Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives.
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.
Sellers
Robert P
RP
Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, United States.
Alexander
Leslie D
LD
Johnson
Victoria A
VA
Lin
Chun-Chieh
CC
Savage
Jeremiah
J
Corral
Ricardo
R
Moss
Jason
J
Slugocki
Tim S
TS
Singh
Erinprit K
EK
Davis
Melinda R
MR
Ravula
Suchitra
S
Spicer
Jamie E
JE
Oelrich
Jenna L
JL
Thornquist
Andrea
A
Pan
Chung-Mao
CM
McAlpine
Shelli R
SR
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
D000970:Antineoplastic Agents; D047630:Depsipeptides; D018841:HSP90 Heat-Shock Proteins; C119376:sansalvamide A