Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro-ku, Tokyo 152-8552, Japan.
Eur J Med Chem. 2013 Aug;66:180-4. doi: 10.1016/j.ejmech.2013.05.030. Epub 2013 Jun 3.
The spirocycle is a key structure found in many bioactive compounds. From the cytotoxic and spirocyclic natural product, spiromamakone A (1) and its analogues, a more synthetically accessible spiroacetal template 4 was designed based on structural similarity analysis. A total of 50 compounds were rapidly synthesized in only one or two synthetic steps from the starting compound, and their cytotoxicity was evaluated. As a result, (±)-(2R*,5R*)-2-(4-iodophenyl)-7-chloro-1,4-dioxa-spiro[4.5]deca-6,9-dien-8-one (7d-II) was discovered and found to be fifteen-fold more cytotoxic than 1. The easily accessible spiroacetal 7d-II appeared to act in a manner similar to the highly oxidized natural product, spiromamakone A (1).
螺环是许多生物活性化合物中发现的关键结构。从细胞毒性和螺环天然产物 spiromamakone A（1）及其类似物中，基于结构相似性分析，设计了更具合成可及性的螺缩醛模板 4。总共 50 种化合物可以从起始化合物通过一步或两步合成得到，评估了它们的细胞毒性。结果发现，（±）-（2R*，5R*）-2-（4-碘苯基）-7-氯-1,4-二氧杂螺[4.5]癸-6,9-二烯-8-酮（7d-II），比 1 高出十五倍的细胞毒性。易于获得的螺缩醛 7d-II 似乎以类似于高度氧化的天然产物 spiromamakone A（1）的方式发挥作用。
