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.
Antineoplastic Agents/chemical synthesis , Depsipeptides/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Amino Acid Sequence , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor , Computer Simulation , Depsipeptides/chemical synthesis , Depsipeptides/toxicity , Drug Design , HSP90 Heat-Shock Proteins/metabolism , Humans , Protein Structure, Tertiary , Structure-Activity Relationship
