A fragmentation study of podophyllotoxin and its 4′‐demethyl‐4<i>β</i>‐substituted derivatives by electrospray ionization ion‐trap time‐of‐flight tandem mass spectrometry

Li, Qianrong; Yan, Guoquan; Ge, Tiefei

doi:10.1002/rcm.3156

Cited by 24 publications

(23 citation statements)

References 29 publications

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“…Fragment 14a is likely the carbene intermediate generated thermally under ESI conditions. The structure of 16 has been previous proposed for the MS fragmentations of 4'-demethylpodophyllotoxin derivatives 32. The observation of these two daughter ions supports the proposal that the compound is diazirine 2 .…”

Section: Resultssupporting

confidence: 77%

A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II

Chee

Yalowich

Bodner

et al. 2010

Bioorganic & Medicinal Chemistry

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Etoposide is a widely used anticancer drug that targets topoisomerase II, an essential nuclear enzyme. However, despite the fact that it has been in use and studied for more than 30 years the specific site on the enzyme to which it binds is unknown. In order to identify the etoposide binding site(s) on topoisomerase II, a diazirine-based photoaffinity etoposide analog probe has been synthesized and its photoreactivity and biological activities have been characterized. Upon UV irradiation, the diazirine probe rapidly produced a highly reactive carbene species that formed covalent adducts containing stable carbon-based bonds indicating that it should also be able to form stable covalent adducts with amino acid residues on topoisomerase II. The human leukemia K562 cell growth and topoisomerase II inhibitory properties of the diazirine probe suggest that it targets topoisomerase II in a manner similar to etoposide. The diazirine probe was also shown to act as a topoisomerase II poison through its ability to cause topoisomerase IIα-mediated double-strand cleavage of DNA. Additionally, the diazirine probe significantly increased protein-DNA covalent complex formation upon photoirradiation of diazirine probe-treated K562 cells, as compared to etoposide-treated cells. This result suggests that the photoactivated probe forms a covalent adduct with topoisomerase IIα. In conclusion, the present characterization of the chemical, biochemical, and biological properties of the newly synthesized diazirine-based photoaffinity etoposide analog indicates that use of a proteomics mass spectrometry approach will be a tractable strategy for future identification of the etoposide binding site(s) on topoisomerase II through covalent labeling of amino acid residues.

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Section: Resultssupporting

confidence: 77%

A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II

Chee

Yalowich

Bodner

et al. 2010

Bioorganic & Medicinal Chemistry

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“…An even more powerful method to investigate mass spectral fragmentations and fragmentation pathways of molecules are ion tree experiments [204–208] (see Fig. 10).…”

Section: Mass Spectral Data Handlingmentioning

confidence: 99%

Advances in structure elucidation of small molecules using mass spectrometry

2010

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The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules.Electronic supplementary materialThe online version of this article (doi:10.1007/s12566-010-0015-9) contains supplementary material, which is available to authorized users.

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“…Mass spectrometry (MS) with the associated high sensitivity and resolution well meets this requirement and has become the routine method in various aspects of medicinal chemistry [4–8]. Tandem MS techniques are particularly useful for ascertaining the relationship between precursor and product ions, by which the fragmentation rules and diagnostic ions of complicated compounds can be easily deduced [9–14]. The LCMS-IT-TOF mass spectrometer equipped with an electrospray ionization source linked to ion-trap and time-of-flight mass analyzers (ESI-IT-TOF) allows fast acquisition of multistage product ion spectra (MS n ) with high accuracy and resolution in both positive and negative modes [15–17].…”

Section: Introductionmentioning

confidence: 99%

A Fragmentation Study on Four Unusual Secoiridoid Trimers, Swerilactones H–K, by Electrospray Tandem Mass Spectrometry

Geng

Chen

2016

Nat. Prod. Bioprospect.

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Swerilactones H–K (1–4) as four unprecedented secoiridoid trimers represent a new type of natural product, which has attracted much interest of natural chemists due to their novel skeletons and promising bioactivity. In order to well understand their MS fragmentation behaviors, they were investigated by electrospray ionization ion-trap time-of-flight multistage product ion mass spectrometry (ESI-IT-TOF-MSn) for the first time. The protonated molecules ([M+H]+) of swerilactones J and K, and deprotonated molecules ([M−H]−) of swerilactones H, J and K were readily observed in the conventional single-stage mass spectra (MS); however only the [M+Cl]− ion for swerilactone I was obtained in negative mode. Based on the MSn study, the fragmentation pathways of swerilactones H and I in negative mode, and swerilactones J and K in both positive and negative modes were proposed. The neutral losses of H2O, CO, CO2 and C2H4O moieties are the particular elimination from the precursor ions due to the presence of hydroxyl, δ-lactone and 1-O-ethyl moieties in their structures, of which the retro-Diels–Alder cleavage was the most particular dissociation. The fragment ions at m/z 341 and 291 in negative mode can be considered as the diagnostic ions for secoiridoid trimers. This investigation will provide valuable information for their fast characterization from complicated natural mixtures and extensive understanding their structural architectures.Electronic supplementary materialThe online version of this article (doi:10.1007/s13659-016-0114-6) contains supplementary material, which is available to authorized users.

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A fragmentation study of podophyllotoxin and its 4′‐demethyl‐4β‐substituted derivatives by electrospray ionization ion‐trap time‐of‐flight tandem mass spectrometry

Cited by 24 publications

References 29 publications

A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II

A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II

Advances in structure elucidation of small molecules using mass spectrometry

A Fragmentation Study on Four Unusual Secoiridoid Trimers, Swerilactones H–K, by Electrospray Tandem Mass Spectrometry

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