Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives |
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Authors: | Robert P. Sellers Leslie D. Alexander Victoria A. Johnson Chun-Chieh Lin Jeremiah Savage Ricardo Corral Jason Moss Tim S. Slugocki Erinprit K. Singh Melinda R. Davis Suchitra Ravula Jamie E. Spicer Jenna L. Oelrich Andrea Thornquist Chung-Mao Pan Shelli R. McAlpine |
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Affiliation: | Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, United States |
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Abstract: | 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. |
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