Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

S-Dihydrodaidzein and 3-(1,3-benzoxazol-2-yl)-benzamide, Two New Potential β-estrogen Receptor Ligands with Anti-adipogenic Activity

Author(s): María F. Torres-Rojas, Gilberto Mandujano-Lazaro, Cesar Lopez-Camarillo, Esther Ramirez-Moreno, Domingo Mendez-Alvarez, Gildardo Rivera and Laurence A. Marchat*

Volume 20, Issue 4, 2024

Published on: 08 January, 2024

Page: [434 - 442] Pages: 9

DOI: 10.2174/0115734064285786231230185457

Price: $65

Abstract

Background: The elucidation of molecular pathways associated with adipogenesis has evidenced the relevance of estrogen and estrogen receptor beta (ERβ). The positive effects of ERβ ligands on adipogenesis, energy expenditure, lipolysis, food intake, and weight loss, make ERβ an attractive target for obesity control. From ligand-based virtual screening, molecular docking, and molecular dynamic simulations, six new likely ERβ ligands (C1 to C6) have been reported with potential for pharmacological obesity treatment.

Objective: In this study, the effect of molecules C1-C6 on adipogenesis using the murine 3T3-L1 cell line was evaluated.

Methods: Cell viability was assessed by MTT assays. Lipid accumulation and gene expression were investigated by ORO staining and real-time quantitative RT-PCR experiments, respectively.

Results: Cell viability was not significantly affected by C1-C6 at concentrations up to 10 μM. Interestingly, treatment with 10 μM of C1 (S-Dihydrodaidzein) and C2 (3-(1,3-benzoxazol-2-yl)- benzamide) for 72 h inhibited adipocyte differentiation; moreover, ORO staining evidenced a reduced intracellular lipid accumulation (40% at day 7). Consistently, mRNA expression of the adipogenic markers, PPARγ and C/EBPα, was reduced by 50% and 82%, respectively, in the case of C1, and by 83% and 59%, in the case of C2.

Conclusion: Altogether, these results show the two new potential β-estrogen receptor ligands, C1 and C2, to exhibit anti-adipogenic activity. They could further be used as lead structures for the development of more efficient drugs for obesity control.

