| 摘要: | 癌症佔世界人口十大死因之一，隨著醫藥研究進步，癌症的治療有更多的選擇，而針對癌細胞內特定的蛋白質作為生物標記，可以更精準又有效地治療癌症，本論文以微管蛋白與蛋白激酶作為開發抗癌藥物的目標。
α與β微管蛋白的組裝構成了參與細胞有絲分裂的微管，癌細胞的有絲分裂易受到微管蛋白抑制劑的作用，使癌細胞有絲分裂停滯並進入細胞凋亡，然而，現今批准用於臨床上的微管抑制劑可能存在多重抗藥性(multidrug resistance)的問題。幸運地是，透過靶向β微管蛋白上的秋水仙素結合位點(colchicine binding site, CBS)，可以克服癌細胞潛在的抗藥性。在本論文中，N-芳基-5,6,7-三甲氧苯並咪唑(N-aryl-5,6,7-trimethoxybenzimidazole)被設計成微管抑制劑的核心結構，運用銅催化分子內的類烏爾曼反應(Ullmann-type reaction)合成出十個苯並咪唑衍生物以探討活性結構關係(structure activity relationship, SAR)。根據抗癌活性(antiproliferative activity)測試，化合物21對於三種不同癌細胞株所的GI50介於0.05-0.09 μM，展現了最佳的抑制活性。
蛋白激酶調控細胞內蛋白質的磷酸化，表現異常的蛋白激酶將使磷酸化失調而導致腫瘤形成。激酶抑制劑與ATP結合位中的樞紐區(hinge region)所產生的氫鍵(hydrogen bond)作用力對於抑制活性是必要的。在本論文中，我們設計出3H-pyrrolo[2,3-c]quinolin-4(5H)-one作為與激酶樞紐區作用的核心結構，利用對甲苯磺醯甲基異腈(toluenesulfonylmethyl isocyanide, TosMIC)作為串聯反應的建構元件(building block)，可以快速合成出一系列三環衍生物以進行激酶抑制活性的評估。在激酶抑制試驗中，化合物80、84、85、88在10 μM的濃度下對於激酶具有50%以上的百分比抑制活性，未來有潛力成為發展激酶抑制劑的前導化合物。
Cancer is one of the top ten causes of death in the world. With the progress of medical research, there are more options for cancer treatment. Treating cancer can be more accurate and effective by targeting specific protein in cancer cells as a biomarker. This thesis is aimed at developing anti-cancer drugs against tubulin and protein kinases.
The assembly of α and β tubulins makes up microtubules, which are involved in the mitosis of cells. The mitosis of cancer cells is susceptible to tubulin inhibitors, causing mitotic arrest and apoptosis. However, the microtubule inhibitors currently approved for clinical use may possess multidrug resistance. Fortunately, the potential drug resistance of cancer cells can be conquered by targeting colchicine binding site on β tubulin. In this thesis, N-aryl-5,6,7-trimethoxybenzimidazole was designed as the core structure, and copper-catalyzed intramolecular Ullmann-type reaction was utilized to synthesize ten benzimidazole derivatives for SAR discussion. According to antiproliferative activity assay, compound 21 has GI50 values between 0.05 to 0.09 μM for three different cancer cell lines, demonstrating the strongest inhibitory activity.
Protein kinases regulate the phosphorylation of proteins in cells. Abnormal expression of protein kinases will lead to phosphorylation dysfunction and tumorigenesis. The hydrogen bond interaction between kinase inhibitor and the hinge region of ATP binding site is vital to inhibitory activity of kinase. In this thesis, we designed 3H-pyrrolo[2,3-c]quinolin-4(5H)-one as the core structure interacting with the hinge region of kinase. By employing TosMIC as the building block of tandem reaction, a series of tricyclic derivatives for evaluation of percentage inhibitory activity of kinase were synthesized expeditiously. In the kinase inhibition assay, compounds 80, 84, 85, and 88 display more than 50% inhibitory activity at a concentration of 10 μM and have potential to become lead compounds for the development of kinase inhibitors in the future. |
