染料木素含磷衍生物的合成及性质研究
摘要
染料木素是大豆中一种非常重要的成分，具有广泛的生物活性，由于与雌二醇在结构上有相似性，因此具有植物雌激素功能，此外它还有预防骨质疏松作用、抗肿瘤抗癌作用、抗氧化及抗菌消炎作用。本文对染料木素的药理作用、提取方法、研究现状等方面进行了综述。
染料木素有着广泛的生物活性，因此引起了人们的关注，结构改造是其中的一个重要方面，人们期望通过结构改造获得一些具有更好的生物活性、低毒、水溶性好、具有较高的生物利用度的化合物。本文的研究工作主要是：
1．本文以五种不同的亚磷酸二烷基酯为磷酰化试剂，通过Atherton-Todd反应分别对染料木素进行磷酰化结构改造，并给出它们的IR、ESI-MS、NMR数据，对相应的NMR数据进行归属，对染料木素的不同酚羟基的反应活性进行了讨论。
2．以β，β′-二氯磷酰胺二氯为磷酰化试剂，对染料木素进行磷酰化结构改造，并给出它们的IR、ESI-MS、NMR数据，对相应的NMR数据进行归属并对核磁数据进行了细致讨论。
3．研究了四种磷酰化染料木素与溶菌酶的弱相互作用，发现改造后的磷酰化产物均能很好的与溶菌酶形成复合物。
Genistein, the simplest of the isoflavonoid compounds of the Leguminosae, is reported to have extensively biological activities, including anti-osteoporosis, anticancery, antibacterial and anti-inflammatory activities. Due to its structural similarity to estradiol, more attention has been paid to its phytoestrogen activities in the past few years. In the work described in the dissertation, the recent studies on pharmacological action, extraction and isolation, pharmacological and structural modifications of genistein were introduced in chapter one.
Many biological activities of genistein have made it common interests as mentioned in many published papers. Lots of efforts have been made to synthesized genistein derivetives with better activities in recent years. Structural modification is one of the most important aspects in terms of increasing its water-solubility, lowering its toxicity and improving its biological assimilation. The studies on phosphorus modifications of genistein and non-covalent interactions with a model protein were shown in this dissertation .The relating works included:
1.Genistein was modified with five different phosphoryl reagents by Atherton-Todd reaction, and the structures of the new compounds were determined by ESI-MS, NMR and IR, the reaction activities of different phenol- hydroxyl of genistein were discussed.
2.Genistein was modified with di-(2-chloroethyl)-phosphoramidic dichloride, and the structure of the new compound was determined by ESI-MS, NMR and IR, furthermore, the data of NMR spectra were assigned completely and analyzed in detail.
3.The interactions between the four phosphorlated genistein derivatives and lysozyme were studied, it is found that all the phosphates could form non-covalent complexes with lysozyme.
染料木素有着广泛的生物活性，因此引起了人们的关注，结构改造是其中的一个重要方面，人们期望通过结构改造获得一些具有更好的生物活性、低毒、水溶性好、具有较高的生物利用度的化合物。本文的研究工作主要是：
1．本文以五种不同的亚磷酸二烷基酯为磷酰化试剂，通过Atherton-Todd反应分别对染料木素进行磷酰化结构改造，并给出它们的IR、ESI-MS、NMR数据，对相应的NMR数据进行归属，对染料木素的不同酚羟基的反应活性进行了讨论。
2．以β，β′-二氯磷酰胺二氯为磷酰化试剂，对染料木素进行磷酰化结构改造，并给出它们的IR、ESI-MS、NMR数据，对相应的NMR数据进行归属并对核磁数据进行了细致讨论。
3．研究了四种磷酰化染料木素与溶菌酶的弱相互作用，发现改造后的磷酰化产物均能很好的与溶菌酶形成复合物。
Genistein, the simplest of the isoflavonoid compounds of the Leguminosae, is reported to have extensively biological activities, including anti-osteoporosis, anticancery, antibacterial and anti-inflammatory activities. Due to its structural similarity to estradiol, more attention has been paid to its phytoestrogen activities in the past few years. In the work described in the dissertation, the recent studies on pharmacological action, extraction and isolation, pharmacological and structural modifications of genistein were introduced in chapter one.
Many biological activities of genistein have made it common interests as mentioned in many published papers. Lots of efforts have been made to synthesized genistein derivetives with better activities in recent years. Structural modification is one of the most important aspects in terms of increasing its water-solubility, lowering its toxicity and improving its biological assimilation. The studies on phosphorus modifications of genistein and non-covalent interactions with a model protein were shown in this dissertation .The relating works included:
1.Genistein was modified with five different phosphoryl reagents by Atherton-Todd reaction, and the structures of the new compounds were determined by ESI-MS, NMR and IR, the reaction activities of different phenol- hydroxyl of genistein were discussed.
2.Genistein was modified with di-(2-chloroethyl)-phosphoramidic dichloride, and the structure of the new compound was determined by ESI-MS, NMR and IR, furthermore, the data of NMR spectra were assigned completely and analyzed in detail.
3.The interactions between the four phosphorlated genistein derivatives and lysozyme were studied, it is found that all the phosphates could form non-covalent complexes with lysozyme.
引文
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[3] Huachen Wei. Isoflavone Geinstein: photoprotection and clinical implication in dermatology [J]. J. Nutr. 2003, 133 (12): 3811-3819.
[4] Martin, P. M., Horwitz, K. B., Ryan, D. S., et al. Phytoe-estrogen interaction with estrogen receptors in human breast cancer cells [J]. Endocrinology. 1978. 103, 1860-1867.
[5] Shutt, D. A., Cox, R. I.. Steroid and phyto-estrogen binding to sheep uterine receptors in vitro [J]. J. Endocrinol. 1972. 52, 299-310.
[6] Akiyama, T., Ishida, J., Nakagawa, S., et al. Genistien, a specific inhibitor of tyrosine-specific protein kinases [J]. J. Biol. Chem. 1987. 262, 5592-5595.
[7] Hsieh, C. Y., Santell, R. C., Haslam, S. Z., et al. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitroand in vivo[J]. Cancer Res. 1998. 58, 3833-3838.
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[10] Peterson, G., Barnes, S. Genistein inhibits both estrogen and growth factor stimul -ated proliferation of human breast cancer cells [J]. Cell Growth Differ. 1996. 7, 1345-1351.
[11] Shao, Z. M., Shen, Z. Z., Fontana, J. A., et al. Genistine's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines [J]. Anticancer Res. 2000. 20, 2409-2416.
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[13] Zava, D.T., Duwe, G.. Esrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro [J]. Nutr Cancer. 1997.27, 31-40.
[14] Allred, C.D., Allred, K.F., Virant, S.M., et al. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner [J]. Cancer Res. 2001.61, 5045-5050.
[15] Gorbach. Isoflavonoids for treatment and prevention of aging skin and wrinkles[P]. United States Patent, 6060070.
[16] Kelly, Graham Edmun. et al.Therapy of estrogen-associated disorders[P]. United States Patent Application, 20030219449.
[17] Kelly, Graham Edmun. et al.Cardiovasular and bone treatment using iosflavones [P]. United States Patent Application, 20040072765.
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