Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors

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• 作者：Ho Shin Kim^a ; Mannkyu Hong^a ; Jihyae Ann^a ; Suyoung Yoon^a ; Cong-Truong Nguyen^a ; Su-Chan Lee^a ; Ho-Young Lee^a ; Young-Ger Suh^a ; Ji Hae Seo^b ; Hoon Choi^b ; Jun Yong Kim^b ; Kyu-Won Kim^b ; ^c ; Joohwan Kim^d ; Young-Myeong Kim^d ; So-Jung Park^e ; Hyun-Ju Park^e ; Jeewoo Lee^a ; ^{jeewoo@snu.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Heat shock protein 90 ; HSP90 ; Hypoxia Inducible Factor-1 ; HIF-1 ; Antitumor ; Deguelin
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：24
• 期：22
• 页码：6082-6093
• 全文大小：5228 K

文摘

Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure–activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.