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Figure 3. Effects of VX-745 treatment on the activation and activity of
p38a in hTERT-immortalised WS cells. Lane 1, WS cells; lane 2, WS
cells + Anisomycin (A); lane 3 WS cells + A + 1.0 lM VX-745; lane 4,
WS cells + A + 2.5 lM SB203580. p-p38 and p-HSP27 indicate the
phosphorylated forms of p38 and HSP27.
7
9
. Pichierri, P.; Franchitto, A. Bioessays 2004, 26, 306.
p-p38a, and moderate levels of p-HSP27 (lane 1). Aniso-
mycin treatment greatly increased the activation of p38a
causing an increase in p-p38a and p-HSP27 levels (lane
1
1
0. Davis, T.; Kipling, D. Rejuv. Res. 2006, 9, 402.
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2
). VX-745 at 1.0 lM and SB203580 at 2.5 lM inhibited
1
the anisomycin-induced activity of p38a, as indicated by
the much-reduced levels of p-HSP27 (lanes 3 and 4). The
prevention of HSP27 phosphorylation appears to be due
to inhibition of p38a, as VX-745 and SB203580 have at
best only a minor effect on anisomycin-induced p38a
activation.
1
In conclusion, the p38a MAPK inhibitor VX-745 can be
prepared rapidly and efficiently using a combination of
microwave irradiation and conductive heating methods.
1
The four-step sequence proceeds by mono-S Ar of 3,6-
N
dichloropyridazine with the corresponding acetonitrile
on microwave irradiation with potassium tert-butoxide,
followed by microwave-mediated palladium-catalyzed
TM
phenylsulfide formation using PEPPSI -IPr, hydrolysis
1
to the amide on irradiation in concentrated sulfuric acid
and treatment with N,N-dimethylformamide dimethyl
acetal to facilitate the heteroannulation to the pyrimi-
do[1,6-b]pyridazinone. Its inhibitory activity in HCA2
and WS cells was confirmed by ELISA and immunoblot
assay, showing excellent selectivity for p38a MAPK
over JNK. Given this selectivity profile, VX-745 would
appear to be ideal for further studies of the accelerated
ageing of WS cells in culture, which are now underway.
1
2
1
1
1
2
9
7.
2
1. Purification by column chromatography on silica, gra-
dient eluting with EtOAc–hexane (7:3) to EtOAc, gave
Acknowledgments
+
VX-745 as a yellow solid, mp 261–264 °C (Found: MH
3
O Cl
5
+
S [MH ] requires 435.9811);
4
35.9806, C19
H
10
N
3
2
F
2
This work is supported by BBSRC SCIBS and EPSRC/
BBSRC SPARC awards.
ꢀ1
IR (nujol) m/cm
6
3019, 2399, 1626, 1600, 1215, 770,
69; H NMR (400 MHz, CDCl ) d (ppm) 6.50 (1H, d,
J 9.8 Hz, 3 or 4-H), 6.80 (1H, d, J 9.8 Hz, 4 or 3-H),
1
3
00 00 0
.00 (2H, m, 5 and 6 -H), 7.20 (1H, t, J 8 Hz, 4 -H),
7
0 0 00
7.30 (2H, d, J 8 Hz, 3 and 5 -H), 7.60 (1H, m, 3 -H),
References and notes
1
3
8
105.0, 113.0, 118.5, 121.5, 123.0, 125.3, 128.2, 128.4,
3
.50 (1H, s, 8-H); C NMR (125 MHz, CDCl ) d (ppm)
1
. (a) Martin, G. M.; Oshima, J.; Gray, M. D.; Poot, M. J.
Am. Geriatr. Soc. 1999, 47, 1136; (b) Yu, C.-E.; Oshima,
J.; Fu, Y.-H.; Wijsman, E. M.; Hisama, F.; Alisch, R.;
Matthews, S.; Nakura, J.; Miki, T.; Ouais, S.; Martin, G.
M.; Mulligan, J.; Schellenberg, G. D. Science 1996, 272,
128.9, 129.0, 130.7, 136.5, 137.8, 149.4, 193.0; MS (ES)
m/z 436 (MH , 100%).
+
22. Shi, Y.; Kotlyarov, A.; Laabeta, K.; Gruber, A. D.; Butt,
E.; Marcus, K.; Meyer, H. E.; Friedrich, A.; Volk, H. D.;
Gaestel, M. Mol. Cell. Biol. 2003, 23, 7732.
258.