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系統識別號 U0026-2908201823383300
論文名稱(中文) 吡唑類化合物衍生物用於治療骨質疏鬆症之合成與研究
論文名稱(英文) Novel Pyrazole Derivatives for Treating Osteoporosis
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 106
學期 2
出版年 107
研究生(中文) 呂侑聰
研究生(英文) Yu-Tsung Liu
學號 s16041036
學位類別 碩士
語文別 英文
論文頁數 40頁
口試委員 指導教授-陳毓宏
共同指導教授-洪欣儀
口試委員-江伯敏
中文關鍵字 骨質疏鬆症  破骨細胞  吡唑類化合物 
英文關鍵字 osteoporosis  osteoclast  pyrazole derivatives  YC-1 
學科別分類
中文摘要 隨著人口老化的情況,伴隨而來的老化問題及疾病變成了威脅人們健康的一大威脅,其中骨質疏鬆症更是大多數中老年人們難以避免的疾病。
骨質疏鬆症的成因是源自於破骨細胞的破骨作用與成骨細胞的骨質新生作用之間的不平衡所產生的,隨著年紀的增長或是外來物質的影響,可能會造成破骨細胞過度活化或是成骨細胞活性降低,因而使得骨質隨著時間不斷流失,最終產生骨質疏鬆症的症狀。近年來也研究出許多用於治療骨質疏鬆症的藥物,然而除了副作用以外病人還得負擔昂貴的藥費,因此,新的骨質疏鬆症的藥物研究仍然是必須繼續進行下去的。
在先前研究中發現化合物YC-1對於造成破骨細胞凋亡具有明顯效果,而另一篇研究中則發現YC-1接上一段含氮側鍊後可以有效降低破骨細胞的成熟與分化,增加了一條側鍊便可以使得原本的化合物具有與原本不同但目的相同的效果,因此我們想合成其他YC-1衍生物來研究YC-1與治療骨質疏鬆症間的SAR關係。
在本篇研究中我們在原本的苯環上第3個位子接上電負度較高的F原子,先前研究中發現第3個位子接上F後可以提升其活性,而呋喃的部分則根據生物電子相似性選擇與O價電子數相同的S,即是以噻吩替換呋喃。在YC-1衍生物用於治療其他疾病的研究中發現呋喃替還成苯環後可以具有活性,因此我們想使用活性較苯環高的吡啶來做為第三個衍生物。最後的側鍊則選擇先前研究中對破骨細胞活化生成具有抑制效果的含氮側鍊,並研究這三種衍生物的合成方式。
最終成功合成噻吩的所有中間產物以及最終產物,呋喃已完成至羧酸產物,吡啶則是已完成鈴木反應成功合成中間產物,這些合成出來的新化合物在接下來的研究中如果測試出對破骨細胞或是成骨細胞具有影響效果的話便有可能進一步開發成治療骨質疏鬆症的新藥。
英文摘要 Osteoporosis is known as an age-related disease that result from an imbalance between the generation and decomposition of the bone matrix. It is caused by either the degeneration of osteoblasts leading to weaker bone forming activity or the promotion of osteoclasts increasing bone resorption activity. To treat osteoporosis, several drugs are available now. However, there are still some drawbacks of the drugs such as many side effects and high cost. According to the situation, we would like to research and synthesize new compounds to treat osteoporosis.
3-(5’-Hydroxymethyl-2’-furyl)-1-benzyl indazole (YC-1) (1) is a pyrazole derivative that has been demonstrated with many potent biological and pathological activities.
YC-1 was also exhibited anti-osteoporosis effects through promoting cGMP by activating sGC, and then reducing osteoclast activity and inducing osteoblast activity. According to the above-mentioned feature, many YC-1 derivatives had been synthesized with different side chains to study structure-activity relationship. Among them, 2-(dimethylamino)ethyl group showed obvious inhibition of osteoclast both in vitro and in vivo. However, previous researches did not include variable side chains; therefore, there is still much room for new YC-1 derivatives to figure out structure-activity relationship (SAR) of YC-1 derivatives. In this study, we would like to synthesize novel YC-1 derivatives that are effective in treating osteoporosis without many side effects and high cost.
Based on the previous research, we modified the side chains on indazole, such as replacement of the furan with pyridine and thiophene. On the other hand, we also transformed the 1-benzyl group with 3-fluorobenzyl group. Then, we characterized the compound structures with 1H and 13C NMR to check that three target compounds were synthesized successfully.
論文目次 Index………………………………………………………………………..1
Figure Index………………………………………………………………...2
Scheme Index……………………………………………………………….3
Chapter 1 Introduction
I. Current treatments for osteoporosis…………………………………4
II. Osteoclast Differentiation Signaling Pathway………………………5
III. Introduction of YC-1………………………………………………...6
IV. Recent studies of YC-1………………………………………………8
Chapter 2 Derivatives Designed……………………….……………………10
Chapter 3 Results and Discussion…………………………………………...12
I. Synthetic routes of YC-1 derivatives (Furan)………………………. 14
II. Synthetic routes of YC-1 derivatives (Thiophene)…………………. 17
III. Synthetic routes of YC-1 derivatives (Pyridine)…………………… .21
Chapter 4 Conclusion……...………………………………………………...22
Chapter 5 Discussion………………………………………………………..23
Chapter 6 Experimental………………………………………………………26
I. Reagents and solvents
II. Instruments and experimental materials
A. Analytical instrument
B. Experimental materials
References……………………………………………………….……………28
Appendix (Spectrum)…………………………………………………………30
參考文獻 (1) Blair, H., Robinson, L. and Zaidi, M. (2005). Osteoclast signalling pathways. Biochemical and Biophysical Research Communications, 328(3), pp.728-738.
