作用于酪氨酸激酶的抗肿瘤小分子抑制剂γ-氟代Goniothalamin类似物的设计与合成  

Design and Synthesis of γ-fluorinated Goniothalamin Analogues:The Antitumor Small-molecule Inhibitor Act on Protein Tyrosine Kinase

作　　者：杨义[1] 李建章[1] 程纯儒[1] 卿凤翎[2] 杨先桃[3] 杨振军[3] 

机构地区：[1]四川理工学院化学与制药工程学院,四川自贡643000 [2]中国科学院上海有机化学研究所有机氟化学实验室,上海200032 [3]北京大学医学部药学院天然药物及仿生药物国家重点实验室,北京100083

出　　处：《四川理工学院学报（自然科学版）》2013年第6期9-17,共9页Journal of Sichuan University of Science & Engineering(Natural Science Edition)

基　　金：国家自然科学基金(2107028;20832008);国家重大基础研究发展计划(2012CB821600);四川理工学院人才引进项目(2012RC17;2012RC15)

摘　　要：蛋白酪氨酸激酶在肿瘤细胞的增殖、分化、转移、侵蚀等信号通路中具有重要的调控功能,已成为肿瘤靶向治疗的重点研究对象。基于靶点导向原则和构效关系研究基础,以抗肿瘤活性天然产物Goniothalamin为母体化合物,修饰合成了一系列γ,γ-二氟取代Goniothalamin类似物(4a-4i,6a-6i)和γ-单氟取代Goniothalamin类似物(7a,7b,7h)。γ,γ-二氟取代的Goniothalamin类似物可从具有光学活性的二氟亚甲基取代的锡试剂出发,经Stille偶联和1,5-氧化关环两步关键反应合成。γ-单氟取代Goniothalamin类似物则经Sharpless不对称环氧化、环氧开环亲核氟化、Lindlar氢化、HWE反应和1,5-氧化关环等反应制备。对所合成的这两类Goniothalamin含氟类似物进行了体外肿瘤细胞抑制活性和酪氨酸激酶抑制活性评估研究,结果表明在Goniothalamin分子的γ位引入一个氟原子进行修饰是较为合理的修饰方式。Protein tyrosine kinases which have an important regulatory function in the proliferation, differentiation, metastasis and corrosion of cancer cells have become one of the most important target enzymes in the study of tumor treatment. Based on the target-oriented principle and structure-activity relationship, the fluorine atoms are introduced at the T position of Goniothalamin （a potent antitumor natural product） in order to obtain more promising anti-proliferative agents. The γ, γ-difluorinated Goniothalamin analogues 4a-4i and 6a-6i are synthesized through two key steps-Stille coupling and 1,5-oxidative cyclization, from the optically active difluorinated stannanes. The γ-monofluorinated Goniothalamin analogues 7a,Tb and 7 h, are obtained through Sharpless asymmetric epoxidation, ring-opening hydrofluorination, Lindlar hydrogenation, HWE reaction, 1,5-oxidative cyclization and so on. The proliferative activity in vitro and the tyrosine kinases inhibitory activity of these fluorinated analogues are biologically evaluated, and the results show that adding one fluorine atom at the γ-position of Goniothalamin is a better modification than introducing two fluorine atoms.

关 键 词：Goniothalamin α β-不饱和δ内酯 含氟化合物 蛋白酪氨酸激酶 抗肿瘤活性 

分 类 号：O64[理学—物理化学]