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Chemical Structure| 328-74-5 Chemical Structure| 328-74-5
Chemical Structure| 328-74-5

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Chayka, Artem ; Danda, Matěj ; Dostálková, Alžběta ; Spiwok, Vojtěch ; Klimešová, Anna ; Kapisheva, Marina , et al.

Abstract: The use of Fpocket and virtual screening techniques enabled us to identify potential allosteric druggable pockets within the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Of the compounds screened, compound 1 was identified as a promising inhibitor, lowering a SARS-CoV-2 RdRp activity to 57% in an enzymatic assay at 10 µM concentration. The structure of compound 1 was subsequently optimized in order to preserve or enhance inhibitory activity. This involved the substitution of problematic and aromatic nitro groups with more inert functionalities. The scaffold with two NH groups was identified as essential for the compound's activity but also exhibited high toxicity in Calu-3 cells. To address this issue, a scaffold hopping approach was employed to replace the urea core with potentially less toxic urea isosteres. This approach yielded several structural analogues with notable activity, specifically 2,2’-bisimidazol (in compound 55 with residual activity = 42%) and (1H-imidazol-2-yl)urea (in compounds 59 and 60, with = 50 and 28%, respectively). Despite these advances, toxicity remained a major concern. These compounds represent a promising starting point for further structure-activity relationship studies of allosteric inhibitors of SARS-CoV-2 RdRp, with the goal of reducing their cytotoxicity and improving aqueous solubility.

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Schumacher, Tanner J ; Iyer, Ananth V ; Rumbley, Jon ; Ronayne, Conor T ; Mereddy, Venkatram R ;

Abstract: Background: Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of significant efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide, IMD-0354 and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors. Methods: To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Metabolic characterization was carried out using Seahorse XFe96 Bioanalyzer and statistical analysis was carried out via ANOVA. Results: Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested. Conclusion: In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

Keywords: Drug repurposing ; Anthelmintic ; BAY-876 ; Niclosamide ; Pyrvinium ; Anticancer

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Tanner J. Schumacher ; Ananth V. Iyer ; Jon Rumbley ; Conor T. Ronayne ; Venkatram R. Mereddy ;

Abstract: Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors. To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested. In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies warrant further investigation into targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

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Alternative Products

Product Details of 3,5-Di(trifluoromethyl)aniline

CAS No. :328-74-5
Formula : C8H5F6N
M.W : 229.12
SMILES Code : NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1
MDL No. :MFCD00000394
InChI Key :CDIDGWDGQGVCIB-UHFFFAOYSA-N
Pubchem ID :9480

Safety of 3,5-Di(trifluoromethyl)aniline

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of 3,5-Di(trifluoromethyl)aniline

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 328-74-5 ]
  • Downstream synthetic route of [ 328-74-5 ]

[ 328-74-5 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 328-74-5 ]
  • [ 367-65-7 ]
References: [1] Tetrahedron, 2012, vol. 68, # 5, p. 1452 - 1459.
  • 2
  • [ 328-74-5 ]
  • [ 367-65-7 ]
References: [1] Patent: US5514680, 1996, A, .
 

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