Construction of a fused grid-based template system of CYP2C9 and its application

Yamazoe, Yasushi; Yamamura, Yoshiyuki; Yoshinari, Kouichi

doi:10.1016/j.dmpk.2022.100451

Cited by 3 publications

(8 citation statements)

References 81 publications

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“…Therefore, possible involvements of hepatic CYP enzymes were examined using several of our CYP Template systems developed 1 , 2 , 3 , 4 , 5 , 7 , 11 , 26 ) . The 7-oxidation of amonafide was expected on CYP3A4 Template at Rings B-A-D-K-Q’(Q) plus Positions 25 and 9’ (data not shown), although the amonafide molecule would pass barely the gate of Bay-1 and Cavity-2.…”

Section: Resultsmentioning

confidence: 99%

“…In consistent, a mono-hydroxylated metabolite of amonafide was isolated in dog excreta 21 ) . A placement for the N -demethylation was constructed on CYP2C9 Template at Rings J(M)-I-D(H)-C-B plus a space around Position 19 (data not shown), but the N -dimethylamino part might be not fastened well like the case of phenylbutazone 3 ) . A placement for the 5,6-oxidation was generated on CYP1A1 Template at Rings eEc-eC2-eC1-C-eC3 for the pro-metabolized molecule) and at Rings eA-A-B-eD-D plus Positions 9 and 4 for the trigger-molecule (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Chemicals including lactone moieties are often ionized at neutral pH ranges. These lactones were treated as ionizable groups for the application of substrates throughout our CYP Template systems 3 , 5 , 11 ) . Thus, non-rigid lactone rings are not allowed to contact with Bay-2 residue and Trigger-residue of CYP1A2 Template in general.…”

Section: Methodsmentioning

confidence: 99%

“…Ligands were applied on specific CYP Templates following published protocols for CYP1A1 1 ) , CYP2C9 3 ) , CYP2C19 4 ) , CYP2E1 5 ) and CYP3A4 7 ) . Renewed CYP1A2 Template was used in the present study (Supplement Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Contiguous hexagonal-grid Templates* were constructed for several CYP enzymes. Template systems combined with ideas of ligand-interacting modes were established on CYP1A1(>350) 1 ) , CYP1A2(>450) 2 ) , CYP2C9(>500) 3 ) , CYP2C19(>450) 4 ) , CYP2E1(>340) 5 ) , CYP3A4 6 , 7 ) , CYP3A5 7 ) and CYP3A7 (>1,100 with CYP3As) 7 ) through reciprocal comparison of simulation and experimental results (numbers of reactions examined are shown in parentheses). Placements of ligands on Template systems of human CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3As offered the information on sites of metabolisms regio- and stereo-selectively with more than 99% of accuracies.…”

Section: Introductionmentioning

confidence: 99%

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Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

2022

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Cytochrome P450 (CYP)-mediated metabolisms of four chemicals have been investigated to understand their unresolved phenomena of their metabolisms using human CYP-Template systems developed in our previous studies (Drug Metab Pharmacokinet 2019, 2021, 2022). Simulation experiments of a topoisomerase-targeting agent, amonafide, offered a possible new inhibitory-mechanism as Trigger-residue inactivation on human CYP1A2 Template. N -Acetylamonafide as well as amonafide would inactivate CYP1A2 through the interference of Trigger-residue movement with their dimethylaminoethyl parts. The mechanism was also supported on the inhibition/inactivation of two other drugs, DSP-1053 and binimetinib. Both the drugs, after other CYP-mediated slight structural alterations, were expected to interact with Trigger-residue for the intense inhibition on CYP1A2 Template. Possible formation of reactive intermediates of amonafide and 3-methylindole was also examined on CYP1A2 Template. Placements of amonafide suggested the scare N -oxidation of the arylamine part due to the Trigger-residue interaction. Placements of 3-methylindole suggested the formation of a reactive intermediate, 3-methyleneindolenine, rather selectively on rodent CYP1A2 than on human CYP1A2, in consistent with the experimental data. These results suggest that CYP Template systems developed are effective tools to warn an appearance of unstable reactive intermediates. Our CYP-Template systems would support confident judgements in safety assessments through offering the mechanistic understandings of the metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

2022

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Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms

et al. 2023

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Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of β-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, β-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.

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Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

Yu,

2023

Beilstein J. Org. Chem.

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Ether derivatives are widespread as essential building blocks in various drugs, natural products, agrochemicals, and materials. Modern economy requires developing green strategies with improved efficiency and reduction of waste. Due to its atom and step-economy, the cross-dehydrogenative coupling (CDC) reaction has become a major strategy for ether functionalization. This review covers C–H/C–H cross-coupling reactions of ether derivatives with various C–H bond substrates via non-noble metal catalysts (Fe, Cu, Co, Mn, Ni, Zn, Y, Sc, In, Ag). We discuss advances achieved in these CDC reactions and hope to attract interest in developing novel methodologies in this field of organic chemistry.

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Construction of a fused grid-based template system of CYP2C9 and its application

Cited by 3 publications

References 81 publications

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

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Construction of a fused grid-based template system of CYP2C9 and its application

Cited by 3 publications

References 81 publications

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp3)–H to construct C–C bonds

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Product

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About

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds