新型双β-咔啉碱的设计合成、抗肿瘤构效关系与作用机理研究

Our previous investigations on structural modification and antitumor structure-activity relationships of β-carbolines indicated that this class of compounds had the potential to be used as novel antitumor drugs, and the position-1, 3, 7 and 9 of β-carboline nucleus played a vital role in determining their antitumor activities and toxicities. The DNA molecules and topoisomerase I may be their underlying targets. However, β-carbolines still present some limitations arising from the relative weak antitumor activities in animal models and the poorly understood mechanism of action. Subsequently, our group investigated the antitumor structure-activity relationships of novel bivalent β-carbolines with 3-10 carbon spacers at positon-3, 7 and 9 of β-carboline nucleus, and the preliminary results suggested that the bivalent β-carbolines had enhanced antitumor activities, reduced toxicities and significantly prolonged half-life in mice. Therefore, in the present research project, our attention will be focused on design, synthesis and antitumor structure-activity relationships of novel bivalent β-carbolines and study in depth the influence of the position and length and type of spacer on antitumor activities, acute toxicities and target selectivities. The purpose of this research project is to elucidate the antitumor structure-activity relationships in finer detail and disclose mechanism of action of novel bivalent β-carbolines, with the ultimate aim of discovering and developing novel antitumor lead compounds with potent antitumor activities as well as lower side effects.

申请人前期对β-咔啉碱进行了比较系统的结构修饰和抗肿瘤构效关系研究，结果表明：β-咔啉碱是一类具有良好开发前景的抗肿瘤化合物，β-咔啉环的1、3、7和9位是重要的抗肿瘤活性位点和毒性位点，DNA和拓扑异构酶I (Topo I）是其潜在的作用靶点。但申请人研究发现β-咔啉碱的体内抑瘤率很难突破60％。申请人随后探索了3、7、9位亚甲基桥连的新型双β-咔啉碱的抗肿瘤构效关系，发现双β-咔啉碱相对单β-咔啉碱具有抗肿瘤活性高、毒性低、体内半衰期长等意想不到的效果。由此，申请人在本课题中拟深入开展新型双β-咔啉碱设计合成和抗肿瘤构效关系研究，考察双β-咔啉碱桥链位置、桥链长度、桥链类型以及β-咔啉环上取代基位置、性质等因素对抗肿瘤活性、毒性以及靶标选择性的影响，并揭示其抗肿瘤构效关系和抗肿瘤作用机理，筛选发现结构新颖、高效低毒、机理明确的新型抗肿瘤先导化合物，为开发抗肿瘤创新药物奠定基础。

以前期研究工作为基础，设计并合成了4个系列共32个新型的双β-咔啉碱化合物，重点考察了桥链位置、桥链长度、桥链性质等对抗肿瘤活性和毒性的影响。采用MTT法和人肿瘤细胞系，对全部新合成的双β-咔啉碱进行了抗肿瘤活性筛选, 结果表明：部分双β-咔啉碱具有显著的体外抗肿瘤活性。采用小鼠急性毒性实验模型和荷瘤小鼠实验模型对优选的4个双β-咔啉碱进行了急性毒性和体内抗肿瘤活性评价，结果表明：BCN-3-5具有良好的体内抗肿瘤活性，其对H22肝癌和Lewsis 肺癌的抑瘤率分别为51.6 和54.0%。抗肿瘤作用机制的初步研究结果表明：双β-咔啉碱化合物不能嵌入DNA 分子、对拓扑异构酶I (Top I ）不表现出明显的抑制活性。进一步的研究发现：双β-咔啉碱化合物可显著抑制鸡胚尿囊膜模型的新生血管形成。因此，双β-咔啉碱的潜在抗肿瘤作用机制是抑制新生血管形成。双β-咔啉碱有可能成为新型血管靶向的抗肿瘤药物。

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