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| Main Authors: | , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Bioorganic chemistry
2026
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41740353/ |
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| _version_ | 1868266082199928833 |
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| author | Luu, Phuong Vu Nguyen, Cuong-Quoc Ton-Nu, Huong Lien Phan, Thuy-Tien Thi Huynh, Quoc-Dung Tran Pham, Ngoc-Thac Le, Huong-Giang Chen, Lo-Yun Chang, Yu-Chia Su, Jui-Hsin Peng, Bo-Rong Lai, Kuei-Hung |
| author_facet | Luu, Phuong Vu Nguyen, Cuong-Quoc Ton-Nu, Huong Lien Phan, Thuy-Tien Thi Huynh, Quoc-Dung Tran Pham, Ngoc-Thac Le, Huong-Giang Chen, Lo-Yun Chang, Yu-Chia Su, Jui-Hsin Peng, Bo-Rong Lai, Kuei-Hung Luu, Phuong Vu Nguyen, Cuong-Quoc Ton-Nu, Huong Lien Phan, Thuy-Tien Thi Huynh, Quoc-Dung Tran Pham, Ngoc-Thac Le, Huong-Giang Chen, Lo-Yun Chang, Yu-Chia Su, Jui-Hsin Peng, Bo-Rong Lai, Kuei-Hung |
| collection | PubMed - marine biology |
| contents | Stereoselective AChE/BChE/BACE1 inhibition by enantiomeric norsesquiterpenoids with an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold from the soft coral Sclerophytum humesi. Luu, Phuong Vu Nguyen, Cuong-Quoc Ton-Nu, Huong Lien Phan, Thuy-Tien Thi Huynh, Quoc-Dung Tran Pham, Ngoc-Thac Le, Huong-Giang Chen, Lo-Yun Chang, Yu-Chia Su, Jui-Hsin Peng, Bo-Rong Lai, Kuei-Hung Animals Cholinesterase Inhibitors Acetylcholinesterase Stereoisomerism Structure-Activity Relationship Anthozoa Molecular Structure Sesquiterpenes Butyrylcholinesterase Humans Dose-Response Relationship, Drug Molecular Docking Simulation Chemical investigation of the soft coral Sclerophytum humesi led to the discovery of (±)-norsclerohumin A (1), a pair of enantiomeric norsesquiterpenoids possessing an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold with a rare C5-O-C8 intramolecular ether-bridge. Their structures were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, ECD, and DP4+ analysis. A plausible biosynthetic pathway is proposed to account for the formation of the unique ether-bridged oxatricyclic framework and the generation of the enantiomeric pair (±)-norsclerohumin A. In addition, the absolute configuration of sinunorcaryophyllenol (2) was fully determined for the first time. Mechanistic studies revealed pronounced stereoselective inhibition of acetylcholinesterase (AChE), in which (-)-1b was far more potent than its antipode (+)-1a, with IC values of 10.08 ± 0.48 μM and 149.8 ± 1.02 μM, respectively. Enzyme kinetics showed that (-)-1b is a mixed-type AChE inhibitor (K = 6.61 μM), binding both the free enzyme and enzyme-substrate complex. Molecular docking indicated that its ether-bridged oxatricyclic skeleton fits optimally in the AChE active site, stabilizing key interactions within both the catalytic and peripheral binding regions. Importantly, (-)-1b displayed selective AChE inhibition without detectable cytotoxicity toward normal cells (IC > 256 μM), underscoring its favorable safety profile. Furthermore, pharmacokinetic predictions and quantum chemical parameters further suggest favorable drug-like properties, including high gastrointestinal absorption, blood-brain barrier permeability, and low risk of P-glycoprotein/cytochrome P450 interactions. These findings highlight the oxatricyclo[7.2.1.0dodecane scaffold as a promising lead for neurotherapeutic development. |
| format | Artículo científico |
| id | pubmed_41740353 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Bioorganic chemistry |
