Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

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• 作者：Ju-Hyeon Lee^a ; ^c ; ¹ ; Sang Chul Shin^b ; ^d ; ¹ ; Seon Hee Seo^a ; Young Ho Seo^e ; Nakcheol Jeong^c ; Chan-Wha Kim^d ; Eunice EunKyeong Kim^b ; ^{eunice@kist.re.kr} ; Gyochang Keum^a ; ^{gkeum@kist.re.kr}
• 关键词：Hsp90 ; Structure-based design ; Cancer ; Antiproliferative ; Pyrrolo[2 ; 3-d]pyrimidines
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：27
• 期：2
• 页码：237-241
• 全文大小：1198 K
• 卷排序：27

文摘

A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50 of 36 nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.