1,4-苯并二氮杂卓-2,5-二酮类抗肿瘤先导物的发现、结构优化及作用机制

癌症的新发病例及死亡人数持续增长，已严重威胁人类健康。目前人类对于某些类型的癌症（如中晚期、已转移的病例）尚无切实有效的治疗手段。现有的抗癌药物存在治愈率低、毒副作用强、耐药性等诸多问题，难以满足临床需求。研究开发具有新型结构、新颖作用机制的抗癌药物，具有重大的社会价值和经济效益。. 本课题组通过随机筛选化学库的方式发现了先导物2，具有新颖结构和显著的体外抗肿瘤活性特点（对60种人类肿瘤细胞株的平均GI50值为50nM，对结肠癌COLO 205细胞株可达13nM），然而也存在吸收差、代谢不稳定等问题。本项目拟以先导物2为结构基础，以提高活性和改善药动学性质为目的，依据经典的药物化学理论制订结构优化策略，同时探讨其作用机制和靶点，以期获得2-3个具有良好药学性质的抗肿瘤药物候选物。

The incidence and mortality of cancer continue to increase largely and it has been a serious threat to human health. However there is still no effective treatment for the advanced or metastic trials. Currently clinically used chemotherapeutic agents exhibit a range of disadvantages, such as low cure rate, adverse effects and drug resistance, can not satisfy the clinical requirements. Thus, it will be of great social value and economic benefits to design and develop novel antitumor agents based on original structure and mechanism...Lead compound 2, a promising small molecule with original structure and significant in vitro antitumor activity, was discovered during screening chemical library of our own. The average GI50 value against 60 human cancer cell lines was 50nM. However， its inacceptable absorption and metabolic instability properties in vivo require for further investigation. In this project, we plan to improve the potency and pharmacokinetics of lead compound 2 by a classical medicinal chemistry strategy. The antitumor mechanism of compound 2 will also be investigated to meet the goal that two or three antitumor drug candidates are defined with favorable potency, novel action and satisfied PK profiles.