Syn th esis of Bioa ctive Sester ter p en olid es fr om en t-Ha lim ic Acid .
15-Ep i-en t-cla d ocor a n A a n d B
I. S. Marcos,* A. B. Pedrero, M. J . Sexmero, D. Diez, P. Basabe, N. Garc´ıa, R. F. Moro,
H. B. Broughton,§ F. Mollinedo,‡ and J . G. Urones
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Qu´ımicas, Universidad de Salamanca,
Plaza de los Ca´ıdos 1-5, 37008 Salamanca, Spain
ismarcos@usal.es
Received May 16, 2003
The bioactive sesterterpenoid γ-hydroxybutenolides 15,18-bisepi-ent-Cladocoran A and B, 1 and 2,
and 15-epi-ent-Cladocoran A and B, 57 and 55, were synthesized from ent-halimic acid. The
synthesized sesterterpenolids 2, 55, 57, and 59 inhibited cellular proliferation (IC50 = 2 µM) of a
number of human leukaemic and solid tumor cell lines.
1. In tr od u ction
kaemia cell lines at low micromolar concentrations.9,18
Because of its unusual structure and its potentially
important physiological activity, dysidiolide has attracted
considerable attention from chemists, biologists, and
pharmacologists.8-19
We have previously communicated the synthesis of 1
and 2 and the epimers of these compounds at C18,
showing that the structures proposed by Fontana et al.
for cladocoran A and B (1 and 2) should be revised.20
Recently, during the preparation of this paper, Yamada
et al. reported the synthesis of the enantiomers of 1 and
2, and their epimers at C18 (optical rotation for enanti-
omers of 1 and 2:21 ent-1, [R]D - 7.2 (c 0.25, CHCl3); ent-
2, [R]D - 64.3 (c 0.28, CHCl3). They went on to describe
the synthesis of the correct structures for cladocoran A
and B (see Figure 1), establishing cladocoran B as an
olefinic regioisomer of dysidiolide and cladocoran A as
its acetate.21
The study of the marine metabolites has been a subject
of great interest in recent years, due to the large number
of such compounds that present very interesting biologi-
cal properties. Among these, a considerable number of
sesterterpenoids1 have been isolated, many of which
possess a γ-hydroxybutenolide2-5 as a significant struc-
tural feature, and in many cases this group is involved
in the biological activities of these compounds.
Cladocoran A and B are sesterterpenolides isolated
from the mediterranean coral6 Cladocora cespitosa (L)
by Fontana et al. These authors proposed structures 1
and 2 on the basis of spectroscopic data. Since the new
carbon skeleton proposed for 1 and 2 was an isoprenyl
ent-halimane, we decided to synthesize it along with some
analogues and to test the biological activity of these
compounds.
Sesterterpenolides 1 and 2 are structural analogues
of the natural sesterterpenolide dysidiolide, isolated in
1996,7 an inhibitor of protein phosphatase cdc25A (IC50
) 9.4µM) and cdc25B (IC50 ) 87µM), which are essential
for cell proliferation. Dysidiolide8 inhibits the growth of
A-549 human lung carcinoma and P388 murine leu-
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* Address correspondence to this author. Fax: 34 923 294574.
§ Current address: Lilly S.A., Avda. de la Industria, 30, 28108
Alcobendas, Madrid, Spain.
‡ Current address: Centro de Investigacio´n del Ca´ncer, CSIC-
Universidad de Salamanca, Campus Miguel de Unamuno, 37007
Salamanca, Spain.
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10.1021/jo034663l CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/23/2003
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J . Org. Chem. 2003, 68, 7496-7504