新型吲哚酮螺四氢硫代吡喃类药性骨架的构建和抗肿瘤活性研究

p53 protein is one of the most important tumor suppressors, and its inactivation is closely related to tumor formation, metastasis and aggravation. In tumor cells, overexpression of MDM2 protein is the main contribution to p53 inactivation. Therefore, it is an attractive and promising strategy for cancer treatment to develop novel MDM2 inhibitors which reactivate p53 antitumor activity. However, existing MDM2 inhibitors contain several chiral centers, which were generally constructed using chiral substrates or enantiomer separation technology. Therefore, it is difficult to synthesize these costly inhibitors which limits their intensive investigation. In our previous work, the organocatalytic enantioselective cascade reactions were developed for constructing the chiral spiro-tetrahydrothiopyran-oxindole scaffold with excellent diastereo- and enantioselectivities which incorporating two privileged drug scaffolds (oxindole and tetrahydrothiopyran), the special chemical property of sulfur atom and the character of MDM2 binding site. Biological evaluation indicated this novel scaffold displayed broad spectrum antitumor activity. More interesting, molecular mechanism study revealed this scaffold was a novel MDM2 inhibitor. For further investigation, receptor based drug design technology and asymmetric organocatalytic methodology will be used for the rational design and synthesis of the derivatives. Moreover, intensive antitumor structure activity relationship (SAR) and mechanism study will be explored. This research project will efficiently identify novel drug-like antitumor lead compounds with self-owned intellectual properties and provide basis for developing broad spectrum, efficient, low toxicity and MDM2 targeted novel antitumor agents.

p53蛋白是重要的肿瘤抑制因子，其失活与肿瘤的发生、转移和恶化密切相关。MDM2蛋白高表达是p53失活的主要原因，因此研发MDM2抑制剂，激活p53抗肿瘤功能是近年肿瘤药物研究的重要策略。目前在MDM2抑制剂研究中，多采用手性源或手性拆分技术，获得多手性中心的化合物，合成难度大、成本高，严重限制了其深入研究。申请者基于两种优势骨架（吲哚酮螺环和四氢硫代吡喃），结合硫原子的特殊性和MDM2活性腔的特点，采用特色的手性催化技术，高立体选择性构建了新颖的吲哚酮螺四氢硫代吡喃结构，并证实它们具有广谱抗肿瘤活性，是新型MDM2抑制剂。本项目拟进一步基于MDM2蛋白进行合理药物设计，并通过手性催化技术，对此类新型骨架进行衍生，再深入研究抗肿瘤构效关系和作用机制，以期获得具有独立自主知识产权、类药性好的抗肿瘤活性先导化合物，为发展广谱、高效、低毒、靶向MDM2新型抗肿瘤药物奠定基础。

研发MDM2抑制剂，重新激活p53抗肿瘤功能是近年来恶性肿瘤药物治疗的重要策略。现有的MDM2抑制剂含多个手性中心，采用手性原料或拆分技术制备，合成难度大、成本高，不利于构效关系深入研究。此外，部分抑制剂被证实存在血液毒性。因此，需要基于新骨架进一步开发广谱、高效、血液毒性低的MDM2类抑制剂。在青年基金资助下,研究团队采用有机小分子催化的不对称串联反应，首次不对称构建了六种新型吲哚酮螺含硫杂环骨架。活性筛选发现这些骨架表现广谱、较好的体外抗肿瘤活性，多个化合物的活性明显优于阳性药Nutlin-3。作用机制研究表明，吲哚酮螺硫杂环骨架抑制了p53与MDM2的结合，重新激活了p53的抗肿瘤功能，进而发挥抗肿瘤活性，并能够明显诱导肿瘤细胞凋亡和阻滞肿瘤细胞周期在G0/G1期。基于“配体-受体”结合模式，研究团队进一步对骨架I和II开展了基于结构的药物设计和改造。其中骨架II的衍生物A6不仅表现优秀的MDM2酶抑制和体外抗肿瘤活性，还能够显著抑制肺癌A549裸鼠移植瘤的生长，体内抑瘤率高达62.4%，并对裸鼠体重无明显影响，显示低毒性特点。该部分研究将有机合成方法学成功应用到药物活性分子的发现过程中，为新药发现提供了一种新思路，并为抗肿瘤化学生物学研究提供了分子探针。本项目发现多个靶向MDM2的全新先导结构，对其深入研究，有望发现靶向MDM2的抗肿瘤创新药物。在青年基金资助下,本项目已发表SCI论文8篇，影响因子5分以上的4篇,申请发明专利5项，已授权4项。