中文摘要：

以噻唑烷酮化合物为例,介绍了先导化合物的研发过程。运用组合化学的方法设计并合成了小分子化合物库,用以发现和优化先导化合物。用肺癌细胞、抗药性肺癌细胞和正常细胞进行高通量筛选,发现了选择性杀伤抗药性肺癌细胞的化合物。作用机制研究表明活性化合物抑制微管蛋白,将细胞阻滞在G2/M期且可诱导细胞凋亡和自噬,其抗癌活性不依赖于P-糖蛋白。这类先导化合物具有良好的细胞膜通透性,体内试验表明其可有效抑制肿瘤的生长。对60个人体肿瘤细胞系的筛选中,发现这类先导化合物具有广谱的抗癌活性,将在未来癌症治疗研究中起到重要的作用。

英文摘要：

Taking thiazolidinone compounds as an example,we discuss the processes leading to the discovery of anti-cancer lead compounds.Using combinatorial chemistry and high throughput screening approaches,we discovered potent compounds against drug-resistant cancer cells.Mechanistic studies indicated that these compounds inhibited microtubule formation,caused G2/M arrest in cell cycle,and induced apoptosis and autophagy.The anti-cancer activity did not depend on the status of P-gp in cells.These compounds had superb membrane permeability and inhibited tumor growth in vivo.Screening them against 60 human cancer cell lines demonstrated broad anti-cancer activities indicating that they will play a significant role in the future of our fight against cancer.