Total syntheses of ningalin A, lamellarin O, lukianol A, and permethyl storniamide A utilizing heterocyclic azadiene Diels-Alder reactions

被引:442
作者
Boger, DL
Boyce, CW
Labroli, MA
Sehon, CA
Jin, Q
机构
[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
关键词
D O I
10.1021/ja982078+
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Concise, efficient total syntheses of ningalin A (I), lamellarin O (2), lukianol A (3), and permethyl storniamide A (5) are detailed on the basis of a common heterocyclic azadiene Diels-Alder strategy (1,2,4,-5-tetrazine --> 1,2-diazine --> pyrrole) ideally suited for construction of the densely functionalized pyrrole cores found in the three classes of marine natural products. Examination of the natural products and a number of synthetic intermediates revealed that some including lamellarin O (2) and lukianol A (3) exhibit modest cytotoxic activity against both wild-type and multidrug-resistant tumor cell lines. Fundamentally more important, a new class of agents including permethyl storniamide A (5) and its precursor 30, which lack inherent cytotoxic activity, are disclosed which reverse the multidrug-resistant (MDR) phenotype, resensitizing a human colon cancer cell line (HCT116/VM46) to vinblastine and doxorubicin at lower doses than the prototypical agent verapamil.
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页码:54 / 62
页数:9
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