresangeliizzag polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT garciakatherineyasminm polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT ratzenbockandreas polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT hussainhidayat polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity
AT macabeoallanpatrickg polyoxygenatedcyclohexenesfromuvariagrandiflorawithmultienzymetargetingpropertiesrelevantintype2diabetesandobesity