槐定酸类似物设计、合成及其抗肿瘤活性与研究.pdfVIP

槐定酸类似物的设计、合成及其抗肿瘤活性研究 毕重文，张彩霞，蒋建东，邵荣光，宋丹青* ( 中国医学科学院、北京协和医学院医药生物技术研究所，北京 100050) 摘要：目的 探讨槐定酸类衍生物的抗肿瘤活性构效关系，寻找新型 抗肿瘤候选物。方法 采用两条路线共合成定酸类化合物，采用磺酰罗丹明 B 染色法进行活性测定。结果 获得 28 个槐定酸类似物，部分化合物对人 肝癌 HepG2 细胞表现出较强的抑制活性，对人肺癌细胞、人乳腺癌细胞和 人口腔表皮样癌细胞的抑制活性均超过阳性药拓扑替康。初步作用机制显 示，化合物9f 阻滞人肝癌HepG2 细胞周期于G1 期。结论 研究结果为将 此类化合物发展成一类新型抗肿瘤化合物提供科学数据。 关键词：槐定酸衍生物；抗肿瘤；构效关系；拓扑异构酶 Design, synthesis and structure-activity relationship of sophoridinic acid derivatives as anti-cancer agents BI Chong-Wen, ZHANG Cai-Xia, JIANG Jian-Dong, SHAO Rong-Guang, SONG Dan-Qing* (Institute of Medicinal Biotechnology, China Academy of Medical Science and Peking Union Medical College, Beijing 100050, China) Abstract: OBJECTIVE To study the structure-activity relationship （SAR）of sophoridinic acid derivatives and seach for novel anti-cancer agents. METHODS 28 derivatives were synthetized through two routes and their anti-cancer activity was evaluated through SRB assay. RESULTS Among all analogs, 6d、9f showed strong inhibition against human HepG2 cells. They afforded a potent effect against multiple human cancer cell lines as well. The primary mechanism showed that cell cycle was 1  blocked at G1 phase in HepG2 cells treated with 9f using flow cytometry assay. CONCLUSION Our results provided a basis for the development of this kind of compounds as novel of anti-cancer agents. Key words: sophoridinic acid derivatives; anti-cancer; structure-activity relationship; topoisomerase 随着人类平均预期寿命的提高以及人口的老龄化，预计未来 20 年内，老年 患者将占新发肿瘤患者的70% 。老年人肿瘤的生理及临床特点决定了肿瘤被发现 时，大多是中晚期，失去了手术治疗和多重放疗的机会，加之老年患者脏器功能 衰退，往往伴有多种合并症，对外界的抵抗力降低，因此老年肿瘤患者难以耐受 传统治疗方案[1-2] 。而中药治疗肿瘤在稳定瘤体、调节机体功能、增强免疫能力、 减轻化疗副作用等方面具有独特疗效。因此，中药治疗成为我国老年肿瘤患者积