The synthesis and structure revision of NSC-134754

Hickin, Jennie A.; Ahmed, Alaa A.; Fucke, Katharina; Ashcroft, Margaret; Jones, Keith

doi:10.1039/c3cc48189a

Cited by 19 publications

(14 citation statements)

References 17 publications

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“…Consistent with this idea, we found that tumour cells with elevated CHCHD4 expression exhibit significantly increased proliferative capacity in normoxia and hypoxia, suggesting that CHCHD4 is capable of promoting tumour cell growth and metabolic adaptive responses, potentially through increased respiratory drive and HIF-mediated signalling respectively. Indeed, we found that our small molecule inhibitor of HIF signalling, NSC-134754 [16,[18][19][20] which exhibits anti-tumour activity in vivo [18,52], could significantly block tumour cell growth and HIF-α (HIF-1α and HIF-2α) protein in tumour cells expressing elevated CHCHD4 without mitochondrial respiratory chain involvement.…”

Section: Discussionmentioning

confidence: 97%

“…Additional file 6a shows our revised chemical structure for NSC-134754 [20]. NSC-134754 blocks HIF activity in U2OS cells in normoxia and hypoxia within the sub-µM range (IC 50 0.25+0.05 µM).…”

Section: Chchd4-mediated Hif-1α Induction Is Blocked By Nsc-134754 Wimentioning

confidence: 99%

“…The mouse monoclonal anti-myc (9B11 clone, #2276, 1:1000)), rabbit polyclonal PHB1 (#2426, 1:1000), rabbit polyclonal HIF-2α (#7096, 1:1000), rabbit polyclonal AIF (#4642, 1:1000), rabbit polyclonal SDHA (#11998, 1:1000) and rabbit monoclonal COXIV (3E11 clone, #4850, 1:1000) antibodies were purchased from Cell Signaling Technology. The Frederick MD and dissolved in dimethyl sulfoxide (DMSO) as we have described previously [16,[18][19][20].…”

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confidence: 99%

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CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

Thomas

Stephen

Esposito

et al. 2019

Preprint

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BACKGROUND: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) is critical for maintaining intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers, correlates with increased tumour progression and poor patient survival.RESULTS: Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS). CONCLUSIONS:Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism, and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology. BACKGROUNDMetabolic reprogramming and altered mitochondrial metabolism is a feature of cancer, and thus has become an attractive area for therapeutic exploitation [1,2]. Given the importance of mitochondria in controlling normal physiological processes, understanding how mitochondrial metabolism underlies tumorigenesis is important for ascertaining its therapeutic potential in cancer.Previously, we discovered the essential redox-sensitive mitochondrial intermembrane space (IMS) protein CHCHD4, is a critical for regulating intracellular oxygen consumption rate and metabolic responses to low oxygen (hypoxia) in tumour cells [3,4]. Overexpression of Thomas et al. 3CHCHD4 in human cancers significantly correlates with the hypoxia gene signature, tumour progression, disease recurrence and poor patient survival [3].CHCHD4 provides an import and oxidoreductase-mediated protein folding function along with the sulfhydryl oxidase GFER (ALR/Erv1) as a key part of the disulphide relay system (DRS) within the mitochondrial IMS [5][6][7]. As such, CHCHD4 controls the import of a number of mitochondrial proteins that contain a twin-CX 9 C or twin-CX 3 C motif [8][9][10].Additio...

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Section: Discussionmentioning

confidence: 97%

Section: Chchd4-mediated Hif-1α Induction Is Blocked By Nsc-134754 Wimentioning

confidence: 99%

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confidence: 99%

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CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

Thomas

Stephen

Esposito

et al. 2019

Preprint

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“…Indoline‐2,3‐diones‐derived alkenes 1 were synthetized according to literatures, and NMR data were consisted with reported . 1,3‐Dipoles 2 were prepared according to the procedures of literatures .…”

Section: Methodsmentioning

confidence: 99%

Catalyst‐free Synthesis of Spiro[indoline‐3,1′‐pyrazolo[5,1‐a]isoquinolines] via Diastereoselective 1,3‐dipolar Cycloaddition under Mild Conditions

Chen

Shibata

et al. 2017

Journal of Heterocyclic Chem

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A highly efficient catalyst‐free1,3‐dipolar cycloaddition reaction of methyleneindolinones and C,N‐cyclic azomethine imines was realized. The reactions afforded a large variety of spirooxindoles in high yields (up to 99%) and excellent diastereoselectivities (dr > 20:1). Furthermore, the configuration of one of the products was determined on the basis of X‐ray structural analysis. Accordingly, a possible transition‐state model was proposed.

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“…249) [654], hippocasine and a diastereomer [655], and sedridine [656]; (8) six-membered ring β,γ-unsaturated lactams [657], including those employed in total syntheses of mehranine and methylenebismehranine and related alkaloids (e.g. 250) [658]; (9) quinolizin-4-ones (e.g.…”

Section: )mentioning

confidence: 99%

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

Herndon

2016

Coordination Chemistry Reviews

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The synthesis and structure revision of NSC-134754

Cited by 19 publications

References 17 publications

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

Catalyst‐free Synthesis of Spiro[indoline‐3,1′‐pyrazolo[5,1‐a]isoquinolines] via Diastereoselective 1,3‐dipolar Cycloaddition under Mild Conditions

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

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