Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives

作者：Sellers Robert P; Alexander Leslie D; Johnson Victoria A; Lin Chun Chieh; Savage Jeremiah; Corral Ricardo; Moss Jason; Slugocki Tim S; Singh Erinprit K; Davis Melinda R; Ravula Suchitra; Spicer Jamie E; Oelrich Jenna L; Thornquist Andrea; Pan Chung Mao; McAlpine Shelli R^*

来源：Bioorganic & Medicinal Chemistry, 2010, 18(18): 6822-6856.

DOI：10.1016/j.bmc.2010.07.042

• Sansalvamide A
• Pancreatic cancer
• Macrocyclic peptides
• Macrocycles
• Cytotoxicity
• Growth inhibition
• Docking
• Hsp90

Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative. Published by Elsevier Ltd.

• 出版日期2010-9-15