(2) Boyce, B., Xiu, Y., Li, J., Xing, L. and Yao, Z. (2015). NF-κB-Mediated Regulation of Osteoclastogenesis. Endocrinology and Metabolism, 30(1), p.35.
(3) DeNiro, M. and Al-Mohanna, F. (2014). Nuclear Factor Kappa-B Signaling Is Integral to Ocular Neovascularization in Ischemia-Independent Microenvironment. PLoS ONE, 9(7), p.e101602.
(4) Iofbonehealth.org. (2018). Treating Osteoporosis | International Osteoporosis Foundation. [online] Available at: https://www.iofbonehealth.org/treating-osteoporosis [Accessed 28 Jul. 2018].
(5) Kim, J. and Kim, N. (2016). Signaling Pathways in Osteoclast Differentiation. Chonnam Medical Journal, 52(1), p.12.
(6) Takeshita, S., Faccio, R., Chappel, J., Zheng, L., Feng, X., Weber, J., Teitelbaum, S. and Ross, F. (2007). c-Fms Tyrosine 559 Is a Major Mediator of M-CSF-induced Proliferation of Primary Macrophages. Journal of Biological Chemistry, 282(26), pp.18980-18990.
(7) Daoud, G., Rassart, É., Masse, A. and Lafond, J. (2006). Src family kinases play multiple roles in differentiation of trophoblasts from human term placenta. The Journal of Physiology, 571(3), pp.537-553.
(8) Friebe, A. and Koesling, D. (1998). Mechanism of YC-1-Induced Activation of Soluble Guanylyl Cyclase. Molecular Pharmacology, 53(1), pp.123-127.
(9) Wang, J., Yeh, C., Chou, S., Lu, K., Chu, T., Chen, W., Chien, J., Yen, M., Chen, T. and Shyu, J. (2017). YC-1 alleviates bone loss in ovariectomized rats by inhibiting bone resorption and inducing extrinsic apoptosis in osteoclasts. Journal of Bone and Mineral Metabolism pp.0774-0866.
(10) Yeo, E., Chun, Y., Cho, Y., Kim, J., Lee, J., Kim, M. and Park, J. (2003). YC-1: A Potential Anticancer Drug Targeting Hypoxia-Inducible Factor 1. JNCI Journal of the National Cancer Institute, 95(7), pp.516-525.
(11) Sheng, R., Li, S., Lin, G., Shangguan, S., Gu, Y., Qiu, N., Cao, J., He, Q.,  Yang, B. and Hu, Y. (2015). Novel potent HIF-1 inhibitors for the prevention of tumor metastasis: discovery and optimization of 3-aryl-5-indazole-1,2,4-oxadiazole derivatives. RSC Advances, 5(100), pp.81817-81830.
(12) Sun, H. and Teng, C. (2007). YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-jB signaling to HIF-1a accumulation during hypoxia. Nature pp.3941-3951.
(13) Takeuchi, A., Hori, M., Sato, S., Ban, H., Kuchimaru, T., Kizaka-Kondoh, S., Yamori, T. and Nakamura, H. (2012). Synthesis and biological activity of furanylindazoles as inhibitors of hypoxia inducible factor (HIF)-1 transcriptional activity. MedChemComm, 3(11), p.1455.
(14) Lien, J., Lee, F., Huang, L., Pan, S., Guh, J., Teng, C. and Kuo, S. (2002). 1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole (YC-1) Derivatives as Novel Inhibitors Against Sodium Nitroprusside-Induced Apoptosis. Journal of Medicinal Chemistry, 45(23), pp.4947-4949.
(15) Bennett, M. (1999). Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovascular Research, 41(2), pp.361-368.
(16) Tulis, D., Bohl Masters, K., Lipke, E., Schiesser, R., Evans, A., Peyton, K., Durante, W., West, J. and Schafer, A. (2002). YC-1-Mediated Vascular Protection through Inhibition of Smooth Muscle Cell Proliferation and Platelet Function. Biochemical and Biophysical Research Communications, 291(4), pp.1014-1021.
(17) Lee, F., Lien, J., Huang, L., Huang, T., Tsai, S., Teng, C., Wu, C., Cheng, F. and Kuo, S. (2001). Synthesis of 1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole Analogues as Novel Antiplatelet Agents. Journal of Medicinal Chemistry, 44(22), pp.3746-3749.
(18) Kuo, T. and Hung, H. (2015). Novel Pyrazole Derivatives Effectively Inhibit Osteoclastogenesis, a Potential Target for Treating Osteoporosis. Journal of Medicinal Chemistry pp.4954-4963.
(19) Name-reaction.com. (2018). Name-Reaction.com. [online] Available at: http://www.name-reaction.com/ [Accessed 28 Jul. 2018].
(20) Martin, R. and Buchwald, S. (2008). Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands. Accounts of Chemical Research, 41(11), pp.1461-1473.
(21) Rajput, A. and Girase, P. (2013). ChemInform Abstract: Review Article on Vilsmeier-Haack Reaction. ChemInform, 44(21), pp.25-43.
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