Structural and Quantum Chemical Studies of 8-Aryl-sulfanyl Adenine Class Hsp90 Inhibitors

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• 作者：Robert M. Immormino ; Yanlong Kang ; Gabriela Chiosis ; Daniel T. Gewirth
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 10, 2006
• 年：2006
• 卷：49
• 期：16
• 页码：4953 - 4960
• 全文大小：333K
• 年卷期：v.49,no.16(August 10, 2006)
• ISSN：1520-4804

文摘

Hsp90 chaperones play a critical role in modulating the activity of many cell signaling proteins and are anattractive 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 domainof human Hsp90. The conformation of 1 when bound to Hsp90 differs from previously reported 8-aryladenine Hsp90 inhibitors including 3 (PU24FCl). While the binding mode for 3 places the 2'-halide of the8-aryl group on top of the adenine ring, for 1 and 2, we show that the 2'-halide is rotated approximately180 away. This difference explains the opposing trends in Hsp90 inhibitory activity for the 2'-halo derivativesof 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 basisfor Hsp90 inhibition. The calculated conformation of 2 agreed well with the crystallographically observedconformations of 1 and 2. The predictive nature of the calculations has allowed the exploration of additionalderivatives based on the 8-aryl adenine scaffold.