神经胶质瘤是临床常见的难治肿瘤，研究发现50%-80%二级神经胶质瘤患者存在异柠檬酸脱氢酶-1基因突变现象，这一突变与胶质瘤的分化及恶化密切相关, 并有研究证实靶向突变型IDH1诱导癌细胞分化是一种潜在的治疗神经胶质瘤的途径。本课题组前期研究发现一些一叶萩型生物碱衍生物具有良好的促神经细胞分化作用，并能与突变型IDH1相互作用。本研究将在此基础上，以突变型IDH1为靶标，以发现的促分化活性化合物15-（脯氨酸乙酯）一叶萩碱为先导化合物，对其进行结构修饰，设计合成一系列一叶萩碱氨基酸轭合物，筛选靶向突变型IDH1的新型促分化抗胶质瘤的苗头化合物；并对合成化合物的抑酶及抗神经胶质瘤的构效关系和作用机制等进行研究，为开发靶向突变型IDH1的促分化抗神经胶质瘤药物提供科学依据。

Glioma is a common clinical cancer, which are rarely curable. Some studies revealed that 50%-80% human grade Ⅱgliomas have isocitrate dehydrogenase-1 (IDH1) mutations, and these mutations were closely associated with the differentiation and deterioration of gliomas. Additionally, a recent discovery identified that inhibition of mutant IDH1 proteins to induce cell differentiation is a potential anti-glioma therapy. Our previous studies showed that some securinine-type alkaloid derivatives have good effect on promoting the differentiation of neural cells, and can interact with mutant IDH1 protein. In this study, we propose to design, synthesize a variety of novel amino acid securinine conjugates based on the structure of the active compound-15-(proline ethyl ester) securinine, and screen leading compounds that active inhibit the mutant IDH1 and against glioma. In addition, the structure-activity relationship for the synthesized compounds as well as the molecular mechanism of the leading compounds will also be investigated. We hope that through this study and explore, to provide foundation and theoretical basis for the further development of anti-glioma agents targeting mutant IDH1 protein.

神经胶质瘤是临床常见的难治肿瘤，研究发现50%-80%二级神经胶质瘤患者存在异柠檬酸脱氢酶-1基因突变现象，这一突变与胶质瘤的分化及恶化密切相关, 并有研究证实靶向突变型IDH1诱导癌细胞分化是一种潜在的治疗神经胶质瘤的途径。本研究以突变型IDH1为靶标，共设计合成新化合物43个，包括一叶萩碱氨基酸轭合物9个、一叶萩碱二聚体衍生物12个、5-羟基-4-吡喃酮衍生物22个。成功筛选得到具有优秀体内2-HG抑制活性的及抗胶质瘤活性的苗头化合物c2。并进一步开展了突变型IDH1抑制剂的3D-QSAR研究，得到了一系列突变型IDH1蛋白抑制剂的构效关系。同时对筛选得到的5-羟基-4-吡喃酮类抗胶质瘤苗头化合物的作用机制进行了初步探索，发现筛选得到的5-羟基-4-吡喃酮类抗胶质瘤苗头化合物除突变型IDH1抑制作用外可能具有全新的2-HG作用机制。本研究为开发靶向突变型IDH1及2-HG的促分化抗神经胶质瘤药物开发提供了新的侯选先导物及科学依据。在本项目资助下已发表通讯作者SCI论文2篇，进一步机制研究仍在进行中，并已着手申请相关专利。在人才培养方面，培养研究生4名（博士1名、硕士3名），项目负责人获2017年度“广州市珠江科技新星”称号，并多次参与国际国内学术交流活动。