title: Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives.
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.
authors: Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, United States.
authors: Robert P
authors: RP
authors: Sellers
authors: Leslie D
authors: LD
authors: Alexander
authors: Victoria A
authors: VA
authors: Johnson
authors: Chun-Chieh
authors: CC
authors: Lin
authors: Jeremiah
authors: J
authors: Savage
authors: Ricardo
authors: R
authors: Corral
authors: Jason
authors: J
authors: Moss
authors: Tim S
authors: TS
authors: Slugocki
authors: Erinprit K
authors: EK
authors: Singh
authors: Melinda R
authors: MR
authors: Davis
authors: Suchitra
authors: S
authors: Ravula
authors: Jamie E
authors: JE
authors: Spicer
authors: Jenna L
authors: JL
authors: Oelrich
authors: Andrea
authors: A
authors: Thornquist
authors: Chung-Mao
authors: CM
authors: Pan
authors: Shelli R
authors: SR
authors: McAlpine
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D018841:HSP90 Heat-Shock Proteins; C119376:sansalvamide A