L. G. León et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5171–5173
5173
a whole, lipophilicity is not sufficient to explain the observed dif-
ferences in growth inhibition.
The data on antiproliferative activity shown in Table 1 allow to
classify the compounds in two groups. A first group is comprised of
the inactive compounds, that is, those derivative with GI50 values
group. Furthermore, we are using in-house methodology for the
transformation of the sulfide and sulfone groups into exo- or endo-
cyclic double bonds. These findings will be reported elsewhere.
In summary, we have synthesized a set of
and b, -fused to carbocycles, using ring closing metathesis as the
cycling strategy. The analysis of the antiproliferative data gives a
structure–activity relationship with the substituents on the -lac-
c-lactones a,b-fused
c
>100
remaining derivatives, which show GI50 values in the range 5.7–
79 M. With the exception of compounds 20 and 21, all active
lM against all cell lines. The second group includes the
c
l
tone modulating the biological activity. Some derivatives showed
products induced growth inhibition in the three cell lines. Overall,
the active compounds did not show a clear trend in terms of spec-
ificity for a particular cell line. However, compound 20 was inac-
tive against the lung cancer cells SW1573 whilst showed good
promising activity against the lung, breast, and colon cancer cell
lines. Privileged structures such as c-lactones, with their inherent
drug-likeness, represent an ideal source of core synthons and cap-
ping fragments for the design and synthesis of drugs targeted at
various receptors. The general methodology reported herein allows
activity against the T-47D breast (5.7
(24 M) cell lines. On the contrary, bicyclic derivative 21 was inac-
tive against WiDr cells and showed a weak activity against the
other cell lines (76–79 M).
The most active compounds of the set are 10a–b with GI50 val-
ues in the range 7.8–13 M. However, the non-silyl-protected
lM) and WiDr colon
l
the quick production of a variety of
the discovery of novel drug leads.
c-lactones that are useful for
l
Acknowledgments
l
equivalent 10c is inactive. This result is also observed for active
compounds 9a–b and inactive 9c. The difference may be explained
by the increased lipophilicity of the silyl-protected derivatives
when compared to the compounds lacking silyl groups, thus facil-
itating drug diffusion through the cell membrane. In our group, this
strategy has been applied successfully to substituted tetrahydropy-
rans16 and naturally occurring catalpol.17 The presence of a silyl
group is not enough premises to induce growth inhibition. That
is the case for compounds 8a–c and 11a–b, which are all inactive.
A direct comparison between compounds 8–11 indicates that the
carboxylic acid group in 9a–b and the hydroxyl group in 10a–b
play a role in the biological effect. Furthermore, the deprotection
of the silyl group in 11a–b leads to inactive derivatives 12a–b.
However, the dialkene analogs 13a–b showed modest GI50 values
This research was supported by the Spanish MEC co-financed by
the European Regional Development Fund (CTQ2005-09074-C02-
01/BQU), and the Canary Islands Government, and the Fundación
Canaria de Investigación y Salud (PI 1/06 and PI 35/06). L.G.L.
thanks the Spanish MSC-FIS for a postdoctoral contract. J.M.P.
thanks the Spanish MEC-FSE for a Ramón y Cajal contract.
References and notes
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in the range 33–57
improved in the corresponding b,
showed GI50 values in the range 17–36
Oxidation of sulfide 10c to give sulfone 15 did not induce
changes in activity, both compounds being inactive. The -alkyl-
l
M. This antiproliferative effect was slightly
-fused -lactones 14a–b, which
M.
c
c
l
a
ated derivatives 16a–b are also inactive. However, dialkenes
17a–b and bicycles 18a–b showed GI50 values in the range 16–
34 lM and 15–28 lM, respectively. When comparing the subset
10. Rodríguez, C. M.; Ravelo, J. L.; Martín, V. S. Org. Lett. 2004, 6, 4787.
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spectroscopic data in full accord with their assigned structures.
13. In this method, for each drug a dose–response curve is generated and three
levels of effect can be calculated, when possible. The effect is defined as
percentage of growth (PG), where 50% growth inhibition (GI50), total growth
inhibition (TGI) and 50% cell killing (LC50) represent the drug concentration at
which PG is +50, 0, and À50, respectively, Skehan, P.; Storeng, P.; Scudeiro, D.;
Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd,
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15. Software-predicted lipophilicity of the compounds was calculated with the
program New ClogP accessible via Internet. Available from: http://
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of compounds 16–18 with that of analogs 12–14, a parallelism in
activity is observed. Thus, hydroxy-alkenes (12 and 16) are inac-
tive; dialkenes (13 and 17) induce cell growth inhibition; and bicy-
cles (14 and 18) show a subtle enhancement in activity. The data
seem to indicate that a sulfone group induces more activity than
a sulfide group.
While the alkylation of 15 in
a position leads to inactive com-
pound 16, the O-alkylation produces active analog 19. Thus, the
O-alkylated derivative 19 shows GI50 values in the range 7.5–
28
l
M, with selectivity against the lung cancer cells SW1573. Fur-
-position of 19 leads to 20, which losses activity
ther alkylation in
a
toward the lung cancer cells. However, it shows an enhancement of
the effect on T-47D cells. The cyclization of derivative 20 produces
a substantial loss in activity.
Despite the large antitumor activity reported for naturally
occurring lactones,1 we show that our set of
c-lactones exhibit a
moderate activity. We speculate that the absence of a ,b-unsatu-
a
rated group may explain this effect. Work is currently conducted to
determine the exact role in activity of the sulfide and the sulfone
17. Pungitore, C. R.; León, L. G.; García, C.; Martin, V. S.; Tonn, C. E.; Padrón, J. M.
Bioorg. Med. Chem. Lett. 2007, 17, 1332.