【作者】 冷志；

【导师】 聂丽娟；

【作者基本信息】 南昌大学 ， 有机化学， 2006， 硕士

【摘要】 DNA拓扑异构酶是细胞的一种核酶，通过调控DNA分子的解旋、松弛、断裂，然后重新闭合，使DNA进行翻译、修补、复制等功能，在细胞周期中维持DNA的拓扑学的结构。喜树碱是拓扑异构酶Ⅰ特异性抑制剂，具有很强的抗肿瘤活性。可用于治疗多种恶性肿瘤，如骨癌、肝癌、膀胱癌和白血病等。但临床研究表明，喜树碱会产生骨髓抑制、呕吐、腹泻和血尿等严重的副作用。此外，其水溶性较差，难以制成合适的剂型，从而使其临床应用受到一定限制。喜树碱在体内存在内酯环形式和羧酸盐形式的平衡。内酯环的结构对抗肿瘤活性非常重要；羧酸盐形式导致抗肿瘤活性降低，并且产生多种毒副作用。人们对喜树碱衍生物的结构进行改造，寻找高效低毒的抗肿瘤喜树碱衍生物。因而喜树碱衍生物成为研究的热点。 本论文通过总结已有的喜树碱类衍生物的构效关系，应用合理药物设计的基本原理，设计了以20(S)—喜树碱为原料，在B环的7位引入苯甲酰基、对-二甲氨基-苯甲酰基，可制成盐酸盐形式，增强其水溶性，有利于药物的吸收和制成各种剂型。 药理试验数据表明：与阳性对照喜树碱相比，本论文合成的7-苯甲酰基喜树碱化合物对人体白血病细胞(HL-60)的细胞毒、人体胃癌细胞(BGC-823)、人体肝癌细胞(Bel-7402)和人鼻咽癌细胞(KB)的都有较强的抗肿瘤活性。更多还原

【Abstract】 Topoisomerase I is an ubiquitous enzyme that solve topological problems generated by key nuclear processes such as DNA replication, transcription, recombination, repair, chromatin assembly, and chromosome segregation. Camptothecin was a cyto-toxic agent and exerted its antitumor activity by inhibiting Topoisomerase I. It was used for curing various malignant tumors, such as the bone cancer, cancer of the liver, theurine bladder cancer and leukemia etc. However, clinical study shows that camptothecin leads to severe adverse effects such as marrow inhibition, vomiting, diarrhca and hemoglobinuria.In vivo camptothecin remains a balance of E-lactone form and Carboxylic salt form. Maintenance of E-lactone is impor- tant for the antitumor activity. People are studying Structure-Activity Relationships of derivatives of camptothecin. To improve the profile of 20 (S)-campptothecin. Therefore, derivatives of camptothecin are becoming the focus of research.This paper summarized the new development on Topoisomerase I and camptothecin research, and discussed Structure-Activity Relationships of camptothecin analogs. Based on Rational Drug Design, We design and synthesesze three new compounds of 7-benzoyl-camptothecin, and 7- dimethyl-benzoyl-camptothecin, Which could Make into the hydrochloride form and increase it water-soluble and be advantageous to the absorption of the medicine and make into various type.The in vitro cytoxicity against HL-60, BGC-823, Bel-7420 and KB cell lines of the 7-benzoyl-camptothecin were evaluated. The results reveal that it posses inhibitory activity against rumor cells .Author: LENGZhi (Organic Chemistry) Directed by Prof. NIE Li-juan更多还原