« Previous Next »
Graphical Abstract

[1]
Sallis, J.F.; Glanz, K. Physical activity and food environments: Solutions to the obesity epidemic. Milbank Q., 2009, 87(1), 123-154.
[http://dx.doi.org/10.1111/j.1468-0009.2009.00550.x] [PMID: 19298418]
[2]
Mauvais-Jarvis, F.; Clegg, D.J.; Hevener, A.L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev., 2013, 34(3), 309-338.
[http://dx.doi.org/10.1210/er.2012-1055] [PMID: 23460719]
[3]
Ko, S.H.; Jung, Y. Energy metabolism changes and dysregulated lipid metabolism in postmenopausal women. Nutrients, 2021, 13(12), 4556.
[http://dx.doi.org/10.3390/nu13124556] [PMID: 34960109]
[4]
Lovre, D.; Lindsey, S.H.; Mauvais-Jarvis, F. Effect of menopausal hormone therapy on components of the metabolic syndrome. Ther. Adv. Cardiovasc. Dis., 2017, 11(1), 33-43.
[http://dx.doi.org/10.1177/1753944716649358] [PMID: 27234158]
[5]
Kumar, R.; Zakharov, M.N.; Khan, S.H.; Miki, R.; Jang, H.; Toraldo, G.; Singh, R.; Bhasin, S.; Jasuja, R. The dynamic structure of the estrogen receptor. J. Amino Acids, 2011, 2011, 1-7.
[http://dx.doi.org/10.4061/2011/812540] [PMID: 22312471]
[6]
Warner, M.; Huang, B.; Gustafsson, J.A. Estrogen receptor β as a pharmaceutical target. Trends Pharmacol. Sci., 2017, 38(1), 92-99.
[http://dx.doi.org/10.1016/j.tips.2016.10.006] [PMID: 27979317]
[7]
Heine, P.A.; Taylor, J.A.; Iwamoto, G.A.; Lubahn, D.B.; Cooke, P.S. Increased adipose tissue in male and female estrogen receptor-α knockout mice. Proc. Natl. Acad. Sci. USA, 2000, 97(23), 12729-12734.
[http://dx.doi.org/10.1073/pnas.97.23.12729] [PMID: 11070086]
[8]
González-Granillo, M.; Savva, C.; Li, X.; Fitch, M.; Pedrelli, M.; Hellerstein, M.; Parini, P.; Korach-André, M.; Gustafsson, J.Å. ERβ activation in obesity improves whole body metabolism via adipose tissue function and enhanced mitochondria biogenesis. Mol. Cell. Endocrinol., 2019, 479, 147-158.
[http://dx.doi.org/10.1016/j.mce.2018.10.007] [PMID: 30342056]
[9]
Yi, K.W.; Shin, J.H.; Seo, H.S.; Lee, J.K.; Oh, M.J.; Kim, T.; Saw, H.S.; Kim, S.H.; Hur, J.Y. Role of estrogen receptor-alpha and -beta in regulating leptin expression in 3T3-L1 adipocytes. Obes, 2008, 16, 2393-2399.
[http://dx.doi.org/10.1038/oby.2008.389]
[10]
Dieudonné, M.N.; Leneveu, M.C.; Giudicelli, Y.; Pecquery, R. Evidence for functional estrogen receptors α and β in human adipose cells: Regional specificities and regulation by estrogens. Am. J. Physiol. Cell Physiol., 2004, 286(3), C655-C661.
[http://dx.doi.org/10.1152/ajpcell.00321.2003] [PMID: 14761887]
[11]
Kramarova, T.V.; Dahlman Wright, K.; Pongratz, I. The role of the estrogen receptors in obesity. Drug Discov. Today Dis. Mech., 2009, 6(1-4), e49-e54.
[http://dx.doi.org/10.1016/j.ddmec.2009.11.001]
[12]
Mueller, S.; Korach, K.S. Estrogen receptors and endocrine diseases: Lessons from estrogen receptor knockout mice. Curr. Opin. Pharmacol., 2001, 1(6), 613-619.
[http://dx.doi.org/10.1016/S1471-4892(01)00105-9] [PMID: 11757817]
[13]
Ng, C.W.; Wong, K.K. Impact of estrogen receptor expression on prognosis of ovarian cancer according to antibody clone used for immunohistochemistry: A meta-analysis. J. Ovarian Res., 2022, 15(1), 63.
[http://dx.doi.org/10.1186/s13048-022-01001-4] [PMID: 35610648]
[14]
Andersen, C.L.; Sikora, M.J.; Boisen, M.M.; Ma, T.; Christie, A.; Tseng, G.; Park, Y.; Luthra, S.; Chandran, U.; Haluska, P.; Mantia-Smaldone, G.M.; Odunsi, K.; McLean, K.; Lee, A.V.; Elishaev, E.; Edwards, R.P.; Oesterreich, S. Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens. Clin. Cancer Res., 2017, 23(14), 3802-3812.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1501] [PMID: 28073843]
[15]
Liu, A.; Zhang, D.; Yang, X.; Song, Y. Estrogen receptor alpha activates MAPK signaling pathway to promote the development of endometrial cancer. J. Cell. Biochem., 2019, 120(10), 17593-17601.
