title: Design of quinolinedione-based geldanamycin analogues.
abstract: Quinoline-5,8-dione-based compounds were designed from the structure of the geldanamycin-bound Hsp-90 active site. The active site model predicted that aromatic substituents should be present at the 2-position, to take advantage of a hydrophobic pocket, and amino substituents should be present at the 6- or 7-position. COMPARE analysis revealed that the LC(50) profile of 2-phenyl-6-(2-chloroethylamino)quinoline-5,8-dione has the highest geldanamycin-like activity (0.74 correlation coefficient).
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287-1604, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: David
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: Edward B
authors.initials: EB
authors.lastname: Skibo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016227:Benzoquinones; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D011809:Quinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D015363:Quinolones; D011809:Quinones; C001277:geldanamycin