Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors
The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v26_n5_p1092_Martinez http://hdl.handle.net/20.500.12110/paper_09680896_v26_n5_p1092_Martinez |
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paper:paper_09680896_v26_n5_p1092_Martinez2023-06-08T15:58:58Z Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors DMHCA Liver X receptors Molecular dynamics Steroid amides 19 acetoxy 2alpha,3alpha epoxy 5ah cholanic acid methyl ester 19 acetoxy 5betah 2 cholenic acid methyl ester 3 oxo 6beta,19 epoxy 4 cholenic acid methyl ester 3alpha hydroxy 2beta,19 epoxy 5alphah cholanic acid methyl ester 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid methyl ester 3beta acetoxy 19 hydroxy 5 cholenic acid methyl ester 3beta acetoxy 5alpha bromo 6beta,19 epoxycholanic acid methyl ester 3beta hydroxy 19 acetoxy 5betah cholanic acid methyl ester 3beta,19 diacetoxy 5alphah cholanic acid methyl ester lithocholic acid liver X receptor liver X receptor alpha liver X receptor beta n,n dimethyl 3alpha hydroxy 2beta,19 epoxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 6beta,19 epoxy 4 cholenamide n,n dimethyl 3alpha,6alpha dihydroxy 5betah cholanamide n,n dimethyl 3beta hydroxy 2beta,19 epoxy 5alphah cholanamide n,n dimethyl 3beta hydroxy 5 cholenamide n,n dimethyl 3beta hydroxycholenamide steroid unclassified drug amide cholane derivative cholic acid derivative isoprotein liver X receptor N,N-dimethyl-3-hydroxy-5-cholenamide Article BHK-21 cell line cell culture chemical modification drug activity drug binding drug conformation drug screening drug structure drug synthesis genetic transfection human human cell hydrogen bond luciferase assay molecular dynamics agonists animal antagonists and inhibitors binding site cell line chemistry hamster metabolism protein tertiary structure synthesis Amides Animals Binding Sites Cell Line Cholanes Cholic Acids Cricetinae Humans Liver X Receptors Molecular Dynamics Simulation Protein Isoforms Protein Structure, Tertiary The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid. The LXRα and LXRβ activity of these analogues was evaluated by using a luciferase reporter assay in BHK21 cells. Compounds were tested in both the agonist and antagonist modes. Results indicated that the agonist/antagonist profile is dependent on the steroid configuration at the A/B ring junction. Notably, in contrast to DMHCA, the amide derived from lithocholic acid (2) with an A/B cis configuration and its 6,19-epoxy analogue 4 behaved as LXRα selective agonists, while the 2,19-epoxy analogues with an A/B trans configuration were antagonists of both isoforms. The binding mode of the analogues to both LXR isoforms was assessed by using 50 ns molecular dynamics (MD) simulations. Results revealed conformational differences between LXRα- and LXRβ-ligand complexes, mainly in the hydrogen bonding network that involves the C-3 hydroxyl. Overall, these results indicate that the synthetized DMHCA analogues could be interesting candidates for a therapeutic modulation of the LXRs. © 2018 Elsevier Ltd 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v26_n5_p1092_Martinez http://hdl.handle.net/20.500.12110/paper_09680896_v26_n5_p1092_Martinez |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
DMHCA Liver X receptors Molecular dynamics Steroid amides 19 acetoxy 2alpha,3alpha epoxy 5ah cholanic acid methyl ester 19 acetoxy 5betah 2 cholenic acid methyl ester 3 oxo 6beta,19 epoxy 4 cholenic acid methyl ester 3alpha hydroxy 2beta,19 epoxy 5alphah cholanic acid methyl ester 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid methyl ester 3beta acetoxy 19 hydroxy 5 cholenic acid methyl ester 3beta acetoxy 5alpha bromo 6beta,19 epoxycholanic acid methyl ester 3beta hydroxy 19 acetoxy 5betah cholanic acid methyl ester 3beta,19 diacetoxy 5alphah cholanic acid methyl ester lithocholic acid liver X receptor liver X receptor alpha liver X receptor beta n,n dimethyl 3alpha hydroxy 2beta,19 epoxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 6beta,19 epoxy 4 cholenamide n,n dimethyl 3alpha,6alpha dihydroxy 5betah cholanamide n,n dimethyl 3beta hydroxy 2beta,19 epoxy 5alphah cholanamide n,n dimethyl 3beta hydroxy 5 cholenamide n,n dimethyl 3beta hydroxycholenamide steroid unclassified drug amide cholane derivative cholic acid derivative isoprotein liver X receptor N,N-dimethyl-3-hydroxy-5-cholenamide Article BHK-21 cell line cell culture chemical modification drug activity drug binding drug conformation drug screening drug structure drug synthesis genetic transfection human human cell hydrogen bond luciferase assay molecular dynamics agonists animal antagonists and inhibitors binding site cell line chemistry hamster metabolism protein tertiary structure synthesis Amides Animals Binding Sites Cell Line Cholanes Cholic Acids Cricetinae Humans Liver X Receptors Molecular Dynamics Simulation Protein Isoforms Protein Structure, Tertiary |
| spellingShingle |
