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.
Duerfeldt
Adam S
AS
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7562, USA.
Brandt
Gary E L
GE
Blagg
Brian S J
BS
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