Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
J Am Chem Soc. 2010 Jul 7;132(26):9175-87. doi: 10.1021/ja103537u.
The dictyostatins are a promising class of potential anti-cancer drugs because they are powerful microtubule-stabilizing agents, but the complexity of their chemical structures is a severe impediment to their further development. On the basis of both synthetic and medicinal chemistry analyses, 16-desmethyl-25,26-dihydrodictyostatin and its C6 epimer were chosen as potentially potent yet accessible dictyostatin analogues, and three new syntheses were developed. A relatively classical synthesis involving vinyllithium addition and macrocyclization gave way to a newer and more practical approach based on esterification and ring-closing metathesis reaction. Finally, aspects of these two approaches were combined to provide a third new synthesis based on esterification and Nozaki-Hiyama-Kishi reaction. This was used to prepare the target dihydro analogues and the natural product. All of the syntheses are streamlined because of their high convergency. The work provided several new analogues of dictyostatin, including a truncated macrolactone and a C10 E-alkene, which were 400- and 50-fold less active than (-)-dictyostatin, respectively. In contrast, the targeted 16-desmethyl-25,26-dihydrodictyostatin analogues retained almost complete activity in preliminary biological assays.
碟豆素类是一类很有前途的潜在抗癌药物，因为它们是强效的微管稳定剂，但它们复杂的化学结构严重阻碍了它们的进一步发展。基于合成和药物化学分析，选择了 16-去甲基-25,26-二氢碟豆素及其 C6 差向异构体作为潜在的有效且可获得的碟豆素类似物，并开发了三种新的合成方法。一种相对经典的合成方法涉及乙烯基锂加成和大环化，让位于基于酯化和环 closing metathesis 反应的更新颖和更实用的方法。最后，将这两种方法的一些方面结合起来，提供了基于酯化和 Nozaki-Hiyama-Kishi 反应的第三种新的合成方法。该方法用于制备目标二氢类似物和天然产物。由于其高收敛性，所有的合成方法都得到了简化。这项工作提供了几种新的碟豆素类似物，包括一个截断的大环内酯和一个 C10 E-烯烃，它们的活性分别比（-）-碟豆素低 400 倍和 50 倍。相比之下，目标 16-去甲基-25,26-二氢碟豆素类似物在初步的生物学测定中保持了几乎完全的活性。
