Harnessing Enzymatic Promiscuity in Myxochelin Biosynthesis for the Production of 5‐Lipoxygenase Inhibitors

Abstract

The siderophore myxochelin A is a potent inhibitor of human 5-lipoxygenase (5-LO). To clarify whether the iron-chelating properties of myxochelin A are responsible for this activity, several analogues of this compound were generated in the native producer Pyxidicoccus fallax by precursor-directed biosynthesis. Testing in a cell-free assay unveiled three derivatives with bioactivity comparable with that of myxochelin A. Furthermore, it became evident that inhibition of 5-LO by myxochelins does not correlate with their iron affinities.

Myxochelin‐Inspired 5‐Lipoxygenase Inhibitors: Synthesis and Biological Evaluation

“…The latter appear not to be very permissive for variations of their substitution patterns. Free phenolic groups in ortho ‐position to the amide substituent turned out to be crucial for 5‐LO inhibition, which is also consistent with our previous study . Additional hydroxy residues in meta ‐position further improve the bioactivity, whereas para ‐oriented hydroxy groups are in general detrimental.…”

“…[11] In this study,t wo engineered analoguess howedm uch lessa ffinity for the coordination of ferric iron than myxochelinA,b ut still maintained significant activity against human 5-LO. [11] To furthere xplore the SAR, we now tested 48 additional derivatives, whichw ere prepared using ar ecently developed synthetic strategy. [12] In particular,w es et out to evaluatet he effects of different aromatic substitution patternso n5 -LO inhibition.…”

“…Only few compounds of this series, namely myxochelins S9 and S10, retained some modest 5-LO inhibitory activity.W ea lso tested as ynthetic analogue with 4hydroxybenzamide rings. In contrast to related myxochelins with 2-or 3-hydroxybenzamide moieties, which had previously been shown to sustain 5-LO inhibitory properties, [11] the exclusive para-hydroxylation pattern in myxochelinS 15 turnedo ut to be disadvantageous for the biological activity.…”

“…The active site of human 5‐LO contains a non‐heme iron, which serves as an electron donor (Fe 2+ ) or acceptor (Fe 3+ ) during catalysis . Our original assumption that the inhibition of human 5‐LO was solely due to the complexation of this active site iron by myxochelin A could be disproven by structure activity relationship (SAR) studies of myxochelin derivatives which were generated by precursor‐directed biosynthesis . In this study, two engineered analogues showed much less affinity for the coordination of ferric iron than myxochelin A, but still maintained significant activity against human 5‐LO .…”

“…Our original assumption that the inhibition of human 5‐LO was solely due to the complexation of this active site iron by myxochelin A could be disproven by structure activity relationship (SAR) studies of myxochelin derivatives which were generated by precursor‐directed biosynthesis . In this study, two engineered analogues showed much less affinity for the coordination of ferric iron than myxochelin A, but still maintained significant activity against human 5‐LO . To further explore the SAR, we now tested 48 additional derivatives, which were prepared using a recently developed synthetic strategy .…”