H. Jayasuriya et al. / Tetrahedron Letters 49 (2008) 3648–3651
3651
presence of more than one amidase for the amide
formation.
CO2H
[O]
[O]
In summary, we have described the isolation, structure,
and activities of homoplatensimide A, a new congener of
platensimycin that contains a C-20 diterpenoid tetracyclic
enoic acid coupled with glutamine. The C-20 diterpenoid,
homoplatensic acid is the likely biosynthetic source of
platensic acid, the C-17 acid of platensimycin. This report
also validated the importance of the 3-amino-2,4-dihy-
droxy-benzoic acid for the activity of platensimycin.
O
O
Ent-kaurene derivatives
O
O
O
O
[O]
HO
HO
O
O
References and notes
Homoplatensic acid
4(Platensic acid)
1. Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.; Galgoci,
A.; Painter, R.; Parthasarathy, G.; Tang, Y.; Cummings, R.; Ha, S.;
Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.;
´
Zhang, C.; Hernandez, L.; Alloco, J.; Basilio, A.; Tormo, J. R.;
Genilloud, O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.;
Michael, B.; Felcetto, T.; Gill, C.; Silver, L. L.; Hermes, J.; Bartizal,
K.; Barrett, J.; Schmatz, D.; Becker, J. W.; Cully, D.; Singh, S. B.
Nature 2006, 441, 358–361.
Homoplatensene
Platensene
Fig. 2. Biogenetic relationship of platensic and homoplatensic acids.
2. Singh, S. B.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K. B.; Zhang,
C.; Zink, D. L.; Tsou, N. N.; Ball, R. G.; Basilio, A.; Genilloud, O.;
Diez, M. T.; Vicente, F.; Pelaez, F.; Young, K.; Wang, J. J. Am.
Chem. Soc. 2006, 128, 11916–11920 and 15547.
3. Jayasuriya, H.; Herath, K. B.; Zhang, C.; Zink, D. L.; Basilio, A.;
Genilloud, O.; Diez, M. T.; Vicente, F.; Gonzalez, I.; Salazar, O.;
Pelaez, F.; Cummings, R.; Ha, S.; Wang, J.; Singh, S. B. Angew.
Chem., Int. Ed. 2007, 46, 4684–4688.
4. Wang, J.; Kodali, S.; Lee, S. H.; Galgoci, A.; Painter, R.; Dorso, K.;
Racine, F.; Motyl, M.; Hernandez, L.; Tinney, E.; Colletti, S.;
Herath, K.; Cummings, R.; Salazar, O.; Gonzalez, I.; Basilio, A.;
Vicente, F.; Genilloud, O.; Pelaez, F.; Jayasuriya, H.; Young, K.;
Cully, D.; Singh, S. B. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 7612–
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unit of platensimycin showed strong interaction with both
active site histidines. To test whether the addition of nega-
tive charge will improve the activity of a non-benzoic acid
substituted analog of platensimycin, (S)-glutamic acid
amide (7) of platensic acid was prepared, and tested against
S. aureus whole cell assay. None of the compounds (com-
pounds 7, the diester derivative 6, and the epoxy derivative
8) show any growth inhibition at 64 lg/mL (the highest
concentration tested). Platensimycin showed MIC value
of 0.5 lg/mL against this strain.
5. Young, K.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K.; Zhang, C.;
Kodali, S.; Galgoci, A.; Painter, R.; Brown-Driver, V.; Yamamoto,
R.; Silver, L. L.; Zheng, Y.; Ventura, J. I.; Sigmund, J.; Ha, S.;
Basilio, A.; Vicente, F.; Tormo, J. R.; Pelaez, F.; Youngman, P.;
Cully, D.; Barrett, J. F.; Schmatz, D.; Singh, S. B.; Wang, J.
Antimicrob. Agents Chemother. 2006, 50, 519–526.
6. Singh, S. B.; Phillips, J. W.; Wang, J. Curr. Opin. Drug Discovery Dev.
2007, 10, 160–166.
7. Herath, K. B.; Zhang, C.; Jayasuriya, H.; Ondeyka, J. G.; Zink, D.
L.; Burgess, B.; Wang, J.; Singh, S. B. Org. Lett., in press,
8. Kodali, S.; Galgoci, A.; Young, K.; Painter, R.; Silver, L. L.; Herath,
K. B.; Singh, S. B.; Cully, D.; Barrett, J. F.; Schmatz, D.; Wang, J. J.
Biol. Chem. 2005, 280, 1669–1677.
9. Herath, K. B.; Attygalle, A. B.; Singh, S. B. J. Am. Chem. Soc. 2007,
129, 15422–15423.
10. Kawasaki, T.; Kuzuyama, T.; Kuwamori, Y.; Matsuura, N.; Itoh, N.;
Furihata, K.; Seto, H.; Dairi, T. J. Antibiot. (Tokyo) 2004, 57, 739–
747.
The discovery of homoplatensimide A is highly signifi-
cant for the study of the biosynthesis of platensimycin.
We have recently shown that the tetracyclic C-17 acid is
derived from a non-mevalonate terpenoid pathway likely
derived from ent-kaurene.9 The existence of an A-ring open
diterpenoid, homoplatensic acid (the carbon skeleton
hydrocarbon named here is homoplatensene) in the same
broth provides a strong evidence for its intermediacy for
the biosynthesis of platensic acid (the carbon skeleton
hydrocarbon named here is platensene). The oxidative exci-
sion of the three carbons (Fig. 2) from homoplatensic acid
would lead to platensic acid. The likely source of the
homoplatensic acid is ent-kaurene (not seco-ent-kaurene)3
or its analogs which is derived from bicyclic diterpenoid
intermediate copalyl diphosphate.10,11 Significant differ-
ences of both amino and acid components between platen-
simycin and homoplatensimide A would suggest the
11. Dairi, T. J. Antibiot. (Tokyo) 2005, 58, 227–243.