三芳基甲烷硼酸类化合物的设计、合成及抗肿瘤活性研究

Triarylmethanes (TRAMs) constitute an important class of compounds that are ubiquitous in medicals, material and dyes. Recently, phenolic derivatives of TRAMs have been reported to show activities of anti-tumor, antioxidant and inhibition of histidine protein kinases. Boronic acids also possess good anti-tumor,antiviral and antibiotic activities. Because of its unique structure, boronic acid group is frequently used to modify drug molecule to increase its targeting and efficacy. Previously, we have studied the antitumor activity of borono-modified flavonoids and the synthesis of TRAMs, good results have been obtained.In this research, we will design and synthesize a series of boronic acid bioisosteres of TRAMs, using boronic acid to mimic the OH group on the benzene ring, in an effort to explore highly active anti-tumor compounds and study their structure-activity relationship.

三芳基甲烷也是一类重要的中间体，具有非常广泛的用途。近些年其酚类衍生物则已被确认表现出了抗肿瘤活性、抗氧化性质和对组氨酸蛋白致活素的抑制性。有机硼酸化合物具有抗肿瘤、抗病毒、抗菌等活性，由于其结构的独特性, 硼酸官能团还被用来修饰药物分子的靶向作用以提高药效。我们前期已经研究了硼酸基黄酮类化合物的抗肿瘤活性及三芳基甲烷类化合物的合成方法，本项目在前期基础上，根据生物电子等排法，设计用硼酸基团替代酚羟基修饰三芳基甲烷类化合物，研究该类化合物的高效合成方法,并测定其抗肿瘤活性，研究其构效关系，为寻找新的高活性先导化合物提供思路。

项目研究发现了氨基磺酸是一种环境友好的、可回收重复利用的合成三芳基甲烷类化合物的催化剂，可以在无溶剂条件下容易的合成硼酸取代的三芳基甲烷类化合物和硼酸取代的三杂芳基甲烷类化合物，并获得了较高的收率。活性测试发现根据电子等排法设计的硼酸基取代的三芳基甲烷类化合物在抑制Hep G2和SMMC-7721肿瘤细胞生长上抑制率与羟基或者其他基团取得的三芳基甲烷类化合物相比有所提高。同时该项目还制备了几种在特定位置上含有核碱基氨基酸的假定转录因子hnRNP LL的核酸结合基序（RRM1）的变体，并用于研究对BCL2 i-motif DNA的结合亲和力。结果表明使用核碱基氨基酸作为蛋白质组分来控制和增强DNA-蛋白质相互作用的想法是可行的。