壹、抗有絲分裂與血管裂解劑：2-羥基-3,4,5-三甲氧基二苯甲酮 貳、設計與合成以喹?類衍生物作為抗癌試劑

I、Antimitotic and Vascular Disrupting Agents:2-Hydroxy-3,4,5-trimethoxybenzophenones II、Design and Synthesis of Quinoline-based Derivatives as Anticancer Agents

張智億(Chih-Yi Chang)

指導教授 ： 劉景平

臺北醫學大學/藥學院/藥學系(碩博士班)/博士(2015年)

摘要

結構與CA-4相似的抗微管蛋白化合物不只在有絲分裂中抑制微管的聚合作用導致癌細胞凋亡，還顯示具有選擇地癌細胞毒殺性的血管裂解劑之新穎性質。經由偽環方法的概念，一系列新型的2-羥基-3,4,5-三甲氧基二苯甲酮化合物已經被討論。A-63、A-65與A-68展現卓越的抗癌細胞增生能力在癌細胞株中。在深入的探討中，這些化合物也表現明顯的微管蛋白親和力在秋水仙素鍵結處與具潛力的血管裂解劑特性。
組蛋白去乙醯酶在抗癌治療的發展中已經被認為是一個有效標靶。組蛋白去乙醯酶抑制劑SAHA在臨床試驗成功激勵更多的探索在發展新穎的組蛋白去乙醯酶抑制劑。根據本實驗室之前的成果，將連接體修飾與特徵結構取代的概念運用在設計新穎的組蛋白去乙醯酶抑制劑。因此一系列苯基磺醯喹?與芳醯喹?已經被合成。在這些化合物中，在癌細胞株中展現具潛力表現的化合物B-37與B-38透露出具關鍵性的官能基醯基羥胺在喹?第七號或第八號位置是較佳的。以外，化合物B-39、B-41與B-43在癌細胞株中顯示傑出的抑制能力，化合物B-39有突出的活性表現在癌細胞株中伴隨半抑制濃度數值從0.08到0.29 μM。並且化合物B-39展現強效的抑制能力對於第一型、第二型與第六型組蛋白去乙醯酶伴隨半抑制濃度數值從10到15 nM。此外，化合物B-43有顯著的選擇性對於第八型組蛋白去乙醯酶在第六型組蛋白去乙醯酶。
近年，第六型組蛋白去乙醯酶在藥物探索中已經是受到關注的標靶。文獻顯示第六型組蛋白去乙醯酶調控許多重要的非組蛋白受質包含在癌細胞成形與神經退化發展中不正常的α型微管蛋白，熱休克蛋白90與tau蛋白。根據在被發表的第六型組蛋白去乙醯酶抑制劑中的特徵結構，一系列新穎的第六型組蛋白去乙醯酶抑制劑已經被設計與合成。化合物C-18與C-21表現強效的抑制活性對於第六型組蛋白去乙醯酶伴隨半抑制濃度數值分別為2.73與4.41 nM。並且上述化合物也顯示出色的選擇性對於第六型組蛋白去乙醯酶在第一型組蛋白去乙醯酶。以化合物C-21做為先導化合物進行更進一步的結構與活性關係探索，置於疏水區域的雙六圓環與在連接部分的氨亞甲基基團是較適合的對於選擇性第六型組蛋白去乙醯酶抑制劑。

關鍵字

抗癌試劑 ； 抗有絲分裂 ； 血管裂解劑 ； 二苯甲酮 ； 喹?

並列摘要

Antitubulin agents structurally related to CA-4 have not only inhibited microtubule polymerization at mitosis with consequent apoptosis in cancer cells but also revealed the novel characteristic of selectively cytotoxic VDAs. A new series of 2-hydroxy-3,4,5-trimethoxybenzophenones based on the concept of pseudo ring approach have been explored. A-63, A-65 and A-68 have demonstrated advanced antiproliferative activities against cancer cell lines. In further investigation, they revealed the distinct tubulin affinity to the colchicine binding site and potential VDA properties.
Histone deacetylases have been considered as the effective target in the development of anticancer therapies. SAHA, the successful HDAC inhibitor in clinical trials, has encouraged further investigation in the development of novel HDAC inhibitors. According to lab’s previous achievement, the concept of linker modification and key motif replacement were applied to the design of novel HDAC inhibitors. Therefore, a series of arylsulfonylquinolines and aroylquinolines have been synthesized. Among them, B-37 and B-38, exhibited potential activities against cancer cell lines, disclosed the critical group of (E)-N-hydroxyacrylamide at the C-7 or C-8 position of quinoline is preferred. Besides, B-39, B-41 and B-43 displayed excellent inhibition against a panel of tumor cells. B-39 had superior activities against cancer cell lines with IC50 values ranging from 0.08 to 0.29 μM. Moreover, B-39 showed potent inhibition of HDAC1, 2, and 6 with IC50 values ranging from 10 to 15 nM. Furthermore, B-43 had the significant selectivity for HDAC8 over HDAC6.
Recently, HDAC6 have been the attractive target for drug discovery. Literatures demonstrated HDAC6 regulate many important non-histone substrates including α-Tubulin, HSP90 and tau, which are abnormal in the development of oncogenesis and neurodegeneration. On the basis of characteristic structures among published HDAC6 inhibitors, a novel class of HDAC6 inhibitors have been designed and synthesized. C-18 and C-21 showed the potent inhibition against HDAC6 with respective IC50 values of 2.73 and 4.41 nM. Moreover, they displayed the outstanding selectivity for HDAC6 over HDAC1 in compared with published HDAC6 inhibitors. In further structure-activity relationship taking C-21 as lead compound, 6-6 fused ring in the hydrophobic area and the aminomethylene group in the connected part is favorable to selective HDAC6 inhibitors.

並列關鍵字

anticancer agent ； antimitotic ； vascular disrupting agent ； benzophenone ； quinoline

參考文獻

1. World Health Organization http://www.who.int/en/

2. 行政院衛生福利部 http://www.mohw.gov.tw/CHT/Ministry/Index.aspx

3. Dumontet, C; Jordan, M. A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 2010, 9, 790-803.

4. Conde, C; Caceres, A. Microtubule assembly, organization and dynamics in axons and dendrites. Nat. Rev. Neurosci. 2009, 10, 319-332.

5. Walczak, C. E; Cai, S.; Khodjakov, A. Mechanisms of chromosome behavior during mitosis. Nat. Rev. Mol. Cell Biol. 2010, 11, 91-102.