title: Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors.
abstract: Hsp90 chaperones play a critical role in modulating the activity of many cell signaling proteins and are an attractive target for anti-cancer therapeutics. We report here the structures of the water soluble 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90alpha. The conformation of 1 when bound to Hsp90 differs from previously reported 8-aryl adenine Hsp90 inhibitors including 3 (PU24FCl). While the binding mode for 3 places the 2'-halide of the 8-aryl group on top of the adenine ring, for 1 and 2, we show that the 2'-halide is rotated approximately 180 degrees away. This difference explains the opposing trends in Hsp90 inhibitory activity for the 2'-halo derivatives of the 3',4',5'-trimethoxy series where Cl > Br > I compared to the 4',5'-methylenedioxy series where I > Br > Cl. We also present quantum chemical calculations of 2 and its analogues that illuminate their basis for Hsp90 inhibition. The calculated conformation of 2 agreed well with the crystallographically observed conformations of 1 and 2. The predictive nature of the calculations has allowed the exploration of additional derivatives based on the 8-aryl adenine scaffold.
authors.affiliation: Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Immormino
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Kang
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Gewirth
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011789:Quantum Theory; D012996:Solutions; D013425:Sulfanilic Acids / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D012996:Solutions; D013425:Sulfanilic Acids; D000225:Adenine