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Bioorganic and Medicinal Chemistry Letters
Volumn 22, Issue 8, 2012, Pages 2856-2860
Medicinal chemistry approaches to avoid aldehyde oxidase metabolism
Author keywords

Aldehyde oxidase; AO; Medicinal chemistry; Metabolism; Oxidation
Indexed keywords

ALDEHYDE DERIVATIVE; ALDEHYDE OXIDASE; HETEROCYCLIC COMPOUND; IMIDAZOPYRIDINE DERIVATIVE; PYRIDINE DERIVATIVE; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR AGONIST;
EID: 84862784570     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.02.069     Document Type: Article
Times cited : (38)
References (22)
  • 17
    • 34547647483 scopus 로고    scopus 로고
    • 2 humidified incubator. Ten microlitre of PBMC supernatant was added to HCV replicon cells prepared in Dulbecco's modified Eagle's medium containing 10% FCS plated in white-well tissue culture-grade 96-well plates (Perkin-Elmer) at 1 × 104 cells/well in a volume of 90 μl, and the cells were incubated for 48 h. Replicon levels were quantified using a Promega Bright Glo luciferase detection kit according to the manufacturer's instructions.
    • (2007) Antimicrob. Agents Chemother. , vol.51 , pp. 2969
    • Thomas, A.1    Laxton, C.2    Rodman, J.3    Myangar, N.4    Horscroft, N.J.5    Parkinson, T.6
  • 19
    • 84862821052 scopus 로고    scopus 로고
    • Rat cytosol incubations were conducted at 37 °C for a period of 45 min (protein 2 mg/mL) in a 96 well plate. To 20 μL of cytosol (BD, Gentest, 20 mg/mL), 170 μL of 100 mM phosphate buffer (pH 7.4) and 10 μL of substrate (20 μM) were added. The plate was vortex mixed and sample aliquots of 40 μL were taken at 0, 5, 15, 30, 45 min time points. The reaction was terminated followed by vortexing for 1 min and then centrifuged. 150 μL of supernatants were transferred to a new 96 deep well plate for LC/MS analysis. Aliquots(10 μL) were injected into the LCMS. Zoniporide was simultaneously run during the incubation and was used as (+) control. Human cytosol incubations were conducted in a similar manner to rat but using human cytosol (Celsis, OLA lot, 20 mg/ml). These assays can be run in the presence or absence of menadione, a specific aldehyde oxidase inhibitor
    • Rat cytosol incubations were conducted at 37 °C for a period of 45 min (protein 2 mg/mL) in a 96 well plate. To 20 μL of cytosol (BD, Gentest, 20 mg/mL), 170 μL of 100 mM phosphate buffer (pH 7.4) and 10 μL of substrate (20 μM) were added. The plate was vortex mixed and sample aliquots of 40 μL were taken at 0, 5, 15, 30, 45 min time points. The reaction was terminated followed by vortexing for 1 min and then centrifuged. 150 μL of supernatants were transferred to a new 96 deep well plate for LC/MS analysis. Aliquots(10 μL) were injected into the LCMS. Zoniporide was simultaneously run during the incubation and was used as (+) control. Human cytosol incubations were conducted in a similar manner to rat but using human cytosol (Celsis, OLA lot, 20 mg/ml). These assays can be run in the presence or absence of menadione, a specific aldehyde oxidase inhibitor.
  • 21
    • 84862782749 scopus 로고    scopus 로고
    • The calculations consisted of four steps. (1) create 3D structures of the substrates, (2) generate 3D structures of the products created by the addition of hydroxyl anion to each position on the substrate where the substituent was hydrogen, and could potentially be extracted by the sulfur atom of MoCo, (3) optimize structures by density functional theory at a B3LYP level with 6-31G basis sets on all constituent atoms, and finally (4) calculate differences between the energy of the products and the substrates plus the hydroxyl anion, which provides reaction energies. No transition state search was performed for the reactive intermediate of the modelled transformation, but was approximated from product stability as suggested by Hammond's postulate
    • The calculations consisted of four steps. (1) create 3D structures of the substrates, (2) generate 3D structures of the products created by the addition of hydroxyl anion to each position on the substrate where the substituent was hydrogen, and could potentially be extracted by the sulfur atom of MoCo, (3) optimize structures by density functional theory at a B3LYP level with 6-31G basis sets on all constituent atoms, and finally (4) calculate differences between the energy of the products and the substrates plus the hydroxyl anion, which provides reaction energies. No transition state search was performed for the reactive intermediate of the modelled transformation, but was approximated from product stability as suggested by Hammond's postulate.

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