Welford Amanda J, Caldwell John J, Liu Manjuan, Richards Meirion, Brown Nathan, Lomas Cara, Tizzard Graham J, Pitak Mateusz B, Coles Simon J, Eccles Suzanne A, Raynaud Florence I, Collins Ian
Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
UK National Crystallography Service, University of Southampton, Southampton, SO17 1BJ, UK.
Chemistry. 2016 Apr 11;22(16):5657-64. doi: 10.1002/chem.201505093. Epub 2016 Mar 1.
The 2,11-cembranoid family of natural products has been used as inspiration for the synthesis of a structurally simplified, functionally diverse library of octahydroisobenzofuran-based compounds designed to augment a typical medicinal chemistry library screen. Ring-closing metathesis, lactonisation and SmI2 -mediated methods were exemplified and applied to the installation of a third ring to mimic the nine-membered ring of the 2,11-cembranoids. The library was assessed for aqueous solubility and permeability, with a chemical-space analysis performed for comparison to the family of cembranoid natural products and a sample set of a screening library. Preliminary investigations in cancer cells showed that the simpler scaffolds could recapitulate the reported anti-migratory activity of the natural products.
天然产物的2,11-西松烷类化合物家族为合成一个结构简化、功能多样的基于八氢异苯并呋喃的化合物库提供了灵感，该化合物库旨在扩充典型的药物化学库筛选。环化复分解、内酯化和SmI₂介导的方法得到了举例说明，并应用于引入第三个环以模拟2,11-西松烷类化合物的九元环。对该化合物库进行了水溶性和渗透性评估，并进行了化学空间分析，以便与西松烷类天然产物家族和一个筛选库的样本集进行比较。在癌细胞中的初步研究表明，较简单的骨架可以重现天然产物所报道的抗迁移活性。
