設計與合成以嘌呤類小分子作為骨架之抗癌藥物

Abstract

肺癌每年造成約有百萬人死亡，是全世界最常見的的癌症之一。根據細胞組織型態的不同，我們又可以將肺癌分類成小細胞肺癌以及非小細胞肺癌。而其中，約有85%的肺癌患者被診斷為非小細胞肺癌。2012年，位於中央研究院的基因體研究中心利用高通量藥物篩選系統，在化合物資料庫中篩選出了嘌呤類化合物1 (GRC0321)，其對於非小細胞肺癌有不錯的抑制效果。 在本篇論文中，我們構想組蛋白脫乙醯酶抑制劑 (HDACIs) 的鋅離子結合部分能與嘌呤類化合物結構進行接合。若將兩個骨架融合為單一化合物，或許能在對抗非小細胞肺癌的治療中產生增效作用。根據此概念，我們設計與合成一系列的雙重抑制劑。其中，異羥肟酸化合物3在生物實驗中對於H1975肺癌細胞、MDA-MB231乳癌細胞以及組蛋白脫乙醯酶的活性都具有良好的抑制效力。未來將會進一步進行小鼠實驗以供後續抗癌藥物的開發。

Lung cancer is one of the most common cancers in the world, causing more than one million deaths per year. Lung cancer can be classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Almost 85% of lung cancer patients are diagnosed as NSCLC. In 2012, a high throughput screening in Academia Sinica revealed that the purine-type compound 1 (GRC0321) was a potent agent against NSCLC. In this study, we conceive that the essential zinc-binding moiety of histone deacetylases inhibitors (HDACIs) can be incorporated into the structure of purine-type compound. Thus, it is possible to merge these two scaffolds into one single conjugate compound, which may exhibit synergistic effect in treatment of NSCLC. This idea prompts us to design and synthesize a series of dual targeting inhibitors. Among the synthesized compounds, hydroxamte compound 3 showed potent toxicity to H1975 lung cancer cells and MDA-MB231 breast cancer cell lines, and also displayed excellent inhibitory activity against HDACs. Thus it was subjected to animal experiments for development of anticancer drug.