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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| Otros Autores: | , , , , , |
| Formato: | Capítulo de libro |
| Lenguaje: | Inglés |
| Publicado: |
Elsevier Ltd
2018
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| Acceso en línea: | Registro en Scopus DOI Handle Registro en la Biblioteca Digital |
| Aporte de: | Registro referencial: Solicitar el recurso aquí |
| LEADER | 12496caa a22016217a 4500 | ||
|---|---|---|---|
| 001 | PAPER-17080 | ||
| 003 | AR-BaUEN | ||
| 005 | 20230518204812.0 | ||
| 008 | 190410s2018 xx ||||fo|||| 00| 0 eng|d | ||
| 024 | 7 | |2 scopus |a 2-s2.0-85042051689 | |
| 024 | 7 | |2 cas |a 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 | |
| 040 | |a Scopus |b spa |c AR-BaUEN |d AR-BaUEN | ||
| 030 | |a BMECE | ||
| 100 | 1 | |a Martínez, M.D. | |
| 245 | 1 | 0 | |a Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors |
| 260 | |b Elsevier Ltd |c 2018 | ||
| 270 | 1 | 0 | |m Burton, G.; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química OrgánicaArgentina; email: burton@qo.fcen.uba.ar |
| 506 | |2 openaire |e Política editorial | ||
| 504 | |a Gabbi, C., Warner, M., Gustafsson, J.A., Action mechanisms of Liver X Receptors (2014) Biochem Biophys Res Commun, 446, pp. 647-650 | ||
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| 504 | |a Tice, C.M., Noto, P.B., Fan, K.Y., Zhuang, L., Lala, D.S., Singh, S.B., The medicinal chemistry of liver X receptor (LXR) modulators (2014) J Med Chem, 57, pp. 7182-7205 | ||
| 504 | |a Hong, C., Tontonoz, P., Liver X receptors in lipid metabolism: opportunities for drug discovery (2014) Nat Rev Drug Discov, 13, pp. 433-444 | ||
| 504 | |a Im, S.S., Osborne, T.F., Liver x receptors in atherosclerosis and inflammation (2011) Circ Res, 108, pp. 996-1001 | ||
| 504 | |a Viennois, E., Mouzat, K., Dufour, J., Morel, L., Lobaccaro, J.M., Baron, S., Selective liver X receptor modulators (SLiMs): what use in human health? (2012) Mol Cell Endocrinol, 351, pp. 129-141 | ||
| 504 | |a Repa, J.J., Liang, G., Ou, J., Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta (2000) Genes Dev, 14, pp. 2819-2830 | ||
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| 504 | |a Torocsik, D., Szanto, A., Nagy, L., Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages (2009) Mol Aspects Med, 30, pp. 134-152 | ||
| 504 | |a Zhao, C., Dahlman-Wright, K., Liver X receptor in cholesterol metabolism (2010) J Endocrinol, 204, pp. 233-240 | ||
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| 504 | |a Kratzer, A., Buchebner, M., Pfeifer, T., Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia (2009) J Lipid Res, 50, pp. 312-326 | ||
| 504 | |a Yu, S., Li, S., Henke, A., Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases (2016) FASEB J, 30, pp. 2570-2579 | ||
