異黃酮衍生物之合成及生物活性評估

Synthesis and Biological Evaluation of 7-Hydroxyisoflavone Derivatives

蔡銀棟(Yin-Tung Tsai)

指導教授 ： 陳義龍

共同指導教授 ： 曾誠齊(Cherng-Chyi Tzeng)

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2007年)

摘要

大豆異黃酮廣泛存在於天然植物中，它擁有各式的生理活性，包括了抗腫瘤、抗菌、抗病毒、抗發炎、抗氧化以及心血管方面的作用。由於更年期間雌激素缺乏，造成大豆異黃酮在預防骨質流失方面受到相當的重視。然而，大豆異黃酮衍生物在抗蝕骨細胞上的結構與活性的關係尚未被確認。為了發展更多有效的藥物，我們合成了一系列異黃酮的衍生物，並探討其抗腫瘤及抑制破骨細胞的活性。其中以7-(6-(piperazin-1-yl)hexyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one　(6o)、7-(7-(piperazin-1-yl)heptyloxy)-3-(4-methoxyphenyl)-4H-chromen　-4-one (6p) 具有明顯的抗腫瘤以及抑制破骨細胞的活性。

關鍵字

異黃酮 ； 抑制破骨細胞 ； 抗癌

並列摘要

Isoflavonoids belongs to one of the ubiquitous families of natural products that possess a wide variety of biological activities including antiproliferative, antifungal, antiviral, anti-inflammatory, antioxidant, and cardiovascular effects. Much attention has been focus on the role of isoflavonoids in preventing bone loss resulted at least in part from the estrogen deficiency. However, the anti-osteoporotic structure-activity relationship (SAR) of isoflavone derivatives has not been established. To explore more potent drug candidates, we have prepared a number of isoflavone derivatives and investigated for their antiproliferative and anti-osteoporotic activities. Among them,　7-(6-(piperazin-1-yl)hexyloxy) -3-(4-methoxyphenyl)-4H-chromen-4-one　(6o)、7-(7-(piperazin-1-yl) heptyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one　(6p) have shown significant antiproliferative and/or anti-osteoporotic activities.

並列關鍵字

Isoflavones

參考文獻

1.Jordan, V. C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. Receptor interactions. J. Med. Chem. 2003, 46, 883-908.

2.Behl, C. Oestrogen as a neuroprotecitve hormone. Nature Rev. Neurosci. 2002, 3, 433-442

3.Stossi, F.; Barnett, D. H.; Frasor, J.; Komm, B.; Lyttle, C. R.; Katzenellenbogen, B. S. Transcriptional profiling of estrogen-regulated gene expression via estrogen receptor (ER) alpha or ERbeta in human osteosarcoma cells: Distinct and common target genes for these receptors. Endocrinology. 2004, 145, 3473-3486.

4.Monroe, D. G.; Getz, B. J.; Johnsen, S. A.; Riggs, B. L.; Khosla, S.; Spelsberg, T. C. Estrogen receptor isoform-specific regulation of endogenous gene expression in human osteoblastic cell lines expressing either ERalpha or ERbeta. J. Cell. Biochem. 2003, 90, 315-326.

5.Zhao, Y.; Agarwal, V. R.; Mendelson, C. R.; Simpson, E. R. Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology. 1996, 137, 5739-5742.