Scheme 4 Schematic of the synthesis of PQS using a Uniqsis FlowSynTM continuous flow reactor.22
analogue syntheses and biological studies should further enhance
our understanding of PQS-mediated quorum sensing systems; this
may facilitate the development of methods that can modulate these
signalling networks in a useful fashion, with possible therapeutic
applications in the treatment of human bacterial infections.
We gratefully acknowledge financial support from the EPSRC,
BBSRC, MRC and Newman Trust.
7 R. Popat, S. A. Crusz and S. P. Diggle, Br. Med. Bull., 2008, 87, 63–75.
8 (a) E. Deziel, S. Gopalan, A. P. Tampakaki, F. Lepine, K. E. Padfield,
M. Saucier, G. Xiao and L. G. Rahme, Mol. Microbiol., 2004,
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10 J. Hodgkinson, S. D. Bowden, W. R. J. D. Galloway, D. R. Spring and
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Notes and references
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11 For recent selected examples of modulating AHL-mediated quroum
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12 For selected examples of limited SAR studies on such molecules in the
context of quorum sensing systems see: (a) S. P. Diggle, K. Winzer, S. R.
Chhabra, K E. Worall, M. Camara and P. Williams, Mol. Microbiol.,
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McKnight, A. S. Kende, E. P. Greenberg and B. H. Iglewski, Proc. Natl.
Acad. Sci. U. S. A., 1999, 96, 11229–11234 Pesci et al. demonstrated
that 3-heptyl-2-hydroxy-4(1H)-quinolone (in which the heptyl- and
hydroxyl subsitutents have been switched positions relative to PQS)
and 2-heptyl-4-hydroxyquinoline N-oxide (a PQS isomer which lacks
the 3-hydroxy group) do not exhibit any biological activity comparable
to that of PQS. In addition, Diggle et al. demonstrated that both 2-
heptyl-4(1H)-quinolone and 3-formyl-2-heptyl-4(1H)-quinolone were
biologically inactive in this context.
13 For example, Pritchard and co-workers have reported a 3-step synthesis
of HHQ from octanoic acid which proceeds in an overall yield of ~ 48%:
D. I. Pritchard, B. W. Bycroft, S. R. Chhabra and D. Hooi. Substitued
4-quinolones. PCT Int. Appl. WO/2002/047686, 2002.
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6 For a recent discussion of PQS-mediated quorum sensing see: J. F.
Dubern and S. P. Diggle, Mol. BioSyst., 2008, 4, 882–888.
15 A similar method for synthesising PQS (via the synthesis and isola-
tion of intermediate (4) has been disclosed: I. C. Purcell, Bacterial
60 | Org. Biomol. Chem., 2011, 9, 57–61
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