Department of Medicinal Chemistry and the Institute for Therapeutics Discovery & Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
Bioorg Med Chem. 2012 Oct 1;20(19):5893-900. doi: 10.1016/j.bmc.2012.07.044. Epub 2012 Aug 3.
Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort. Here, we present a concise synthetic approach to N-substituted phenanthropiperidines, which enabled a systematic investigation of structure-activity relationships at an underexplored region of the tylophorine scaffold. This work suggests that ring E of tylophorine is essential for the anti-proliferative activity of the 6,7,10,11-tetramethoxy-1,2,3,4-tetrahydrodibenzo[f,h]isoquinoline core scaffold.
千里光菲灵碱和许多相关的苯并菲啶生物碱是非常有效的抗增殖剂。尽管这些生物碱具有令人印象深刻的抗癌活性，但由于其溶解度差和神经副作用，它们的临床开发受到了阻碍。尽管有人提出开发极性苯并菲啶类化合物将减轻这些不良特性，但缺乏合成此类类似物的实用方法限制了这方面的努力。在这里，我们提出了一种简洁的合成方法，用于合成 N-取代的苯并菲啶类化合物，这使得我们能够对千里光菲灵碱支架中一个研究较少的区域进行系统的构效关系研究。这项工作表明，千里光菲灵碱的环 E 对于 6,7,10,11-四甲氧基-1,2,3,4-四氢二苯并[f,h]异喹啉核心支架的抗增殖活性是必不可少的。
