62499-04-1Relevant articles and documents
Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents
Kim, Ho Shin,Hoang, Van-Hai,Hong, Mannkyu,Chul Kim, Kyung,Ann, Jihyae,Nguyen, Cong-Truong,Seo, Ji Hae,Choi, Hoon,Yong Kim, Jun,Kim, Kyu-Won,Sub Byun, Woong,Lee, Sangkook,Lee, Seungbeom,Suh, Young-Ger,Chen, Jie,Park, Hyun-Ju,Cho, Tae-Min,Kim, Ji Young,Seo, Jae Hong,Lee, Jeewoo
supporting information, p. 1370 - 1381 (2019/03/04)
On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.
Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy
An, Hongchan,Lee, Seungbeom,Lee, Jung Min,Jo, Dong Hyun,Kim, Joohwan,Jeong, Yoo-Seong,Heo, Mi Jeong,Cho, Chang Sik,Choi, Hoon,Seo, Ji Hae,Hwang, Seyeon,Lim, Jihye,Kim, Taewoo,Jun, Hyoung Oh,Sim, Jaehoon,Lim, Changjin,Hur, Joonseong,Ahn, Jungmin,Kim, Hyun Su,Seo, Seung-Yong,Na, Younghwa,Kim, Seok-Ho,Lee, Jeewoo,Lee, Jeeyeon,Chung, Suk-Jae,Kim, Young-Myeong,Kim, Kyu-Won,Kim, Sang Geon,Kim, Jeong Hun,Suh, Young-Ger
, p. 9266 - 9286 (2018/10/24)
Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
