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J.M.Bueno et al./ Bioorg.Med.Chem.Lett.12 (2002) 1697–1700
Acknowledgements
The authors would like to thank our colleagues at Bio-
processing Pilot Plant for providing natural starting
material and M. T. Quesada for the technical support in
the preparation of intermediates as well as to A. I.
Alvarez, J. Gomez and F. Fernandez for the analytical
support. We also thank our collegues of Mycology
laboratory for running the MIC’s assays.
References and Notes
1. Kennedy, T. C.; Webb, G.; Cannell, R. J. P.; Kinsmann,
O. S.; Middleton, R. F.; Sidebottom, P. J.; Taylor, N. L.;
Dawson, M. J.; Buss, A. D. J.Antibiot. 1998, 51, 1012.
2. Hauser, D.; Sigg, H. P. Helv.Chim.Acta 1971, 54, 1178.
3. Ogita, J.; Hayashi, T.; Sato, A.; Furutani, W. JP Patent 62-
40292, 1987; Chem Abstr. 1987, 107, 5745.
Scheme 2. (a) (i) Bu2SnO, toluene, reflux; (ii) PMBCl, TBAF, rt, 67%;
(b) (i) NaH, THF, 0 ꢀC; (ii) allyl bromide, THF, rt, 95%; (c) DDQ,
DCM/H2O, rt, quant; (d) (i) NaH, THF, 0 ꢀC; (ii) CS2, imidazole; (iii)
MeI, 86%; (e) Bu3SnH (1 equiv), AIBN, toluene, reflux; (f) H2, Pd/C,
EtOAc, rt, quant.
4. Gomez Lorenzo, M. G.; Garcıa Bustos, J. F. J.Biol.Chem.
1998, 273, 25041.
5. Bueno, J. M.; Cuevas, J. C.; Fiandor, J. M.; Garcıa-Ochoa,
S.; Gomez de las Heras, F. Bioorg.Med.Chem.Lett. 2002, 12,
121.
6. Herreros, E.; Martınez, C. M.; Almela, M. J.; Marriott,
M. S.; Gomez de las Heras, F.; Gargallo-Viola, D. Antimicrob.
Agents Chemother. 1998, 42, 2863.
tetrahydrofuran ring is structurally similar to S isomer
6b, as demonstrated its 1H NMR spectrum and the high
MIC’s values observed in the above mentioned strains.
A complete in vitro study of compound 6a has been
already reported.6
7. Large scale bioproduction of GR135402 was performed at
the Bioprocessing Pilot Plant (GlaxoSmithKline, UK).
8. Du, Y.; Kong, F. Carbohydr.Res. 1995, 275, 259.
9. Motherwell, W. B.; Crich, D. In Free Radical Chain Reac-
tions in Organic Synthesis; Academic: London, San Diego,
1991; p 213.
On the other hand, this effect seems to be no significant
to the antifungal activity in (C40-C)-tetrahydrofuran
derivatives. Compounds 9a and 9b, having S and R
configuration respectively, show very similar antifungal
profile, being very potent against C.albicans , C.pseu-
dotropicalis and C.tropicalis,
whereas moderately
10. The configuration at the carbon atom bearing the sub-
stituents attached to the tetrahydrofuran ring has been estab-
lished in basis of 1H NMR spectra. In particular, it is
noteworthy the effect exerted by the position of the alkyl sub-
stituent on the coupling constants for protons at position 10 of
the sugar moieties in S isomers (alkyl substituents in endo
position). Molecular modelling studies have suggested that
this effect could be attributed to a conformational change in
the six-membered ring, which takes a ‘twisted boat’-like con-
formation in order to accomodate the substituent at endo
position. These studies will be the subject matter of a future
paper.
11. Wolff, S.; Agosta, W. C. J.Chem.Res.(S) 1981, 78.
12. National Committee for Clinical Laboratory Standards.
Reference method for broth dilution antifungal susceptibility
testing of yeasts (1997). Approved Standard Document M27-
A.N.C.C.L.S. Villanova, Palo Alto, USA.
potent against C.glabrata and C.neoformans . Both
compounds were inactive against C.parapsilosis and
A.flavus .
In conclusion, the attachment of tetrahydrofuran rings
to the C30-C40 bond of the original sugar moiety, has led
to a dramatic enhacement of the antifungal activity
within the Sordarin family of compounds. The differ-
ences found between stereoisomers having R and S
configuration at the carbon bearing the substituent
attached to the tetrahydrofuran ring, suggest a highly
stereospecific interaction of these Sordarin derivatives in
their Ribosome–EF2 complex binding site, and warrant
further exploration on the synthesis of these new class
of antifungals.