Design, synthesis, and biological evaluation of conformationally constrained cis-amide Hsp90 inhibitors.
Conformationally constrained cis-amide chimeric inhibitors of Hsp90 have been synthesized and evaluated for their Hsp90 inhibitory activity. These new compounds exhibited Hsp90 ATPase inhibition and induced Hsp90-dependent client protein degradation in a dose-dependent manner. Biological data reported herein suggests that amide bond isomerization of geldanamycin derivatives plays an important role in affinity for the heteroprotein complex present in cancer cells.
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7562, USA.
Adam S
AS
Duerfeldt
Gary E L
GE
Brandt
Brian S J
BS
Blagg
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism
D000577:Amides; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D000251:Adenosine Triphosphatases; C001277:geldanamycin