Solution-phase synthesis and biological evaluation of triostin A and its analogues

Hattori, Kota; Koike, Kota; Okuda, K; Hirayama, Tasuku; Ebihara, Masahiro; Takenaka, Mei; Nagasawa, Hideko

doi:10.1039/c5ob02505b

Cited by 16 publications

(54 citation statements)

References 37 publications

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“…Consequently, it inhibits cell proliferation [ 281 ] and induces apoptotic cell death [ 283 ]. The echinomycin biosynthetic precursor triostin A and its derivatives are also potent inhibitors of HIF1 effective on hypoxia model and induce cell death in MCF7 cancer model [ 284 ].…”

Section: Targeting Transcription Factor At the Protein/dna Interacmentioning

confidence: 99%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

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Section: Targeting Transcription Factor At the Protein/dna Interacmentioning

confidence: 99%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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“…Triostin A is a cyclic depsipeptide with good antibacterial and anti‐tumor activity. Triostin A and its analogs were reported to be potent HIF‐1 inhibitors by Hattori et al . Triostin A inhibited HIF‐1α transcriptional activation with an IC 50 value of 26.9 nM in a luciferase reporter assay in HEK293 cells.…”

Section: Miscellaneousmentioning

confidence: 99%

“…Triostin A is a cyclic depsipeptide with good antibacterial and anti-tumor activity. Triostin A and its analogs were reported to be potent HIF-1 inhibitors by Hattori et al 79…”

Section: Triostin a And Its Analogsmentioning

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

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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.

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“…2D). Although echinomycin is a DNA intercalater, it also affects the expression level of HIF-1α protein depending on the cell line 11 ; in 3T3-L1 cells, echinomycin reduced HIF-1α protein expression (Fig. 2D left panel ).…”

Section: Resultsmentioning

confidence: 99%

“…It binds to HRE sequences and decreases HIF-1 transcriptional activity. Whether echinomycin affects the expression of HIF-1α protein depends on the cell line; in U251, HepG2, and HeLa cells, HIF1-α protein level is not affected 7, 8, 10 ; in MCF-7 cells, it is decreased 11 . In 3T3-L1 cells, echinomycin inhibited HIF-1α protein expression and HIF-1 activity.…”

Section: Discussionmentioning

confidence: 98%

Echinomycin inhibits adipogenesis in 3T3-L1 cells in a HIF-independent manner

Yamaguchi

Tanaka

Saito

et al. 2017

Sci Rep

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Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion. The dose required to exert the effect was surprisingly low and the time was short. Interestingly, its inhibitory effect was independent of HIF-1 pathways. Time-course DNA microarray analysis of drug-treated and untreated preadipocytes extracted a major transcription factor, CCAAT/enhancer-protein β, as a key target of echinomycin. Echinomycin also inhibited adipogenesis and body weight gain in high fat diet mice. These findings highlight a novel role of echinomycin in suppressing adipocyte differentiation and offer a new therapeutic strategy against obesity and diabetes.

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Solution-phase synthesis and biological evaluation of triostin A and its analogues

Cited by 16 publications

References 37 publications

Targeting Transcription Factors for Cancer Treatment

Targeting Transcription Factors for Cancer Treatment

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

Echinomycin inhibits adipogenesis in 3T3-L1 cells in a HIF-independent manner

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