設計並合成Benzimidazole衍生物作為抗癌藥物; Design and Synthesis of Benzimidazole Derivatives as Potential AnticancerAgents

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Title:	設計並合成Benzimidazole衍生物作為抗癌藥物;Design and Synthesis of Benzimidazole Derivatives as Potential AnticancerAgents
Authors:	張凱惟;Kai-Wei Chang
Contributors:	中國醫藥大學：藥物化學研究所碩士班
Keywords:	Benzimidazole衍生物;Benzimidazole Derivatives
Date:	2009-07-24
Issue Date:	2009-08-13 09:37:25 (UTC+8)
Abstract:	對抗癌藥物而言，微小管無疑是一個重要的作用目標，而持續研究及發展可用作化學治療的抗有絲分裂藥物是刻不容緩的。微小管抑制劑可被區分為兩大類：(1) 微小管去聚合抑制劑；(2)微小管聚合抑制劑。其中又以CA-4最受重視，因為CA-4抑制癌細胞增生的關鍵在於鍵結在colchicine binding sites來抑制tubulin聚合，還可抑制內皮細胞（endoethelial cell）的增生，藉由改變腫瘤血管內皮細胞的型態，阻斷血液的供應（vascular shutdown）。CA-4面臨的最大問題是溶解度不佳，因此，將它發展成為磷酸鹽類 (CA-4 p) 來改善的溶解度的問題它的磷酸二鈉鹽 (CA-4 p) 前驅藥已經進入人體臨床試驗。由於現有的文獻報告中顯示有benzimidazole基團者，具有多樣的藥理活性，如抗B型肝炎、抗真菌、抗細菌、抗原蟲、抗高血壓、抗發炎、抗病毒、抗過敏、抗精神病、5α-reductase inhibitor等，另外，benzimidazole在抗癌的研究方面已發現benzimidazole衍生物具有抑制helicases、topoisomerase及poly(ADP-ribose) polymerase等作用，顯示benzimidazole衍生物具有不錯的抗癌活性潛力。我們嘗試利用這兩種化合物的優點合成出benzimidazole為主結構之新穎化合物，一方面能制止癌細胞分裂，更能抑止癌組織血管增生。我們合成出benzimidazole衍生物，篩選結果顯示，benzimidazole衍生物具有不錯的抗肺癌 (A549)、抗攝護腺癌 (PC3)、表現大量P-glycoprotein 的乳癌細胞、抗肝癌活性 (HepG2、Hep3B) 及骨癌 (JJ)，其IC50濃度大約介於0.25到3.7 ?嵱。我們歸納出結構和活性之間的關係，如果在第六位上有取代基取代會導致活性的下降；而第五位上的取代對於活性的影響是很重要的，其中以推電子基團 (CH3、OCH3、N,N-dimethyl, pyrrolidinyl)，第二位以苯環上具有鄰位的取代 (OH、OCH3、OC2H5) 和雜環類 (thiophen-2-yl、2-furyl、nicotinyl)的取代活性表現效果較佳。 Microtubules are valids target for anticancer drugs, and it is necessary to continue developing those antimitotic drugs as chemotherapeutic agents. Mcrotubulin inhibitors can be divided two classes：(1) MT depolymerization inhibitors; (2) MT polymerization inhibitors. CA-4 is one of the most potent antitubulin agents binding to the colchicine-binding site and inducing morphological changes in the endoethelial cells of the tumor’s blood vessel so as to irreversibly shut down the blood flow to neoplastic cells. Because of its poor solubility in water, a more soluble prodrug, CA-4 phosphate, has been developed as the selected lead in in vivo and in human studies. Benzimidazoles are very useful intermediates or subunits for the development of molecules of pharmaceutical or biological interest. Benzimidazole derivatives are of wide interest because of their diverse biological activity and clinical applications. Substituted benzimidazole derivatives have diverse therapeutic applications as they exhibit antihistamine, antiulcerative, anti-inflammatory, analgesic, antioxidant, anti-HIV-1, antibacterial, antiproliferative, antiallergic, antitumour, antikinase and potential anticancer activities. Nowadays, benzimidazoles are regarded as a promising class of anti-angiogenesis agents. We attempted to merge both the structural concept of benzimidazole and CA-4 to design new compounds for anticancer activity. Herein, the synthesis of several trimethoxybenzyl benzimidazole derivatives substituted in position 2 with aromatic, heteroaromatic or cycloaliphatic group was reported. This series of compounds inhibited cell growth in various cancer cell lines including prostate cancer, hepatocellular carcinoma, non-small cell lung cancer, P-glycoprotein-rich breast cancer and chondrosarcoma. The potent compound demonstrated an IC50 value in 0.25 ?嵱 to 3.7 ?嵱 range. As a result of the structure-activity relationship (SAR) studies, introduction of substituents at the 6-position led to compounds with reduced or little activity. However, 5-substituent of benzimidazoles was very important for inhibitory activity. With an electron-donating group (CH3、OCH3、N,N-dimethyl, pyrrolidinyl) in the C-5 benzimidazoles and aromatic ring (o-OH、o-OCH3、o-OC2H5) or heterocyclic ring (thiophen-2-yl、2-furyl、nicotinyl) in the C-2 benzimidazoles could enhance activity against cancer cell.
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