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A novel 7-O-modified genistein derivative with acetylcholinesterase inhibitory effect, estrogenic activity and neuroprotective effect

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Abstract

To find the multi-target-directed compounds for the treatment of Alzheimer’s disease (AD), we synthesized 7-(4-(diethylamino)butoxy)-5-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one, a novel 7-O-modified genistein derivative (GS-14), and investigated its acetylcholinesterase (AChE) inhibitory effect, estrogenic activity and neuroprotective effect. GS-14 acted as a selective AChE inhibitor in vitro, with an IC50 value of 0.17 μM and showed no inhibition activity against butyrylcholinesterase (BuChE). The Lineweaver-Burk plot revealed that GS-14 was a non-competitive AChE inhibitor with a Ki value of 0.23 μM and the molecular docking model indicated that GS-14 interacted with the peripheral anionic site (PAS) of AChE. The MCF-7 proliferation assay demonstrated that GS-14 possessed estrogenic activity and GS-14 exhibited a high specificity for estrogen receptor β (ERβ) with a dissociation constant (Ki) of 2.86 nM compared with that of 1.01 μM for estrogen receptor α (ERα) in the molecular docking study. GS-14 also possessed a neuroprotective effect and showed the best protective effect against the β-amyloid protein-induced injury on SH-SY5Y cells at a concentration of 1 nM. Considering its AChE-inhibition activity, estrogenic activity and neuroprotective effect, GS-14 may be a potential multi-target agent for the treatment of AD.

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References

  • An, J., Tzagarakis-Foster, C., Scharschmidt, T. C., Lomri, N., and Leitman, D. C., Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens. J. Biol. Chem., 276, 17808–17814 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Arias, E., Gallego-Sandin, S., Villarroya, M., Garcia, A. G., and Lopez, M. G., Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells: role of nicotinic receptors. J. Pharmacol. Exp. Ther., 315, 1346–1353 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Bang, O. Y., Hong, H. S., Kim, D. H., Kim, H., Boo, J. H., Huh, K., and Mook-Jung, I., Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity. Neurobiol. Dis., 16, 21–28 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Bartolini, M., Bertucci, C., Cavrini, V., and Andrisano, V., beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem. Pharmacol., 65, 407–416 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Beresford, S. A., Weiss, N. S., Voigt, L. F., and McKnight, B., Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet, 349, 458–461 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Blennow, K., de Leon, M. J., and Zetterberg, H., Alzheimer’s disease. Lancet, 368, 387–403 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Bolognesi, M. L., Cavalli, A., Valgimigli, L., Bartolini, M., Rosini, M., Andrisano, V., Recanatini, M., and Melchiorre, C., Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer’s disease. J. Med. Chem., 50, 6446–6449 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Bores, G. M., Huger, F. P., Petko, W., Mutalib, A. E., Camacho, F., Rush, D. K., Selk, D. E., Wolf, V., Kosley, R. W., Davis, L., and Vargas, H. M., Pharmacological evaluation of novel Alzheimer’s disease therapeutics: acetylcholinesterase inhibitors related to galanthamine. J. Pharmacol. Exp. Ther., 277, 728–738 (1996).

    PubMed  CAS  Google Scholar 

  • Bourne, Y., Grassi, J., Bougis, P. E., and Marchot, P., Conformational flexibility of the acetylcholinesterase tetramer suggested by x-ray crystallography. J. Biol. Chem., 274, 30370–30376 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Brann, D. W., Dhandapani, K., Wakade, C., Mahesh, V. B., and Khan, M. M., Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids, 72, 381–405 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Collaborative Group on Hormonal Factors in Breast Cancer, Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet, 350, 1047–1059 (1997).

    Google Scholar 

  • Case, D. A., Darden, T., Cheatham, T. E., III, Simmerling, C., Wang, J., Duke, R. E., Luo, R., Merz, K. M., Pearlman, D. A., Crowley, M., Walker, R., Zhang, W., Wang, B., Hayik, S., Roitberg, A., Seabra, G., Wong, K., Paesani, F., Wu, X., Brozell, S., Tsui, V., Gohlke, H., Yang, L., Tan, C., Mongan, J., Hornak, V., Cui, G., Beroza, P., Mathews, D. H., Schafmeister, C., Ross, W. S., and Kollman, P. A., AMBER 9. University of California, San Francisco, CA, (2006).

    Google Scholar 

  • Cavalli, A., Bolognesi, M. L., Capsoni, S., Andrisano, V., Bartolini, M., Margotti, E., Cattaneo, A., Recanatini, M., and Melchiorre, C., A small molecule targeting the multi-factorial nature of Alzheimer’s disease. Angew. Chem. Int. Ed., 46, 3689–3692 (2007).

    Article  CAS  Google Scholar 

  • ChemOffice, CambridgeSoft Corporation, Available from: http://www.cambridgesoft.com/. (2005).

  • Choudhary, M. I., Nawaz, S. A., Zaheer-ul-Haq, Azim, M. K., Ghayur, M. N., Lodhi, M. A., Jalil, S., Khalid, A., Ahmed, A., Rode, B. M., Atta-ur-Rahman, Gilani, A. U., and Ahmad, V. U., Juliflorine: a potent natural peripheral anionic-sitebinding inhibitor of acetylcholinesterase with calciumchannel blocking potential, a leading candidate for Alzheimer’s disease therapy. Biochem. Biophys. Res. Commun., 332, 1171–1177 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Cummings, J. L., Alzheimer’s disease. N. Engl. J. Med., 351, 56–67 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Cummings, J. L., Cholinesterase inhibitors: A new class of psychotropic compounds. Am. J. Psychiatry, 157, 4–15 (2000).

    PubMed  CAS  Google Scholar 

  • Datki, Z., Juhasz, A., Galfi, M., Soos, K., Papp, R., Zadori, D., and Penke, B., Method for measuring neurotoxicity of aggregating polypeptides with the MTT assay on differentiated neuroblastoma cells. Brain Res. Bull., 62, 223–229 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Ellman, G. L., Courtney, K. D., Andres, V., Jr., and Feather-Stone, R. M., A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 7, 88–95 (1961).

    Article  PubMed  CAS  Google Scholar 

  • Forette, F., Anand, R., and Gharabawi, G., A phase II study in patients with Alzheimer’s disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (ExXelon). Eur. J. Neurol., 6, 423–429 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Goedert, M. and Spillantini, M. G., A century of Alzheimer’s disease. Science, 314, 777 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Henderson, V. W., Estrogen-containing hormone therapy and Alzheimer’s disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience, 138, 1031–1039 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Hsieh, C. Y., Santell, R. C., Haslam, S. Z., and Helferich, W. G., Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res., 58, 3833–3838 (1998).

    PubMed  CAS  Google Scholar 

  • **, Z., Yang, L., Liu, S. J., Wang, J., Li, S., Lin, H. Q., Wan, D. C. C., and Hu, C., Synthesis and Biological Evaluation of 3,6-diaryl-7H-thiazolo[3,2-b] [1,2,4]triazin-7-one Derivatives as Acetylcholinesterase Inhibitors. Arch. Pharm. Res., 33, 1641–1649 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Jung, H. A., Lee, E. J., Kim, J. S., Kang, S. S., Lee, J. H., Min, B. S., and Choi, J. S., Cholinesterase and BACE1 inhibitory diterpenoids from Aralia cordata. Arch. Pharm. Res., 32, 1399–1408 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Lahiri, D. K., Rogers, J. T., Greig, N. H., and Sambamurti, K., Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents. Curr. Pharm. Des., 10, 3111–3119 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Lee, K. Y., Sung, S. H., Kim, S. H., Jang, Y. P., Oh, T. H., and Kim, Y. H., Cognitive-enhancing activity of loganin isolated from cornus officinalis in scopolamine-induced amnesic mice. Arch. Pharm. Res., 32, 677–683 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Min, B. S., Cuong, T. D., Lee, J. S., Shin, B. S., Woo, M. H., and Hung, T. M., Cholinesterase inhibitors from Cleistocalyx operculatus buds. Arch. Pharm. Res., 33, 1665–1670 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., and Olson, A. J., Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 19, 1639–1662 (1998).