| 504 | |a Alvarez, L.D., Dansey, M.V., Grinman, D.Y., Destabilization of the torsioned conformation of a ligand side chain inverts the LXRbeta activity (2015) Biochim Biophys Acta Mol Cell Biol Lip, 1851, pp. 1577-1586 | ||
| 504 | |a Viktorsson, E.O., Gabrielsen, M., Kumarachandran, N., Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations (2017) Steroids, 118, pp. 119-127 | ||
| 504 | |a Peng, D., Hiipakka, R.A., Dai, Q., Antiatherosclerotic effects of a novel synthetic tissue-selective steroidal liver X receptor agonist in low-density lipoprotein receptor-deficient mice (2008) J Pharmacol Exp Ther, 327, pp. 332-342 | ||
| 504 | |a Fu, J., Cheng, K., Zhang, Z.M., Fang, R.Q., Zhu, H.L., Synthesis, structure and structure-activity relationship analysis of caffeic acid amides as potential antimicrobials (2010) Eur J Med Chem, 45, pp. 2638-2643 | ||
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| 504 | |a Humphrey, W., Dalke, A., Schulten, K., VMD: visual molecular dynamics (1996) J Mol Graph, 14, pp. 27-38 | ||
| 520 | 3 | |a 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 |l eng | |
| 536 | |a Detalles de la financiación: Agencia Nacional de Promoción Científica y Tecnológica, PICT 2014-0626 | ||
| 536 | |a Detalles de la financiación: Universidad de Buenos Aires, 20020130100367 | ||
| 536 | |a Detalles de la financiación: Consejo Nacional de Investigaciones Científicas y Técnicas, PIP 112-201101-00702 | ||
| 536 | |a Detalles de la financiación: This work was supported by Agencia Nacional de Promoción Científica y Tecnológica ( PICT 2014-0626 ), CONICET -Argentina ( PIP 112-201101-00702 ) and Universidad de Buenos Aires (Grant 20020130100367 ). A | ||
| 593 | |a Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina | ||
| 593 | |a Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina | ||
| 593 | |a CONICET – Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina | ||
| 593 | |a CONICET – Universidad de Buenos Aires, IFIBYNE, Buenos Aires, Argentina | ||
| 690 | 1 | 0 | |a DMHCA |
| 690 | 1 | 0 | |a LIVER X RECEPTORS |
| 690 | 1 | 0 | |a MOLECULAR DYNAMICS |
| 690 | 1 | 0 | |a STEROID AMIDES |
| 690 | 1 | 0 | |a 19 ACETOXY 2ALPHA,3ALPHA EPOXY 5AH CHOLANIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 19 ACETOXY 5BETAH 2 CHOLENIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3 OXO 6BETA,19 EPOXY 4 CHOLENIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3ALPHA HYDROXY 2BETA,19 EPOXY 5ALPHAH CHOLANIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3ALPHA HYDROXY 6BETA,19 EPOXY 4 CHOLENIC ACID |
| 690 | 1 | 0 | |a 3ALPHA HYDROXY 6BETA,19 EPOXY 4 CHOLENIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3BETA ACETOXY 19 HYDROXY 5 CHOLENIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3BETA ACETOXY 5ALPHA BROMO 6BETA,19 EPOXYCHOLANIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3BETA HYDROXY 19 ACETOXY 5BETAH CHOLANIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a 3BETA,19 DIACETOXY 5ALPHAH CHOLANIC ACID METHYL ESTER |
