以四链核酸为靶标的抗肿瘤药物的设计,合成及生物活性研究

针对端粒和癌基因序列在小分子的作用下可以被稳定或诱导形成G-四链核酸结构的特征, 我们设计﹑合成并筛选能对G-四链核酸有选择性结合,并能很好稳定G-四链核酸结构的小分子, 使得这些被稳定的G-四链核酸能对肿瘤高表达的端粒酶或癌基因的下调蛋白具有很好的抑制作用,从而达到对肿瘤细胞的抑制或杀伤作用,达到抗肿瘤的目的。针对上述设想,我们将开展: 1)设计并合成偶氮苯酚类化合物, 经过结构修饰后, 这些小分子能对四链核酸结构进行调控, 达到对端粒酶抑制或富含癌基因的下调的抑制,可以进一步达到抗肿瘤的目的;2) 设计并合成苯酚-西佛碱类化合物, 进一步筛选对G-四链核酸有很好的稳定性作用,同时具有对G-四链核酸具有高选择性的化合物, 达到对肿瘤细胞的抑制作用;3)利用黑色素瘤中酪氨酸酶高表达的特性, 我们设计并合成系列能直接针对癌基因序列和G-四链核酸结构的苯酚类小分子, 研究它们的抗肿瘤活性。

Small molecules targeting telomere or promoter region of oncogenes could regulate these sequences to form G-quadruplexes or stabilize the structures of C-quadruplexes DNA. We shall design, synthesize and characterize these compounds targeting to G-quadruplex DNA. We shall screen them based on their selectivity to G-quadruplex DNA comparing with dsDNA. Furthermore, these compounds with highly selectivity to bind to G-quadruplex DNA will be studied to their anti-tumor activities with inhibiting telomerase activities or inhibit expression of the c-myc gene finally resulting in tumor death. In our purposal, we shall focus on: 1) design and synthesis of azobenzene derivatives which could regulate and stabilze G-quadruplex DNA, and study their anti-tumor activites; 2) design and synthesize pyridine-amide derivstives and characterize them. These compounds will be deeply studied for their abilities to regulate and stabilize G-quadruplex DNA and their anti-tumor activities; 3) design and synthesize phenol-Schiff base derivatives which could be catalyzed to form quinone intermediate by tyrosinase in melanoma cells(tyrosinase-expressing cells). We shall detailed study their interaction mechanism between phenol-Schiff base derivatives and G-quadruplex DNA in cmyc seuqences of oncogenes promoter. After triggered by tyrosinase, these melanoma cells could be killed.