| record_format | pubmed |
| spellingShingle | Stereoselective AChE/BChE/BACE1 inhibition by enantiomeric norsesquiterpenoids with an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold from the soft coral Sclerophytum humesi. Luu, Phuong Vu Nguyen, Cuong-Quoc Ton-Nu, Huong Lien Phan, Thuy-Tien Thi Huynh, Quoc-Dung Tran Pham, Ngoc-Thac Le, Huong-Giang Chen, Lo-Yun Chang, Yu-Chia Su, Jui-Hsin Peng, Bo-Rong Lai, Kuei-Hung Animals Cholinesterase Inhibitors Acetylcholinesterase Stereoisomerism Structure-Activity Relationship Anthozoa Molecular Structure Sesquiterpenes Butyrylcholinesterase Humans Dose-Response Relationship, Drug Molecular Docking Simulation Stereoselective AChE/BChE/BACE1 inhibition by enantiomeric norsesquiterpenoids with an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold from the soft coral Sclerophytum humesi. Luu, Phuong Vu Nguyen, Cuong-Quoc Ton-Nu, Huong Lien Phan, Thuy-Tien Thi Huynh, Quoc-Dung Tran Pham, Ngoc-Thac Le, Huong-Giang Chen, Lo-Yun Chang, Yu-Chia Su, Jui-Hsin Peng, Bo-Rong Lai, Kuei-Hung Animals Cholinesterase Inhibitors Acetylcholinesterase Stereoisomerism Structure-Activity Relationship Anthozoa Molecular Structure Sesquiterpenes Butyrylcholinesterase Humans Dose-Response Relationship, Drug Molecular Docking Simulation Chemical investigation of the soft coral Sclerophytum humesi led to the discovery of (±)-norsclerohumin A (1), a pair of enantiomeric norsesquiterpenoids possessing an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold with a rare C5-O-C8 intramolecular ether-bridge. Their structures were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, ECD, and DP4+ analysis. A plausible biosynthetic pathway is proposed to account for the formation of the unique ether-bridged oxatricyclic framework and the generation of the enantiomeric pair (±)-norsclerohumin A. In addition, the absolute configuration of sinunorcaryophyllenol (2) was fully determined for the first time. Mechanistic studies revealed pronounced stereoselective inhibition of acetylcholinesterase (AChE), in which (-)-1b was far more potent than its antipode (+)-1a, with IC values of 10.08 ± 0.48 μM and 149.8 ± 1.02 μM, respectively. Enzyme kinetics showed that (-)-1b is a mixed-type AChE inhibitor (K = 6.61 μM), binding both the free enzyme and enzyme-substrate complex. Molecular docking indicated that its ether-bridged oxatricyclic skeleton fits optimally in the AChE active site, stabilizing key interactions within both the catalytic and peripheral binding regions. Importantly, (-)-1b displayed selective AChE inhibition without detectable cytotoxicity toward normal cells (IC > 256 μM), underscoring its favorable safety profile. Furthermore, pharmacokinetic predictions and quantum chemical parameters further suggest favorable drug-like properties, including high gastrointestinal absorption, blood-brain barrier permeability, and low risk of P-glycoprotein/cytochrome P450 interactions. These findings highlight the oxatricyclo[7.2.1.0dodecane scaffold as a promising lead for neurotherapeutic development. |
| title | Stereoselective AChE/BChE/BACE1 inhibition by enantiomeric norsesquiterpenoids with an unprecedented oxatricyclo[7.2.1.0]dodecane scaffold from the soft coral Sclerophytum humesi. |
| topic | Animals Cholinesterase Inhibitors Acetylcholinesterase Stereoisomerism Structure-Activity Relationship Anthozoa Molecular Structure Sesquiterpenes Butyrylcholinesterase Humans Dose-Response Relationship, Drug Molecular Docking Simulation |
| url | https://pubmed.ncbi.nlm.nih.gov/41740353/ |