Harvey Natalie L, Krysiak Joanna, Chamni Supakarn, Cho Sung Wook, Sieber Stephan A, Romo Daniel
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, TX 77842 (USA) http://www.chem.tamu.edu/rgroup/romo/index.html.
Chemistry. 2015 Jan 19;21(4):1425-8. doi: 10.1002/chem.201405980. Epub 2014 Dec 8.
An eleven-step synthesis of (±)-spongiolactone from 1,3-cyclohexanedione is reported that relies on a diastereoselective, nucleophile-catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β-lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure-activity studies that revealed a regio- and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.
报道了一种从1,3 - 环己二酮出发的十一步合成（±） - 海绵内酯的方法，该方法依赖于一种非对映选择性、亲核试剂催化的羟醛内酯化（NCAL）过程，该过程使用一种高级酮酸中间体，构建了天然产物预期的β - 内酯药效基团。此外，向取代的环己酮中进行立体选择性环己烯基锌加成反应，同时构建了两个全取代的邻位立体中心。所报道的合成方法使得初步的构效关系研究得以开展，该研究揭示了一种海绵内酯的区域和立体异构体衍生物，其对白血病（K562）细胞系具有更强的抗增殖活性。此外，观察到这些海绵内酯衍生物对K562细胞系具有异常的抗增殖选择性，而对所测试的乳腺癌、肝癌和肺癌细胞系均无抑制作用。
