Communication
studies have also shown that the uptake of hydrophobic quinol-
one antibiotics by S. aureus and E. coli occurs by passive diffu-
sion, whereas uptake by P. aeruginosa was found to be more
complex.[20] An inadequate uptake may explain why P. aerugi-
nosa showed to be insensitive to the tested natural products.
One hypothesis for the observed growth defect by the natural
product quinolones such as 1–4, PQS and possibly other natural
quinolones produced by bacteria, is that such quinolones could
be functioning in multi-bacterial communities in the natural en-
vironment to perturb the growth of competing bacterial spe-
cies.
Keywords: Synthetic methods · Cross-coupling · C–C
coupling · Nitrogen heterocycles · Natural products ·
Antibiotics
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Conclusions
In conclusion we have developed an efficient and direct syn-
thetic route to four quinolone natural products 1–4 produced
by the actinomycete Pseudonocardia sp. The route involved a
traditionally challenging sp2–sp3 Suzuki step between various
functionalised quinolone cores and a common lateral chain,
which proceeded in high stereoselectivity. The quinolone core
building blocks and lateral chain could be readily prepared from
easily accessible starting materials (longest linear sequence of
four steps). It was established that the natural products 1–4 do
not interfere with signalling by the quinolone receptor protein
PqsR of P. aeruginosa. However, similar to PQS the natural pro-
ducts were found to slow the growth of other bacterial species,
including E. coli and S. aureus. Further studies of such quinol-
ones and their biological activities in bacterial species should
lead to a greater understanding of inter-species signaling in the
natural environment and potential novel antibacterial agents.
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Experimental Section
Supporting Information (see footnote on the first page of this
article): Full experimental protocols, characterisation data, and 1H
and 13C NMR spectra.
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Acknowledgments
The research leading to these results has received funding from
the European Reserach Council (ERC) under the European Un-
ion's Seventh Framework Programme (FP7/2007-2013) and ERC
grant agreement number 279337/DOS. Research in the D. R. S.
lab is also supported by the Engineering and Physical Sciences
Research Council (EPSRC), Biotechnology and BiologicalScien-
ces Research Council (BBSRC), Medical Research Council (MRC),
Cancer Research UK, and the Wellcome Trust. Work in the M. W.
lab is supported by the BBSRC and MRC. J. T. H. was supported
by Trinity College Cambridge. Data accessibility: all data sup-
porting this study are provided as Supporting Information ac-
companying this paper.
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Received: November 5, 2015
Published Online: December 21, 2015
Eur. J. Org. Chem. 2016, 434–437
437
© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim