Fragmentation pathways of new aza derivatives of 16‐membered macrolide antibiotic—analog of Josamycin investigated by ESI and FAB mass spectrometric methods

Przybylski, Piotr; Pyta, Krystian; Brzeziński, Bogumił

doi:10.1002/jms.1612

Cited by 4 publications

(4 citation statements)

References 22 publications

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“…As presented in Figure , the structures of a new component, which was named as josamycin A, and two acid degradation impurities in josamycin were characterized preliminarily by 2D LC/IT‐TOF MS in positive and negative electrospray ionization mode. Based on MS n data, the structures and fragmentation pathways of the new component and the acid degradation impurities of josamycin were elucidated by referring to a published article on structural analogues . Subsequently, josamycin A was synthesized and the degradation impurities were separated by preparative HPLC for structural confirmation, and the structures of josamycin A and impurities were confirmed by NMR.…”

Section: Introductionsupporting

confidence: 90%

“…MS 3 experiment of the fragment ion at m/z 598.3113 resulted in the ions at m/z 407.2010 and m/z 192.1227, which corresponded to the cleavage of the ether bond between the 16‐membered ring and mycaminose. The fragmentation pathways of losingone mycarose and one mycaminose was in agreement with a previous published paper . Furthermore, the fragment ion at m/z 407.2010 lost one H 2 O, one CH 3 COOH and one CH 3 OH successively resulting in product ions at m/z 389.1929, 329.1714 and 297.1460, respectively.…”

Section: Resultsmentioning

confidence: 94%

“…As presented in Figure 1, the structures of a new component, which was named as josamycin A, and two acid degradation impurities in elucidated by referring to a published article on structural analogues. 28 Subsequently, josamycin A was synthesized and the degradation impurities were separated by preparative HPLC for structural confirmation, and the structures of josamycin A and impurities were confirmed by NMR. The formation mechanisms of josamycin A and degradation impurities in josamycin were also studied.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a new component and impurities in josamycin by trap‐free two‐dimensional liquid chromatography coupled to ion trap time‐of‐flight mass spectrometry

Liu

Sang

et al. 2019

Rapid Comm Mass Spectrometry

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Rationale The toxicities of the impurities of a drug will affect the clinical effects and cause potential health risk; therefore, it is essential to study profiles of the impurities. In this study, a new structural type of component and two acid degradation impurities in josamycin were discovered and characterized for the further improvement of official monographs in pharmacopoeias. Methods The component and acid degradation impurities in josamycin were separated and preliminary characterized by trap‐free two‐dimensional liquid chromatography coupled to high‐resolution ion trap time‐of‐flight mass spectrometry (2D LC/IT‐TOF MS) in both positive and negative electrospray ionization mode. The eluent of each peak from the first dimensional chromatographic system was trapped by a switching valve and subsequently transferred to the second dimensional chromatographic system, which was connected to the mass spectrometer. Full scan MS was firstly conducted to obtain the exact m/z values of the molecules. Then LC/MS/MS and LC/MS/MS/MS experiments were performed on the compounds of interest. Results A new structural type of component, which was named as josamycin A, and two acid degradation impuritiess, which were identified as impurity I and impurity II, were discovered in josamycin. Their structures and fragmentation pattern were deduced according to MSn data. Furthermore, josamycin A was synthesized and impurity I was separated by preparative HPLC. The structures of josamycin A and the impurities were confirmed by 1H NMR and 13C NMR data. Conclusions Josamycin A was produced when the hydroxyl group on the macrolide of josamycin was oxidized into a carbonyl group. Impurity I and impurity II were produced by the loss of one molecule of acetyl mycaminose from josamycin and josamycin A, respectively. Compared with josamycin, the experimental results showed that josamycin A had a higher antibacterial activity with similar cytotoxicity, while impurity I had no antibacterial activity but a higher cytotoxicity. As a result, the control of impurity I is significant.

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Section: Introductionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Characterization of a new component and impurities in josamycin by trap‐free two‐dimensional liquid chromatography coupled to ion trap time‐of‐flight mass spectrometry

Liu

Sang

et al. 2019

Rapid Comm Mass Spectrometry

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“…Recently, we have obtained aminoalkyl derivatives of α,β-unsaturated josamycin by 'one pot' reductive amination at C-20 position and elimination of one acetic acid molecule from aglycone. [18,19] The NMR method combined with different 2D correlations is a useful tool for investigation of large macrocyclic structures and was used previously for detailed conformational studies of demycarosyl-4-O-isovaleryl josamycin [20] in CDCl 3 and josamycin [21] in D 2 O or D 2 O/DMSOd 6 solutions. It is well known that hydrogen bonds play important role in stabilising structures of many small and large organic compounds.…”

Section: Introductionmentioning

confidence: 99%

Structure elucidation, complete NMR assignment and PM5 theoretical studies of new hydroxy‐aminoalkyl‐α,β‐unsaturated derivatives of the macrolide antibiotic josamycin

Przybylski

Pyta

Stefańska

et al. 2010

Magnetic Reson in Chemistry

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Four new hydroxy-aminoalkyl derivatives of alpha,beta-unsaturated macrolide-josamycin (2-5) have been synthesised and their structures have been studied by means of (1)H and (13)C NMR and FT-IR methods. Complete assignment of resonances in the (1)H and (13)C NMR spectra has been made on the basis of (1)H-(13)C HSQC, (1)H-(13)C HMBC, (1)H-(1)H COSY, (1)H-(1)H NOESY 2D experiments. Spectroscopic data indicated that for the derivatives 3 and 4 some equilibrium between two different structures exists in contrast to derivatives 2 and 5. The lowest-energy structures of the new derivatives of josamycin have been calculated and visualised by PM5 method at semi-empirical level of theory, taking into account the NMR and FT-IR data. The most significant differences between the structures of josamycin and its newly synthesised derivatives' were found in the conformation of the macrolide aglycone part and in the mutual orientation of the 4-O-isovalerylmycarosylmycaminose moiety relative to the aglycone part. PM5 semi-empirical calculations indicated that the structures of the new macrolide derivatives are stabilised by rather weak intramolecular hydrogen bonds in agreement with spectroscopic data. Antimicrobial properties of the new derivatives 2-5 as well as those having an acetate group at C-3 (6 and 7) were determined and compared to that of the parent macrolide antibiotic josamycin (1).

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2009

J. Mass Spectrom.

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Fragmentation pathways of new aza derivatives of 16‐membered macrolide antibiotic—analog of Josamycin investigated by ESI and FAB mass spectrometric methods

Cited by 4 publications

References 22 publications

Characterization of a new component and impurities in josamycin by trap‐free two‐dimensional liquid chromatography coupled to ion trap time‐of‐flight mass spectrometry

Characterization of a new component and impurities in josamycin by trap‐free two‐dimensional liquid chromatography coupled to ion trap time‐of‐flight mass spectrometry

Structure elucidation, complete NMR assignment and PM5 theoretical studies of new hydroxy‐aminoalkyl‐α,β‐unsaturated derivatives of the macrolide antibiotic josamycin

Current literature in mass spectrometry

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