Tandem Mass Spectrometry Of Polyketide Natural Products

Kearney, Gordon Christopher (2003). Tandem Mass Spectrometry Of Polyketide Natural Products. MPhil thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f72a

Abstract

The polyketides form a group of natural products, related biochemically to both fatty acids and non-ribosomal peptides, that contains many important antibiotic drugs.

The macrolide polyketide drugs, such as erythromycin, are biosynthesised on giant, modular enzymes. These may be manipulated genetically, leading to the production of novel analogues of the original compound. These analogues must be structurally characterised.

Tandem mass spectrometry (MS/MS) can provide a spectrum of characteristic fragment ions. The collision induced dissociation (CID) of protonated erythromycin A and sec- butylerythromycin B was investigated using MS/MS on an ion-trap mass spectrometer. In order to investigate the nature of the fragmentation processes that occurred the experiments were repeated, after substitution of exchangeable hydrogens for deuterium.

MS/MS experiments were also carried out on a quadrupole/time of flight (Q-ToQ mass spectrometer. Accurate-mass Q-Tof spectra allowed the assignment of elemental compositions to fragment ions. 18O labelling of the C-9 carbonyl group gave insight into the first elimination of water from the parent ion.

In order to probe further the mechanisms of unimolecular dissociation for this class of molecule MS/MS experiments were carried out on roxithromycin and oleandomycin, two compounds similar to erythromycin. The C-9 oxime group of roxithromycin is eliminated in an analogous way to the C-9 carbonyl group of erythromycin A. Also, since oleandomycin has no C-6 hydroxyl group, macrolide ring opening reactions do not occur.

A scheme is tentatively proposed for the CID fragmentation reactions of erythromycin A.

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