具有逆转肿瘤细胞多药耐药性和诱导自噬双重作用的β-咔啉类抗肿瘤剂的设计、合成及作用机理研究

Base on the Project (30901843), 48 novel β-carboline intercalators were synthesized. The antitumor activities were evaluated by their anti-proliferation for human carcinoma cell lines. Antitumor activities in vivo, Stacking constants, 3D QSAR and docking were studied to meet the design requirements of high efficiency, low toxicity and drug resistance. 6 full papers were published in international famous scientific and technical periodicals (total IF 16.44), 7 national invention patents were applied. 4 Ph D candidates and 4 Master candidates were trained. However, this applying project focuses on the autophagy of tumor cells to continue the study of the former youth national natural science finding. According to the β-carboline intercalation design templates, the model compound has been obtained. Based on good results of preliminary studies, the aim of the study is to definite the structural details of the β-carboline autophagic inducer, explicit the dual activity of induced autophagy and reverse drug resitance activity, achieve the novel anti-tumor candidate compounds with dual activity on the anti-tumor and reverse tumor cell resistance.

在青年科学基金资助下(30901843)，合成48 种由Anchor、Linker 和Activator 三个基本元素构成以Stacking 为关键步骤的β-咔啉类嵌插剂，评价了它们的体内、外抗肿瘤活性、测定它们对CT DNA 双链的Stacking 速度常数、分析3DQSAR、进行柔性分子对接，建立了满足高效、低毒和逆转耐药三位一体的设计要求的分子设计模板。在国际知名期刊发表了6篇SCI论文(累计IF16.44)。第一作者的学术论文4篇(累计IF9.641)。申请了7项国家发明专利。协助培养了4名博士研究生和4名硕士研究生。根据前期研究的正性结果，该申请项目将通过持续研究确定β-咔啉类肿瘤细胞自嗜诱导剂的结构细节、确定β-咔啉类肿瘤细胞自嗜诱导剂对细胞自嗜的诱导作用在抗肿瘤活性和逆转肿瘤细胞耐药活性的地位、发现以肿瘤细胞自嗜为靶点的具有抗肿瘤和逆转肿瘤细胞耐药双重活性的抗肿瘤候选化合物。

根据前期研究的正性结果，基于本项目（81270046）我们设计合成了40个β -咔啉类肿瘤细胞自嗜诱导剂，其在低于阿霉素20倍剂量下抑制小鼠肿瘤生长、保持体重增长和脾指数都明显超过阿霉素。急性毒性实验显示LD50大于500 mg/kg、不影响肝肾功能、逆转对阿霉素耐药的宫颈癌细胞对阿霉素的敏感性。这三个特性是阿霉素无法比拟的。上述性质说明β-咔啉类自嗜诱导剂具有抗肿瘤、逆转肿瘤细胞耐药和低毒3个特点。本项目确定了β -咔啉类肿瘤细胞自嗜诱导剂的结构细节、确定了β -咔啉类肿瘤细胞自嗜诱导剂对细胞自嗜的诱导作用在抗肿瘤活性和逆转肿瘤细胞耐药活性的地位、发现以肿瘤细胞自嗜为靶点的具有抗肿瘤和逆转肿瘤细胞耐药双重活性的抗肿瘤候选化合物。项目资助的相关研究成果，在国际知名期刊发表了18篇SCI 论文(累计IF65.57)。申请了10项国家发明专利，8项获得授权。协助培养了1名博士研究生和6名硕士研究生。