Synthesis of Hsp90 inhibitor dimers as potential antitumor agents.
Structure-based drug design was used to systematically synthesize PU3-dimers. The cytotoxicity of PU3 dimers 6 against breast cancer cell lines was evaluated, and their potency increased as the length of the bridging linker increased. Among the compounds tested, 6e with a C-20 linker was the most potent and exhibited a 20- to 30-fold increase in activity compared with that of the parent compound 5. Western blot analyses of the cell lysates treated with 6c revealed that 6c resulted in the concentration-dependent degradation of the Hsp90 client protein Her2, which is consistent with other Hsp90 inhibitors.
Muranaka
Kazuhiro
K
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Sano
Akiko
A
Ichikawa
Satoshi
S
Matsuda
Akira
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D000840:Anisoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019281:Dimerization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism
C494601:9-(n-butyl)-8-((3,4,5-trimethoxyphenyl)methyl)adenine; D000840:Anisoles; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D010446:Peptide Fragments; C035359:monorden; D000225:Adenine; C001277:geldanamycin