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

Kim, Ho Shin; Hong, Mannkyu; Ann, Jihyae; Yoon, Suyoung; Nguyen, Cong Truong; Lee, Su-Chan; Lee, Ho‐Young; Suh, Young‐Ger; Seo, Ji Hae; Choi, Hoon; Kim, Jun Yong; Kim, Kyu‐Won; Kim, Joohwan; Kim, Young‐Myeong; Park, So‐Jung; Park, Hyun-Ju; Lee, Jeeyeon

doi:10.1016/j.bmc.2016.09.067

Cited by 28 publications

(9 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Extensive SAR studies of other C‐ring‐truncated deguelin derivatives with robust changes in the linker and bicyclic heterocyclic structures on both sides of the linker led to the discovery of potent HIF‐1α inhibitors . When the A, B ring is replaced with 6,7‐dimethoxyquinolin‐4‐yl, the new analogs with linkers including cyclopropanecarboxylate 60 , thioacetal 61 , and methoxy oxime 62 showed better activity than deguelin (WB = 54 ± 12, WB = 59 ± 16, and WB = 54 ± 19 at 100 nM concentration for 60, 61 , and 62 , respectively, Figure ).…”

Section: Ring‐truncated Deguelin Derivativesmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

View full text Add to dashboard Cite

Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors.

show abstract

Section: Ring‐truncated Deguelin Derivativesmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…2a,b ). The IC 50 values of NCT-50 on the inhibition of NSCLC cell viability were about 2 μM on average (Table 1 ), which was comparable or superior to previously developed deguelin analogs 23 , 24 , 26 , novobiocin, and its analogs 22 , 28 , 30 . The inhibitory effect of NCT-50 on the viability and anchorage-dependent colony formation of drug-resistant sublines (H1299/CsR, H1299/PmR, and H226B/PcR) was comparable with that on the corresponding naïve cells (H1299 and H226B), suggesting the effectiveness of NCT-50 for both chemo-naïve and chemo-resistant NSCLC cells (Fig.…”

Section: Resultsmentioning

confidence: 58%

“…NCT-50 displayed significant cytotoxic and proapoptotic effects on NSCLC cells without significantly affecting the growth of normal cells derived from lung epithelium, retinal pigment epithelium, vascular endothelium and hippocampus. The potency of the inhibitory effect of NCT-50 on the viability of NSCLC cells and Hsp90 function were comparable or superior to that of previously developed deguelin analogs, novobiocin and its analogs, and Hsp90 inhibitors in clinical trials 22 – 24 , 26 , 28 , 30 , emphasizing the potential of NCT-50 as a novel and efficacious Hsp90 inhibitor. In addition, considering liver and ocular toxicities are drawbacks of the currently available Hsp90 inhibitors 58 , the reduced toxicity of NCT-50 in vitro and in vivo compared with known Hsp90 inhibitors or deguelin appears to be a clinically favorable feature.…”

Section: Discussionmentioning

confidence: 70%

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

Hyun

Nguyen

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. The molecular chaperone heat shock protein 90 (Hsp90) plays important roles in the maturation of oncogenic proteins and thus has been considered as an anticancer therapeutic target. Here we show the efficacy and biological mechanism of a Hsp90 inhibitor NCT-50, a novobiocin-deguelin analog hybridizing the pharmacophores of these known Hsp90 inhibitors. NCT-50 exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy. In contrast, NCT-50 showed minimal effects on the viability of normal cells. NCT-50 induced apoptosis in NSCLC cells, inhibited the expression and activity of several Hsp90 clients including hypoxia-inducible factor (HIF)-1α, and suppressed pro-angiogenic effects of NSCLC cells. Further biochemical and in silico studies revealed that NCT-50 downregulated Hsp90 function by interacting with the C-terminal ATP-binding pocket of Hsp90, leading to decrease in the interaction with Hsp90 client proteins. These results suggest the potential of NCT-50 as an anticancer Hsp90 inhibitor.

show abstract

“…Although its underlying mechanism has not been fully delineated, this inhibition appears to be related to the attenuation of the binding of clients to ATP-binding pocket of HSP90 by deguelin and to the accelerated decomposition of HIF-1 [6]. Previously, a variety of deguelin analogs were synthesized and screened for HSP90 inhibition [7,8]. In particular, we noted that SH-1242 (2-(3,4-dimethoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanone) possessed a potent anti-proliferative activity against human cancer cells [9] and suppressed hypoxia-mediated retinal neovascularization/vascular leakage in diabetic retinas [10].…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of Analytical Method for SH-1242 in the Rat and Mouse Plasma by Liquid Chromatography/Tandem Mass Spectrometry

et al. 2020

Self Cite

View full text Add to dashboard Cite

SH-1242, a novel inhibitor of heat shock protein 90 (HSP90), is a synthetic analog of deguelin: It was previously reported that the treatment of SH-1242 led to a strong suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retinas by inhibiting the hypoxia-induced upregulation of expression in hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). In this study, an analytical method for the quantification of SH-1242 in biological samples from rats and mice was developed/validated for application in pharmacokinetic studies. SH-1242 and deguelin, an internal standard of the assay, in plasma samples from the rodents were extracted with methanol containing 0.1% formic acid and analyzed at m/z transition values of 368.9→151.0 and 395.0→213.0, respectively. The method was validated in terms of accuracy, precision, dilution, matrix effects, recovery, and stability and shown to comply with validation guidelines when it was used in the concentration ranges of 1–1000 ng/mL for rat plasma and of 2–1000 ng/mL for mouse plasma. SH-1242 levels in plasma samples were readily determined using the developed method for up to 480 min after the intravenous administration of 0.1 mg/kg SH-1242 to rats and for up to 120 min to mice. These findings suggested that the current method was practical and reliable for pharmacokinetic studies on SH-1242 in preclinical animal species.

show abstract

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

Cited by 28 publications

References 28 publications

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

Development and Validation of Analytical Method for SH-1242 in the Rat and Mouse Plasma by Liquid Chromatography/Tandem Mass Spectrometry

Contact Info

Product

Resources

About