| 690 | 1 | 0 | |a LITHOCHOLIC ACID |
| 690 | 1 | 0 | |a LIVER X RECEPTOR |
| 690 | 1 | 0 | |a LIVER X RECEPTOR ALPHA |
| 690 | 1 | 0 | |a LIVER X RECEPTOR BETA |
| 690 | 1 | 0 | |a N,N DIMETHYL 3ALPHA HYDROXY 2BETA,19 EPOXY 5BETAH CHOLANAMIDE |
| 690 | 1 | 0 | |a N,N DIMETHYL 3ALPHA HYDROXY 5BETAH CHOLANAMIDE |
| 690 | 1 | 0 | |a N,N DIMETHYL 3ALPHA HYDROXY 6BETA,19 EPOXY 4 CHOLENAMIDE |
| 690 | 1 | 0 | |a N,N DIMETHYL 3ALPHA,6ALPHA DIHYDROXY 5BETAH CHOLANAMIDE |
| 690 | 1 | 0 | |a N,N DIMETHYL 3BETA HYDROXY 2BETA,19 EPOXY 5ALPHAH CHOLANAMIDE |
| 690 | 1 | 0 | |a N,N DIMETHYL 3BETA HYDROXY 5 CHOLENAMIDE |
| 690 | 1 | 0 | |a N,N DIMETHYL 3BETA HYDROXYCHOLENAMIDE |
| 690 | 1 | 0 | |a STEROID |
| 690 | 1 | 0 | |a UNCLASSIFIED DRUG |
| 690 | 1 | 0 | |a AMIDE |
| 690 | 1 | 0 | |a CHOLANE DERIVATIVE |
| 690 | 1 | 0 | |a CHOLIC ACID DERIVATIVE |
| 690 | 1 | 0 | |a ISOPROTEIN |
| 690 | 1 | 0 | |a LIVER X RECEPTOR |
| 690 | 1 | 0 | |a N,N-DIMETHYL-3-HYDROXY-5-CHOLENAMIDE |
| 690 | 1 | 0 | |a ARTICLE |
| 690 | 1 | 0 | |a BHK-21 CELL LINE |
| 690 | 1 | 0 | |a CELL CULTURE |
| 690 | 1 | 0 | |a CHEMICAL MODIFICATION |
| 690 | 1 | 0 | |a DRUG ACTIVITY |
| 690 | 1 | 0 | |a DRUG BINDING |
| 690 | 1 | 0 | |a DRUG CONFORMATION |
| 690 | 1 | 0 | |a DRUG SCREENING |
| 690 | 1 | 0 | |a DRUG STRUCTURE |
| 690 | 1 | 0 | |a DRUG SYNTHESIS |
| 690 | 1 | 0 | |a GENETIC TRANSFECTION |
| 690 | 1 | 0 | |a HUMAN |
| 690 | 1 | 0 | |a HUMAN CELL |
| 690 | 1 | 0 | |a HYDROGEN BOND |
| 690 | 1 | 0 | |a LUCIFERASE ASSAY |
| 690 | 1 | 0 | |a MOLECULAR DYNAMICS |
| 690 | 1 | 0 | |a AGONISTS |
| 690 | 1 | 0 | |a ANIMAL |
| 690 | 1 | 0 | |a ANTAGONISTS AND INHIBITORS |
| 690 | 1 | 0 | |a BINDING SITE |
| 690 | 1 | 0 | |a CELL LINE |
| 690 | 1 | 0 | |a CHEMISTRY |
| 690 | 1 | 0 | |a HAMSTER |
| 690 | 1 | 0 | |a METABOLISM |
| 690 | 1 | 0 | |a PROTEIN TERTIARY STRUCTURE |
| 690 | 1 | 0 | |a SYNTHESIS |
| 690 | 1 | 0 | |a AMIDES |
| 690 | 1 | 0 | |a ANIMALS |
| 690 | 1 | 0 | |a BINDING SITES |
| 690 | 1 | 0 | |a CELL LINE |
| 690 | 1 | 0 | |a CHOLANES |
| 690 | 1 | 0 | |a CHOLIC ACIDS |
| 690 | 1 | 0 | |a CRICETINAE |
| 690 | 1 | 0 | |a HUMANS |
| 690 | 1 | 0 | |a LIVER X RECEPTORS |
| 690 | 1 | 0 | |a MOLECULAR DYNAMICS SIMULATION |
| 690 | 1 | 0 | |a PROTEIN ISOFORMS |
| 690 | 1 | 0 | |a PROTEIN STRUCTURE, TERTIARY |
| 700 | 1 | |a Ghini, A.A. | |
| 700 | 1 | |a Dansey, M.V. | |
| 700 | 1 | |a Veleiro, A.S. | |
| 700 | 1 | |a Pecci, A. | |
| 700 | 1 | |a Alvarez, L.D. | |
| 700 | 1 | |a Burton, G. | |
| 773 | 0 | |d Elsevier Ltd, 2018 |g v. 26 |h pp. 1092-1101 |k n. 5 |p Bioorg. Med. Chem. |x 09680896 |w (AR-BaUEN)CENRE-3989 |t Bioorganic and Medicinal Chemistry | |
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