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

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 18; pp. 6822 - 6856
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-09-2010; Elsevier
• Subjects: Amino Acid Sequence; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Colon cancer; Computer Simulation; Cytotoxicity; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - toxicity; Docking; Drug Design; General aspects; Growth inhibition; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Macrocycles; Macrocyclic peptides; Medical sciences; Pancreatic cancer; Pharmacology. Drug treatments; Protein Structure, Tertiary; Sansalvamide A; Structure-Activity Relationship; Hsp90; San A-amide; Pancreatic cancer; Sansalvamide A; Macrocyclic peptides; Cytotoxicity; Docking; Macrocycles; Growth inhibition; San A; Antineoplastic agent; Solid tumor; Cyclic peptides; Partition coefficient; Modeling; Signal transduction; Structure activity relation; Molecular model; Heat shock protein; Colon; Chemical synthesis; Tumor cell; Heat shock protein 90; Human; Absorption Distribution Metabolisme Excretion; Enzyme; Chaperone; Adenosinetriphosphatase; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Macrocydic peptides; Cell line; Hydrolases; Property structure relationship; Peptide synthesis; Solid phase; Pharmacokinetics; Lipophilicity; Physicochemical properties
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.07.042

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.