    Article  CAS  Google Scholar 

  • Norman, B. H., Dodge, J. A., Richardson, T. I., Borromeo, P. S., Lugar, C. W., Jones, S. A., Chen, K., Wang, Y., Durst, G. L., Barr, R. J., Montrose-Rafizadeh, C., Osborne, H. E., Amos, R. M., Guo, S., Boodhoo, A., and Krishnan, V., Benzopyrans are selective estrogen receptor beta agonists with novel activity in models of benign prostatic hyperplasia. J. Med. Chem., 49, 6155–6157 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Rosales-Corral, S. A., Acuna-Castroviejo, D., Coto-Montes, A., Boga, J. A., Manchester, L. C., Fuentes-Broto, L., Korkmaz, A., Ma, S., Tan, D. X., and Reiter, R. J., Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J. Pineal Res., 52, 167–202 (2011).

    Article  PubMed  Google Scholar 

  • Sanner, M. F., Python: a programming language for software integration and development. J. Mol. Graphics Model., 17, 57–61 (1999).

    CAS  Google Scholar 

  • Tiwari-Woodruff, S., Morales, L. B., Lee, R., and Voskuhl, R. R., Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc. Natl. Acad. Sci. U. S. A., 104, 14813–14818 (2007).

    Article  PubMed  Google Scholar 

  • Whitehouse, P. J., Cholinergic therapy in dementia. Acta Neurol. Scand. Suppl., 149, 42–45 (1993).

    PubMed  CAS  Google Scholar 

  • Wimo, A., Winblad, B., Aguero-Torres, H., and von Strauss, E., The magnitude of dementia occurrence in the world. Alzheimer Dis. Assoc. Disord., 17, 63–67 (2003).

    Article  PubMed  Google Scholar 

  • Zeng, H., Chen, Q., and Zhao, B., Genistein ameliorates betaamyloid peptide (25–35)-induced hippocampal neuronal apoptosis. Free Radic. Biol. Med., 36, 180–188 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, L. N., Cao, P., Tan, S. H., Gu, W., Shi, L., and Zhu, H. L, Synthesis and antimicrobial activities of 7-O-modified genistein derivatives. Eur. J. Med. Chem., 43, 1543–1551 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Zheng, X. Y., Zhang, Z. J., Chou, G. X., Wu, T., Cheng, X. M., Wang, C. H., and Wang, Z. T., Acetylcholinesterase inhibitive activity-guided isolation of two new alkaloids from seeds of Peganum nigellastrum Bunge by an in vitro TLC-bioautographic assay. Arch. Pharm. Res., 32, 1245–1251 (2009).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Functional Biomolecules, Jiangsu Key Laboratory of Molecular Medicine, State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nan**g University, Nan**g, 210093, China

    Da-Hua Shi, Li-Na Zhang, Yu-Rong Wang, Chun-** Jiang & Jun-Hua Wu

  2. School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang, 222005, Jiangsu Province, China

    Da-Hua Shi

  3. National Laboratory of Solid State Microstructure and Department of Physics, Nan**g University, Nan**g, 210093, China

    Zhi-Qiang Yan

  4. The First Clinical Medical College, Nan**g University of Chinese Medicine, Nan**g, 210046, Jiangsu Province, China

    Chun-** Jiang

  5. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School, Nan**g University, Nan**g, 210008, Jiangsu Province, China

    Chun-** Jiang

  6. Medical School, Nan**g University, Nan**g, 210093, Jiangsu Province, China

    Jun-Hua Wu

  7. Medical School, Nan**g University, Nan**g, 210008, Jiangsu Province, China

    Chun-** Jiang

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  1. Da-Hua Shi
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  2. Zhi-Qiang Yan
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Correspondence to Chun-** Jiang or Jun-Hua Wu.

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Shi, DH., Yan, ZQ., Zhang, LN. et al. A novel 7-O-modified genistein derivative with acetylcholinesterase inhibitory effect, estrogenic activity and neuroprotective effect. Arch. Pharm. Res. 35, 1645–1654 (2012). https://doi.org/10.1007/s12272-012-0916-y

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  • DOI: https://doi.org/10.1007/s12272-012-0916-y

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