DMHCA Liver X receptors Molecular dynamics Steroid amides 19 acetoxy 2alpha,3alpha epoxy 5ah cholanic acid methyl ester 19 acetoxy 5betah 2 cholenic acid methyl ester 3 oxo 6beta,19 epoxy 4 cholenic acid methyl ester 3alpha hydroxy 2beta,19 epoxy 5alphah cholanic acid methyl ester 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid methyl ester 3beta acetoxy 19 hydroxy 5 cholenic acid methyl ester 3beta acetoxy 5alpha bromo 6beta,19 epoxycholanic acid methyl ester 3beta hydroxy 19 acetoxy 5betah cholanic acid methyl ester 3beta,19 diacetoxy 5alphah cholanic acid methyl ester lithocholic acid liver X receptor liver X receptor alpha liver X receptor beta n,n dimethyl 3alpha hydroxy 2beta,19 epoxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 6beta,19 epoxy 4 cholenamide n,n dimethyl 3alpha,6alpha dihydroxy 5betah cholanamide n,n dimethyl 3beta hydroxy 2beta,19 epoxy 5alphah cholanamide n,n dimethyl 3beta hydroxy 5 cholenamide n,n dimethyl 3beta hydroxycholenamide steroid unclassified drug amide cholane derivative cholic acid derivative isoprotein liver X receptor N,N-dimethyl-3-hydroxy-5-cholenamide Article BHK-21 cell line cell culture chemical modification drug activity drug binding drug conformation drug screening drug structure drug synthesis genetic transfection human human cell hydrogen bond luciferase assay molecular dynamics agonists animal antagonists and inhibitors binding site cell line chemistry hamster metabolism protein tertiary structure synthesis Amides Animals Binding Sites Cell Line Cholanes Cholic Acids Cricetinae Humans Liver X Receptors Molecular Dynamics Simulation Protein Isoforms Protein Structure, Tertiary Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| topic_facet |
DMHCA Liver X receptors Molecular dynamics Steroid amides 19 acetoxy 2alpha,3alpha epoxy 5ah cholanic acid methyl ester 19 acetoxy 5betah 2 cholenic acid methyl ester 3 oxo 6beta,19 epoxy 4 cholenic acid methyl ester 3alpha hydroxy 2beta,19 epoxy 5alphah cholanic acid methyl ester 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid 3alpha hydroxy 6beta,19 epoxy 4 cholenic acid methyl ester 3beta acetoxy 19 hydroxy 5 cholenic acid methyl ester 3beta acetoxy 5alpha bromo 6beta,19 epoxycholanic acid methyl ester 3beta hydroxy 19 acetoxy 5betah cholanic acid methyl ester 3beta,19 diacetoxy 5alphah cholanic acid methyl ester lithocholic acid liver X receptor liver X receptor alpha liver X receptor beta n,n dimethyl 3alpha hydroxy 2beta,19 epoxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 5betah cholanamide n,n dimethyl 3alpha hydroxy 6beta,19 epoxy 4 cholenamide n,n dimethyl 3alpha,6alpha dihydroxy 5betah cholanamide n,n dimethyl 3beta hydroxy 2beta,19 epoxy 5alphah cholanamide n,n dimethyl 3beta hydroxy 5 cholenamide n,n dimethyl 3beta hydroxycholenamide steroid unclassified drug amide cholane derivative cholic acid derivative isoprotein liver X receptor N,N-dimethyl-3-hydroxy-5-cholenamide Article BHK-21 cell line cell culture chemical modification drug activity drug binding drug conformation drug screening drug structure drug synthesis genetic transfection human human cell hydrogen bond luciferase assay molecular dynamics agonists animal antagonists and inhibitors binding site cell line chemistry hamster metabolism protein tertiary structure synthesis Amides Animals Binding Sites Cell Line Cholanes Cholic Acids Cricetinae Humans Liver X Receptors Molecular Dynamics Simulation Protein Isoforms Protein Structure, Tertiary |
| description |
The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid. The LXRα and LXRβ activity of these analogues was evaluated by using a luciferase reporter assay in BHK21 cells. Compounds were tested in both the agonist and antagonist modes. Results indicated that the agonist/antagonist profile is dependent on the steroid configuration at the A/B ring junction. Notably, in contrast to DMHCA, the amide derived from lithocholic acid (2) with an A/B cis configuration and its 6,19-epoxy analogue 4 behaved as LXRα selective agonists, while the 2,19-epoxy analogues with an A/B trans configuration were antagonists of both isoforms. The binding mode of the analogues to both LXR isoforms was assessed by using 50 ns molecular dynamics (MD) simulations. Results revealed conformational differences between LXRα- and LXRβ-ligand complexes, mainly in the hydrogen bonding network that involves the C-3 hydroxyl. Overall, these results indicate that the synthetized DMHCA analogues could be interesting candidates for a therapeutic modulation of the LXRs. © 2018 Elsevier Ltd |
| title |
Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| title_short |
Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| title_full |
Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| title_fullStr |
Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| title_full_unstemmed |
Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| title_sort |
synthesis and activity evaluation of a series of cholanamides as modulators of the liver x receptors |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v26_n5_p1092_Martinez http://hdl.handle.net/20.500.12110/paper_09680896_v26_n5_p1092_Martinez |
| _version_ |
1768542849748434944 |