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required for cell death. Compound 1 was investigated
1.4
1.2
1
for effects against a urothelial carcinoma EJ cell line,
containing the Harvey ras oncogene. However, in this
cell line at least, compound 1 does not inhibit the ras
process. The full biological results, including the PFTase
activity of 1 and related analogues, will be determined in
due course.
*
**
0.8
0.6
0.4
0.2
0
Acknowledgements
**
We gratefully acknowledge Prof. Phillip Crews and
co-workers (University of California, USA) for the
generous gift of naturally occurring jaspaquinol. I.J.S.F.
thanks the University of York for funding. Johnson
Matthey PLC (Dr. P. Bishop, UK) is thanked for their
kind donation ofpalladium salts.
**
**
0
0.39 0.78 1.56 3.13 6.25 12.5 25 50 100
Concentration (µM) of jaspaquinol, 1
Figure 3. Effect of 1 on NHU cell growth at day 3. MTT assay at day
3. The mean relative A570 nm was determined by normalisation to a
solvent control (0 lM treatment). Each data point is the average ofsix
replicates, and standard deviations are shown by error bars.
(ꢀP < 0:05, ꢀꢀP < 0:01).
References and notes
1. Murray, L. M.; Johnson, A.; Diaz, M. C.; Crews, P. J.
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2. Carroll, J.; Jonsson, E. N.; Ebel, R.; Hartman, M. S.;
Holman, T. R.; Crews, P. J. Org. Chem. 2001, 66, 6847.
3. Biller, S. A.; Neuenschwander, K.; Ponpipom, M. M.;
Poulter, C. D. Curr. Pharm. Des. 1996, 2, 1.
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5. Lebowitz, P. F.; Prendergast, G. C. Oncogene 1998, 17,
1439.
6. Marriott, J. H.; Moreno Barber, A. M.; Hardcastle, I. R.;
Rowlands, M. G.; Grimshaw, R. M.; Neidle, S.; Jarman,
M. J. Chem. Soc., Perkin Trans. 1 2000, 4265.
7. (a) Fairlamb, I. J. S.; Pike, A. C.; Ribrioux, S. P. C. P.
Tetrahedron Lett. 2002, 43, 5327; (b) Fairlamb, I. J. S.;
Dickinson, J. M.; Pegg, M.; Cohen, L. H.; van Thiel, C.
Bioorg. Chem. 2003, 31, 80.
8. Mechelke, M.; Wiemer, D. F. J. Org. Chem. 1999, 64,
4821.
9. Mechelke, M.; Wiemer, D. F. Tetrahedron Lett. 1998, 39,
783.
10. For recent references see: (a) Radetich, B.; Corey, E. J. J.
Am. Chem. Soc. 2002, 124, 2430; (b) Liu, X.-H.; Prestwich,
G. D. J. Am. Chem. Soc. 2002, 124, 20.
11. Sharpless, K. B.; Umbreit, M. A. J. Am. Chem. Soc. 1977,
99, 5526, and references cited therein.
1.2
**
**
1
0.8
0.6
0.4
0.2
0
**
*
*
**
**
**
**
0
0.39 0.78 1.56 3.13 6.25 12.5 25 50 100
Concentration (µM) of jaspaquinol, 1
Figure 4. Effect of 1 on EJ cell growth at day 3. MTT assay at day 3.
The mean relative A570 nm was determined by normalisation to a
solvent control (0 lM treatment). Each data point is the average ofsix
replicates, and standard deviations are shown by error bars.
(ꢀP < 0:05, ꢀꢀP < 0:01).
12. Yields for these reactions also tend to vary depending on
the purity and supplier ofSeO 2, see: Fairlamb, I. J. S.;
Dickinson, J. M.; Pegg, M. Tetrahedron Lett. 2001, 42,
2205.
13. Available in three steps from b-ionone, see: Crombie, B.
S.; Smith, C.; Varnavas, C. Z.; Wallace, T. W. J. Chem.
Soc., Perkin Trans. 1 2001, 206, and references cited
therein.
After 3 days, EJ cells showed no morphological differ-
ences in response to doses of25 lM and under. Treat-
ment with 50 lM of 1 caused some cell death, whilst
there was increased cell death in response to 100 lM of
1. The MTT data reflects these observations as there was
a sharp drop-off in cell viability in response to doses
over 25 lM.
14. Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett.
1972, 13, 4339.
15. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
ꢀ
Dıaz, C. G. Synlett 2000, 1561.
In conclusion, we have identified two synthetic routes to
jaspaquinol 1. Each route has potential for the intro-
duction ofa range ofhydrophobic and hydrophilic
moieties. The viability ofnormal human urothelial
NHU cells treated with 1 has been studied, which
demonstrates that relatively high concentrations of 1 are
16. Various Pd-complexes ofgeranyl chloride demonstrate
that the distal olefin forms a stable chelated system (NMR
and X-ray structure) see: (a) Akermark, B.; Hansson, S.;
Krakenberger, B.; Vitagliano, A.; Zetterberg, K. Organo-
metallics 1984, 3, 679; (b) Akermark, B.; Vitagliano, A.
Organometallics 1985, 4, 1275.