Chemistry Tipping the Biological Seesaw
Sophie C. Royall & David J. Fox*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, U.K.
Email: s.c.royall@warwick.ac.uk, d.j.fox@warwick.ac.uk
During a biological inflammatory response, patrolling leukocytes (white blood cells) release chemokines - a type of peptide
cytokine - to summon other leukocytes. Inhibition of this process could provide a mechanism for new anti-inflammatory drugs.
Traditionally inhibition has been sought by blocking chemokine receptors with antagonists, but we have found useful molecules by
inhibiting functional cell migration – with great success.
We would not have discovered Broad-Spectrum Chemokine Inhibitors (BSCIs) using a receptor antagonist approach as our
functional screening approach has discovered a new biological target for anti-inflammatory drug design – the sstr2 receptor.
Somatostatin is a peptide involved in
growth hormone (GH)regulation.2
 Sometimes
inflammation
is
inappropriate and can exacerbate
certain diseases for example cancer,
arthritis and asthma.
The aim of my project is
 Due to their role in initiating
inflammation
chemokines
are
therefore a good target for antiinflammatory drugs – for example
BSCIs.
to synthesise a catalogue of molecules
C
S
L
C
S
WSomatostatin
S C
14
K
S
T
T
F
molecules for tipping sstr2 from GH to BSCI
function.
GH regulation
 An example of an sstr2 ligand
based on the WKF. motif.
BSCIs
inhibition
Q
I
NR58-3.14.3 W
D
H HN
GH regulated
K
P
K
O
O
HH O
N
O
H2N
sstr2 receptor
sstr2 receptor
sstr2 ligand based on WKF critical motif
 Functional selectivity is the ability
for a receptor to have different
functions depending on the molecule
to which it is bound.
chemokines
regulated?
GH regulated?
NH
O
FX97L 40 pM BSCI
The sstr2 receptor therefore displays
functional
selectivity
–
when
somatostatin is bound GH is affected
but
when
BSCIs
are
bound
chemokines are affected.4
sstr2 receptor
However, it has been discovered that
BSCIs do not bind to chemokine
receptors but to the sstr2 receptor for
somatostatin.
GH and chemokines
regulated?
Somatostatin analogue (KWF)
O
H2N
Hybrid? (KWFQ)
O
O
1
2
HN
O
S
O
N
O
S
O
N
O
S
O
4
HN
N
O
S
O
O
NH
5
HN
N
O
S
O
N
OO
O
S
O
H
N
O
+
O O
S
Cl
O
1) Et3N
N
N
H
OH
3) HCl/dioxane
H NHBoc
O
OH
H
N
H NH
2
1) HATU, Et3N, R-NH2
2) MeSO2OH
O
O
NHH
H
N
O
O O
H
N
+
ClH3N
O
S
O
N
HN
O
O O
H
N
HN
O
H
8
HN
N
OH
N
O
S
O
1) HATU, Et3N
NH
2) H2/Pd/C
H
N
H
N
H NH
2
O
H NH
2
NH
HN
O
HO
H
N
7
4) 4-ClSO2C6H4COOH, Et3N
F analogue, 9
H
N
O O
O
S
O
OBn
N
O
S
O
NH
O
1) Boc2O, Na2CO3
2) BnBr, KOH
O
N
H
OH
NH
HN
HN
 Synthesis:
O O
S
N
6
O
HN
OH
O
NH
HN
O
O
O
O
O
3
HN
O
NH
NH
O
NH
O
NH
NH
NH
NH
NH
NH
NH
O
BSCI analogue (WFQ)
H2N
O
H2N
H2N
HN
O
NH
H
chemokines regulated
Q
 FX97L is a 40 pM BSCI.1 The Q
motif is mimicked by a caprolactam
which retains the amide and has
been found
to be a successful
pharmacological component.
O
O O
S
N
H
N
sstr2 receptor
sstr2 receptor
A
G
K
F
to investigate the important part of the
somatostatin
N
F
analogous to both somatostatin and BSCIs
 NR58-3.14.3 is a BSCI. It is a cyclic
peptide with the critical motif being
WIQ.
chemokine
C
S
 It is a cyclic peptide with the critical
motif being KWF.3
O
NH
O
O
NH
NH2
FQ analogue, 10
(commerically available)
O
CbzHN
KW analogue, 11
9 or 10
CbzHN
KW analogue, 12
W analogue, 13
W analogue, 14
1) HATU, Et3N, amines 11, 12, 13 or 14
2) Pd,C, H2
compounds 1 - 8
 Future Work – The balance of BSCI vs. GH regulating activity for these compounds will be tested in a range of in vitro and in
vivo models testing leukocyte migration, anti-inflammatory activity, sstr2 binding and GH regulation.
1. D. J. Fox, J. Reckless, H. Lingard, S. Warren and D. J. Grainger, J. Med. Chem., 2009, 52, 3591-3595.
2. B. A. Hay, B. M. Cole, F. DiCapua, G. W. Kirk, M. C. Murray, R. A. Nardone, D. J. Pelletier, A. P. Ricketts, A. S.
Robertson and T. W. Siegel, Bioorg. Med. Chem. Lett., 2001, 11, 2731-2734.
3. D. J. Fox, J. Reckless, S. M. Wilbert, I. Greig, S. Warren and D. J. Grainger, J. Med. Chem., 2005, 48, 867-874.
4. A. Schonbrunn, Mol. Cell. Endocrinol., 2008, 286, 35-39.
Thanks to
Funxional Therapeutics Ltd , Dr D. J. Grainger
& Dr D J Fox