Comparison of (bio-)transformation methods for the generation of metabolite-like compound libraries of p38α MAP kinase inhibitors using high-resolution screening

Falck, David; Pirkolachachi, Fatie Rahimi; Giera, Martin; Honing, Maarten; Kool, Jeroen; Niessen, W.M.A.

doi:10.1016/j.jpba.2013.08.045

Cited by 7 publications

(13 citation statements)

References 37 publications

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“…This paper reports the structure elucidation of a wide variety of related substances of four kinase inhibitors, generated in different ways. Comparison between these compound conversion tools and the effect of conversion on bioactivity are reported elsewhere . This discussion may serve as an example to demonstrate the power of MS n in combination with HRMS in structure elucidation of related substances but can evenly well be used, if one wants, to highlight the limitations of such strategy.…”

Section: Resultsmentioning

confidence: 97%

“…The resulting mixtures of CPs were analysed by LC coupled to a continuous‐flow p38α enzyme‐binding assay and parallel HRMS to obtain MS 2 and MS 3 data. The interpretation of MS 3 data is discussed in this paper, whereas affinity data for the CPs and comparison between the various modification strategies are discussed elsewhere …”

Section: Resultsmentioning

confidence: 99%

“…Electrochemistry adds (reduction) or removes (oxidation) electrons from the substrate on a surface electrode, which results in further reaction for example with the solvent . During incubation with (human) liver microsomes or with mutants of cytochrome P450 BM3, the enzymes present catalyse specific reactions such as hydroxylation. Oxidation with hydrogen peroxide occurs mainly via reactive oxygen species, whereas photochemical conversion is the result of the excitation of electrons in the substrate by intense visible light irradiation …”

Section: Methodsmentioning

confidence: 99%

“…Alternatively, other (chemical) means such as photochemistry or oxidative reagents can be applied. These different means to create chemical diversity of p38α kinase inhibitors are compared in a separate study, involving assessment of bioaffinity and identity by the HRS platform …”

Section: Introductionmentioning

confidence: 99%

“…These different means to create chemical diversity of p38a kinase inhibitors are compared in a separate study, involving assessment of bioaffinity and identity by the HRS platform. [15] This paper focuses on the structure elucidation aspect of the HRS platform with special attention on MS fragment interpretation. The study resulted in a wealth of MS/MS data, not only for the kinase inhibitors itself but also for their related substances, that is, their CPs.…”

Section: Introductionmentioning

confidence: 99%

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Tandem mass spectrometry study of p38α kinase inhibitors and related substances

et al. 2013

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The p38 mitogen-activated protein kinase α (p38α) is an important drug target widely investigated for therapy of chronic inflammatory diseases. Its inhibitors are rather lipophilic and as such not very favourable lead compounds in drug discovery. Therefore, we explored various approaches to access new chemical space, create diversity, and generate lead libraries with improved solubility and reduced lipophilicity, based on known p38α inhibitors, e.g., BIRB796 and TAK-715. Compound modification strategies include incubation with human liver microsomes and bacterial cytochrome P450 mutants from Bacillus megaterium and treatment by electrochemical oxidation, H2O2, and intense light irradiation. The MS/MS fragmentation pathways of p38α inhibitors and their conversion products have been studied in an ion-trap-time-of-flight MS(n) instrument. Interpretation of accurate mass MS(n) data for four sets of related compounds revealed unexpected and peculiar fragmentation pathways that are discussed in detail. Emphasis is put on the usefulness of HRMS(n)-based structure elucidation in a screening setting and on peculiarities of the fragmentation with regard to the analytes and the MS instrument. In one example, an intramolecular rearrangement reaction accompanied by the loss of a bulky group is observed. For BIRB796, the double-charge precursor ion is used in MS(2), providing a wider range of fragment ions in our instrument. For TAK-715, a number of related compounds could be produced in a large-scale incubation with a Bacillus megaterium mutant, thus enabling comparison of the structure elucidation by (1)H NMR and MS(n). A surprisingly large number of homolytic cleavages are observed. Competition between two fragmentation pathways involving either the loss of CH3(•) or OH(•) radicals was observed for SB203580 and its conversion products.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tandem mass spectrometry study of p38α kinase inhibitors and related substances

et al. 2013

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High‐Resolution Screening: Post‐Column Continuous‐Flow Bioassays

Falck

Niessen

Kool

2015

Analyzing Biomolecular Interactions by Mass Spectrometry

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Enzymatic Late‐Stage Oxidation of Lead Compounds with Solubilizing Biomimetic Docking/Protecting groups

Vickers

Backfisch

Oellien

et al. 2018

Chemistry A European J

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Late‐stage functionalization of lead compounds is of high interest in drug discovery since it offers an easy access to metabolites and derivatives of a lead compound without the need to redesign an often long multistep synthesis. Owing to their high degree of chemoselectivity, biocatalytic transformations, enzymatic oxidations in particular, are potentially very powerful because they could allow the synthesis of less lipophilic derivatives of a lead compound. In the majority of cases, enzymatic oxidations have been used in an empirical way as their regioselectivity is difficult to predict. In this publication, the concept of using docking/protecting groups in a biomimetic fashion was investigated, which could help steer the regioselectivity of a P450BM3‐mediated oxidation. A novel set of docking/protecting groups was designed that can be cleaved under very mild conditions and address the often problematic aqueous solubility of the substrates. Vabicaserin was used as tool compound containing typical groups such as basic, aliphatic, and aromatic moieties. The results were rationalized with the help of in silico docking and molecular dynamic studies.

show abstract

Comparison of (bio-)transformation methods for the generation of metabolite-like compound libraries of p38α MAP kinase inhibitors using high-resolution screening

Cited by 7 publications

References 37 publications

Tandem mass spectrometry study of p38α kinase inhibitors and related substances

Tandem mass spectrometry study of p38α kinase inhibitors and related substances

High‐Resolution Screening: Post‐Column Continuous‐Flow Bioassays

Enzymatic Late‐Stage Oxidation of Lead Compounds with Solubilizing Biomimetic Docking/Protecting groups

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