合成Alkylaminobenzoquinones為抗癌試劑

癌症仍然是現今世界上最可怕的疾病之一，是一種嚴重威脅人類生命和健康的常見病症。根據世界衛生組織(WHO)的報導，癌症是導致人類死亡的主要病因，預計全世界因癌症而死亡的人數將繼續增加，2030年估計將有1310萬人死於癌症。在開發中國家，目前已經有超過三分之二的人因為新發現的癌症病例而死亡，癌症的發病率以驚人的速度而持續增加中。因此，研發抗癌藥物來治療目前危害人類的癌症是當前癌症治療研究的重大課題之一。天然物是具有生物活性化合物的豐富來源，現今的許多抗癌藥物是直接來自天然物或經由化學修飾所合成的衍生物，所以修飾天然物作為抗癌藥物在新藥開發上是具有潛力和發展力的。 Denbinobin是中國草藥石斛中的化學成分，最早是在1981年由Dendrobium nobile (金釵石斛)所分離出來的天然物，由近期的研究中發現denbinobin具有抗發炎、抗腫瘤、抗氧化的作用及抗纖維化活性，在生物活性方面上具有很大的潛力，可作為先導化合物發展。 Denbinobin所具有的抗癌活性引起本實驗室的興趣，分別在2005年及2011年開發出全合成denbinobin的方法，希望能夠利用簡單、快速、便宜的方法合成出denbinobin，並進一步研究其結構與活性的關係(SAR)，發展一系列的denbinobin衍生物。因此，本實驗接續實驗室2011年所開發的denbinobin全合成方法，經由Perkin condensation、酯化、環化、水解、去羧基等反應步驟，並改良使反應產率提高，成功合成出denbinobin。使用前述方法可大量合成denbinobin，故本論文利用denbinobin作為設計核心，探討在3號位上的取代基活性，合成各種alkylaminobenzoquinones為抗癌試劑，期望可以得到更有活性的化合物。由表中的抗增殖活性數據顯示，發現在3號位接上cyclopropylamine的化合物47具有很好的抗癌活性，對於人類肺腺癌上皮A549細胞的GI50值為0.28 μM，比標準品denbinobin強13.2倍；而對於人類前列腺癌PC3細胞的GI50值為0.20 μM，比標準品denbinobin強11.4倍。

關鍵字

抗癌藥物；天然物；苯醌Denbinobin

並列摘要

Cancer is one of the most dreaded diseases in the world today, and it is a common disease of a serious threat to human life and health. According to the World Health Organization (WHO) reports, cancer is a leading cause of death worldwide. Deaths from cancer worldwide are projected to continue to rise to over 13.1 million in 2030. Already more than two-thirds of these new cancer cases and deaths occur in developing countries where cancer incidence continues to increase at alarming rates. Therefore, the research and development of anticancer drugs to treat the human cancer is one of the major issues of the current cancer treatment research. Natural products are a rich source of biological active compounds, nowadays, many anticancer drugs directly derived from natural products or synthetic derivatives through chemical modification. Modifications of natural products as anticancer drugs are potential trend on new drug development. Denbinobin is the chemical constituent of Chinese herb “Shi-Hu”, as a natural product first isolated from Dendrobium nobile in 1981. Recent studies found that it exhibits antioxidant effect, antitumor, anti-inflammatory, and anti-fibrotic activities, indicating that it could be a potential lead compound for further development. The anticancer activity of denbinobin attracted our interest; therefore, we have developed a total synthetic method of denbinobin in 2005, and 2011, respectively. All the efforts were made to synthesize denbinobin with a simple, rapid, and inexpensive method, as well as the achievement of structure-activity relationships of a series of denbinobin derivatives. This thesis continue previous synthetic approaches to denbinobin in our laboratory by using Perkin condensation, esterification, cyclization, hydrolysis, and decarboxylation reaction steps, etc. and eventually improve the overall reaction yield of denbinobin. This thesis provided a synthetic methodology to obtain denbinobin in large-scale. Additionally, this thesis plans to use the denbinobin as the central core and develops various alkylaminobenzoquinones as potent anticancer agents. The substitution effects at C-3 position on biological activity is discussed as well with the expection to afford more active compounds. Compound 47 at with a C3 cyclopropylamine inhibited A549 and PC-3 cancer cell lines with GI50 values of 0.28 and 0.20 μM, respectively. It is respectively 13.2 and 11.4 fold more potent than denbinobin (1) against A549 and PC-3 cancer cells.