Fradcarbazole A衍生物的设计、合成及其抗白血病活性研究

Staurosporine derivatives have showed significant anti-tumor activities and been attractive to researchers. For example, UCN-01 and PKC-412 are currently on phase II/III clinical trials for treatment of Lymphoma and leukaemia respectively. Fradcarbazole A, isolated from a mutant marine Streptomyces strain, possesses a unique skeleton consisting of staurosporine core, a thiazole ring and an indole fragment and good cytotoxic activities against HL-60, K562 and MV4-11 cell lines. The synthesis of Fradcarbazole A has been accomplished by using biomimetic intramolecular cyclization and dehydration to construct the staurosporine-thiazole-indole skeleton. Several halogenated and heterocyclic substituted derivatives of Fradcarbazole A show strong binding energy with FLT-3, CDK2 and c-Kit via computation based virtual screening. This research will focus on design and preparation of Fradcarbazole A derivatives/analogues and studies on their cytotoxicities and structure-activity relationships. We are trying to provide practical scientific experience for research and development of new Staurosporine-like antitumor drugs.

十字孢碱的衍生物具有很好的抗肿瘤活性， PKC-412和UCN-01分别处于治疗肿瘤的临床三期和临床二期研究。Fradcarbazole A是从一株突变的海洋链霉菌中分离得到的一个十字孢碱类似物，其具有新颖十字孢碱-噻唑环-吲哚环相连的结构，对HL-60、K562和MV4-11细胞株表现出了较好的细胞毒活性。在前期的研究工作中，以十字孢碱为原料完成了Fradcarbazole A的仿生合成，并设计了其卤代及杂环取代的衍生物与Flt-3、CDK2和c-Kit等靶蛋白进行虚拟筛选，发现了多个与靶蛋白具有较强结合能的化合物。本课题拟在前期工作基础上对Fradcarbazole A的衍生物和结构类似物进行设计合成，研究抗白血病活性构效关系，获得具有开发潜力的抗白血病候选分子，为开发具有自主知识产权的抗肿瘤药物提供科学依据。

十字孢碱的衍生物PKC-412作为Flt-3等激酶抑制剂，已被FDA批准用于急性骨髓性白血病的治疗。Fradcarbazole A是从海洋链霉菌中分离得到的一个十字孢碱的衍生物，具有十字孢碱-噻唑-吲哚三环相连的分子骨架，本课题设计合成了49个Fradcarbazole A的衍生物，评价了其三种白血病细胞株（人急性髓系白血病细胞MV4-11、人慢性髓系白血病细胞K562和人早幼粒白血病细胞HL-60）、一种实体瘤细胞株（肺癌细胞A549）和一种人正常细胞（人外周血单核细胞PBMC）的细胞毒活性，大部分化合物对Flt-3高表达的MV4-11细胞具有较强的抑制作用、但对人正常细胞株PBMC细胞的毒性较弱，可深入研究。本研究申请了PCT专利1项、国家发明专利3项，发表标注的SCI论文1篇。