[http://dx.doi.org/10.1002/jcb.29027] [PMID: 31140648]
[16]
Ponnusamy, S.; Tran, Q.T.; Harvey, I.; Smallwood, H.S.; Thiyagarajan, T.; Banerjee, S.; Johnson, D.L.; Dalton, J.T.; Sullivan, R.D.; Miller, D.D.; Bridges, D.; Narayanan, R. Pharmacologic activation of estrogen receptor α increases mitochondrial function, energy expenditure, and brown adipose tissue. FASEB J., 2017, 31(1), 266-281.
[http://dx.doi.org/10.1096/fj.201600787rr] [PMID: 27733447]
[17]
Setchell, K.D.R.; Clerici, C.; Lephart, E.D.; Cole, S.J.; Heenan, C.; Castellani, D.; Wolfe, B.E.; Nechemias-Zimmer, L.; Brown, N.M.; Lund, T.D.; Handa, R.J.; Heubi, J.E. S-Equol, a potent ligand for estrogen receptor β, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora1–4. Am. J. Clin. Nutr., 2005, 81(5), 1072-1079.
[http://dx.doi.org/10.1093/ajcn/81.5.1072] [PMID: 15883431]
[18]
Mandujano-Lázaro, G.; Galaviz-Hernández, C.; Reyes-López, C.A.; Almanza-Pérez, J.C.; Giacoman-Martínez, A.; López-Camarillo, C.; Huang, F.; Marchat, L.A. A short S-equol exposure has a long-term inhibitory effect on adipogenesis in mouse 3T3-L1 cells. Appl. Sci., 2021, 11(20), 9657.
[http://dx.doi.org/10.3390/app11209657]
[19]
Méndez-Álvarez, D.; Torres-Rojas, M.F.; Lara-Ramirez, E.E.; Marchat, L.A.; Rivera, G. Ligand-based virtual screening, molecular docking, and molecular dynamic simulations of new β-estrogen receptor activators with potential for pharmacological obesity treatment. Molecules, 2023, 28(11), 4389.
[http://dx.doi.org/10.3390/molecules28114389] [PMID: 37298864]
[20]
Turner, J.V.; Agatonovic-Kustrin, S.; Glass, B.D. Molecular aspects of phytoestrogen selective binding at estrogen receptors. J. Pharm. Sci., 2007, 96(8), 1879-1885.
[http://dx.doi.org/10.1002/jps.20987] [PMID: 17518366]
[21]
Setchell, K.D.R.; Clerici, C. Equol: History, chemistry, and formation. J. Nutr., 2010, 140(7), 1355S-1362S.
[http://dx.doi.org/10.3945/jn.109.119776] [PMID: 20519412]
[22]
Mayo, B.; Vázquez, L.; Flórez, A.B. Equol: A bacterial metabolite from the daidzein isoflavone and its presumed beneficial health effects. Nutrients, 2019, 11(9), 2231.
[http://dx.doi.org/10.3390/nu11092231] [PMID: 31527435]
[23]
Kuiper, G.G.J.M.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.Å. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 1998, 139(10), 4252-4263.
[http://dx.doi.org/10.1210/endo.139.10.6216] [PMID: 9751507]
[24]
Fuentes, N.; Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol., 2019, 116, 135-170.
[http://dx.doi.org/10.1016/bs.apcsb.2019.01.001] [PMID: 31036290]
[25]
Singh, S.; Veeraswamy, G.; Bhattarai, D.; Goo, J.I.; Lee, K.; Choi, Y. Recent advances in the development of pharmacologically active compounds that contain a benzoxazole scaffold. Asian J. Org. Chem., 2015, 4(12), 1338-1361.
[http://dx.doi.org/10.1002/ajoc.201500235]
[26]
Chan, K.K.L.; Siu, M.K.Y.; Jiang, Y.; Wang, J.; Leung, T.H.Y.; Ngan, H.Y.S. Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer. Cancer Cell Int., 2018, 18(1), 65.
[http://dx.doi.org/10.1186/s12935-018-0559-2] [PMID: 29743815]
[27]
Hwang, J.T.; Kim, S.; Choi, I.; Choi, S.Y. 3,5-Dimethoxy-(4-methoxyphenyl)benzamide suppresses adipogenesis in 3T3-L1 cells. Acta Pol. Pharm., 2014, 71(1), 35-38.
[PMID: 24779192]
[28]
Sharma, D.; Sharma, S.; Chauhan, P.; Kumar, A.; Sharma, A.; Kumari, N. Acetylation of histone and modification of gene expression via HDAC inhibitors affects the obesity. Biomed. Pharmacol. J., 2021, 14(1), 153-161.
[http://dx.doi.org/10.13005/bpj/2110]
[29]
Zaib, M.; Malik, M.N.H.; Shabbir, R.; Mushtaq, M.N.; Younis, W.; Jahan, S.; Ahmed, I.; Kharl, H.A.A. Imine derivatives of benzoxazole attenuate high-fat diet-induced hyperlipidemia by modulation of lipid-regulating genes. ACS Omega, 2023, 8(17), 15306-15317.
[http://dx.doi.org/10.1021/acsomega.3c00443] [PMID: 37151544]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy