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Martínez, M.D.; Ghini, A.A.; Dansey, M.V.; Veleiro, A.S.; Pecci, A.; Alvarez, L.D.; Burton, G. "Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors" (2018) Bioorganic and Medicinal Chemistry. 26(5):1092-1101
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Abstract:

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

Registro:

Documento: Artículo
Título:Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors
Autor:Martínez, M.D.; Ghini, A.A.; Dansey, M.V.; Veleiro, A.S.; Pecci, A.; Alvarez, L.D.; Burton, G.
Filiación:Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, IFIBYNE, Buenos Aires, Argentina
Palabras clave: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
Año:2018
Volumen:26
Número:5
Página de inicio:1092
Página de fin:1101
DOI: http://dx.doi.org/10.1016/j.bmc.2018.01.025
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:lithocholic acid, 434-13-9; amide, 17655-31-1; Amides; Cholanes; Cholic Acids; Liver X Receptors; N,N-dimethyl-3-hydroxy-5-cholenamide; Protein Isoforms
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v26_n5_p1092_Martinez

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Citas:

---------- APA ----------
Martínez, M.D., Ghini, A.A., Dansey, M.V., Veleiro, A.S., Pecci, A., Alvarez, L.D. & Burton, G. (2018) . Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors. Bioorganic and Medicinal Chemistry, 26(5), 1092-1101.
http://dx.doi.org/10.1016/j.bmc.2018.01.025
---------- CHICAGO ----------
Martínez, M.D., Ghini, A.A., Dansey, M.V., Veleiro, A.S., Pecci, A., Alvarez, L.D., et al. "Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors" . Bioorganic and Medicinal Chemistry 26, no. 5 (2018) : 1092-1101.
http://dx.doi.org/10.1016/j.bmc.2018.01.025
---------- MLA ----------
Martínez, M.D., Ghini, A.A., Dansey, M.V., Veleiro, A.S., Pecci, A., Alvarez, L.D., et al. "Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors" . Bioorganic and Medicinal Chemistry, vol. 26, no. 5, 2018, pp. 1092-1101.
http://dx.doi.org/10.1016/j.bmc.2018.01.025
---------- VANCOUVER ----------
Martínez, M.D., Ghini, A.A., Dansey, M.V., Veleiro, A.S., Pecci, A., Alvarez, L.D., et al. Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors. Bioorg. Med. Chem. 2018;26(5):1092-1101.
http://dx.doi.org/10.1016/j.bmc.2018.01.025