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<p>The natural product cortistatin A and its derivative didehydro-cortistatin A exhibit potent biological activity in different disease states, indicating the potential utility of their derivatives as treatments for a variety of diseases. The synthesis of the unique ring system found in these compounds is challenging, and therefore we designed analogs with a conventional steroidal scaffold that retained the A-ring functionalities with the stereochemistries found in the natural product, building on a previous report of simplified didehydro-cortistatin A analogs. The steroidal derivatives were synthesized in 9 steps from prednisone with different isoquinoline isomers incorporated at C17 via a Stille coupling in the last step. The analogs exhibited antiproliferative activity in HCT 116 colon cancer cells with low micromolar potency (HCT 116 IC<sub>50</sub> = 4.80–11.5 <i>µ</i>M) and rapid onset. The methodology described here can be used to prepare additional simplified didehydro-cortistatin A analogs for future biological applications.</p><p></p>

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Synthesis of simplified didehydro-cortistatin A derivatives as anti-proliferative agents

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Jeremy S. Coleman,
  • Larissa Costa de Almeida,
  • Laura E. Hanold,
  • Michael J. Ferracane,
  • Hendrik Luesch,
  • Jane V. Aldrich

摘要

The natural product cortistatin A and its derivative didehydro-cortistatin A exhibit potent biological activity in different disease states, indicating the potential utility of their derivatives as treatments for a variety of diseases. The synthesis of the unique ring system found in these compounds is challenging, and therefore we designed analogs with a conventional steroidal scaffold that retained the A-ring functionalities with the stereochemistries found in the natural product, building on a previous report of simplified didehydro-cortistatin A analogs. The steroidal derivatives were synthesized in 9 steps from prednisone with different isoquinoline isomers incorporated at C17 via a Stille coupling in the last step. The analogs exhibited antiproliferative activity in HCT 116 colon cancer cells with low micromolar potency (HCT 116 IC50 = 4.80–11.5 µM) and rapid onset. The methodology described here can be used to prepare additional simplified didehydro-cortistatin A analogs for future biological applications.