The Discovery of Potent Antitumor Agent C11-Deoxypsymberin/irciniastatin A: Total Synthesis and Biology of Advanced Psymberin Analogs
The Discovery of Potent Antitumor Agent C11-Deoxypsymberin/irciniastatin A: Total Synthesis and Biology of Advanced Psymberin Analogs
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DOI：
10.1021/ol802772s
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发表时间：
2009-02-19
期刊：
影响因子：
5.2
通讯作者：
Seidel-Dugan, Cynthia
中科院分区：
文献类型：
--
作者：
Huang, Xianhai;Shao, Ning;Seidel-Dugan, Cynthia
通过修饰抗癌海洋天然产物psymberin/irciniastatin A(1)的不饱和侧链进行的构效关系研究表明，C4和C5上的取代对psymberin的细胞毒性很重要，但末端双键对活性不是必需的。芳基是取代烯烃的很好的替代品。结构简化的C11-脱氧顺铂(29)的全合成完成，其活性一直高于天然产物，这为进一步研究顺铂和顺铂家族提供了一个独特的机会。初步的机制研究表明，psymberin的作用方式是通过细胞凋亡。
Structure-activity relationship (SAR) studies by modification of the unsaturated side chain of potent anticancer marine natural product psymberin/irciniastatin A (1) suggest that substitution at C4 and C5 is important for the cytotoxicity of psymberin, but the terminal double bond is not essential for activity. An aryl group is a good replacement for the olefin. The total synthesis of structurally simplified C11-deoxypsymberin (29) was completed, and its activity is consistently more potent than the natural product which provides a unique opportunity for further SAR studies in the psymberin and pederin family. Preliminary mechanism studies suggest the mode of action of psymberin is through cell apoptosis.