Samarium(II) promoted stereoselective synthesis of antiproliferative cis-β-alkoxy-γ-alkyl-γ-lactones

Article abstract of DOI:10.1016/j.bmcl.2006.10.005

Samarium(II) iodide promotes the stereoselective synthesis of cis-β-alkoxy-γ-alkyl-γ-lactones under mild conditions starting from linear precursors. The in vitro antiproliferative activities were examined in the human solid tumor cell lines from diverse origin A2780, SW1573, and WiDr. From the growth inhibition data a structure-activity relationship was obtained. Overall the results point to the relevant role of cis-β-alkoxy-γ-alkyl-γ-lactones as novel scaffolds for the development of new anticancer drugs.

Full text of DOI:10.1016/j.bmcl.2006.10.005

Bioorganic & Medicinal Chemistry Letters 17 (2007) 18–21
Samarium(II) promoted stereoselective synthesis of
antiproliferative cis-b-alkoxy-c-alkyl-c-lactones
a,b
a,c
a,
a,d,
*
*
Osvaldo J. Donadel, Tom a´ s Mart ´ı n, V ´ı ctor S. Mart ´ı n and Jos e´ M. Padr o´ n
a
Instituto Universitario de Bio-Org a´ nica ‘‘Antonio Gonz a´ lez’’, Universidad de La Laguna, C/ Astrof ı´ sico Francisco S a´ nchez 2,
8206 La Laguna, Spain
3
b
INTEQUI-CONICET, Facultad de Qu ı´ mica, Bioqu ı´ mica y Farmacia, Universidad Nacional de San Luis,
Chacabuco y Pedernera -5700- San Luis, Argentina
c
Instituto de Productos Naturales y Agrobiolog ı´ a, Consejo Superior de Investigaciones Cient ı´ ficas, C/ Astrof ı´ sico Francisco S a´ nchez 3,
8206 La Laguna, Spain
3
BioLab, Instituto Canario de Investigaci o´ n del C a´ ncer (ICIC), C/ Astrof ı´ sico Francisco S a´ nchez 2, 38206 La Laguna, Spain
d
Received 6 September 2006; revised 3 October 2006; accepted 4 October 2006
Available online 6 October 2006
Abstract—Samarium(II) iodide promotes the stereoselective synthesis of cis-b-alkoxy-c-alkyl-c-lactones under mild conditions start-
ing from linear precursors. The in vitro antiproliferative activities were examined in the human solid tumor cell lines from diverse
origin A2780, SW1573, and WiDr. From the growth inhibition data a structure–activity relationship was obtained. Overall the
results point to the relevant role of cis-b-alkoxy-c-alkyl-c-lactones as novel scaffolds for the development of new anticancer drugs.
ꢀ
2006 Elsevier Ltd. All rights reserved.
Lactones are common structural elements present in sev-
eral natural products that are known to exhibit diverse
biological and pharmacological activities. In particular,
c-lactones display a broad biological profile including
strong antibiotic, antihelmintic, antifungal, antitumor,
antiviral, antiinflammatory, and cytostatic properties,
which makes them interesting lead structures for the
to high yields (17–82%), by the intermolecular coupling
6
of aldehydes or ketones with a,b-unsaturated esters.
More recently, it has been reported the synthesis of
b-alkoxy-c,c-dialkyl-c-lactones from ketones and
7
b-alkoxyacrylates.
Within our program directed at the synthesis of novel
8
1
development of new drugs.
antitumor compounds and bioactive substances of mar-
9
ine origin, these synthetically challenging structures
Several syntheses of lactones are available in the litera-
2
have attracted our interest in the development of new
methodologies for their synthesis. We report herein on
the synthesis of b-alkoxy-c-alkyl-c-lactones by means
ture. However, reports on the synthesis of cis-b,c-di-
substituted-c-lactones compared with that of the trans
form are limited. Moreover, in the construction of the
3
of one-pot SmI -mediated coupling of n-octanal with
2
two stereogenic centers in b,c-disubstituted-c-lactone te-
dious stepwise methods have been employed.
b-alkoxyacrylates. To the best of our knowledge, we de-
scribe for the first time the intermolecular coupling of
b-alkoxyacrylates with aldehydes in a stereoselective
4
Samarium(II) iodide (SmI ) is a mild single-electron
2
manner and promoted by SmI . The antitumor profile
2
reducing agent that has been widely used in the field
5
of the obtained c-lactones was evaluated in vitro against
a panel of the human solid tumor cell lines A2780 (ovar-
ian cancer), WiDr (colon cancer), and SW1573 (non-
small cell lung cancer, NSCLC).
of organic chemistry. This reagent has been employed
in the past to obtain substituted c-lactones in modest
The general synthetic pathway used to obtain the com-
pounds in this study is outlined in Scheme 1. The neces-
sary b-alkoxyacrylates are prepared in high yields (69–
72%) in THF from the appropriate alcohol 1, an
Keywords: c-Lactones; Samarium(II) iodide; Anticancer drugs; Solid
tumors; Structure–activity relationship.
*
Corresponding authors. Tel.: +34 922 318 580; fax: +34 922 318 571
J.M.P); e-mail addresses: vmartin@ull.es; jmpadron@ull.es
(
0
960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.005

O. J. Donadel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 18–21
-C H
19
n
7
15
O
O
H
O
H
a
b
O
CO Me
R1
H
1
ROH
2
R
RO
RO
O
(
III)
O
O
O
2
R
O
(III)
Sm
O
Sm
1
2
3
H
H
R2
H
Scheme 1. Reagents and conditions: (a) HC„CCO
2 3
Me, (n-Bu) P,
A
B
THF, 51–72%; (b) n-octanal, SmI
2
, MeOH, THF, 0 ꢁC, 11–52%.
cis lactone
trans lactone
equimolar amount of methyl propyolate, and half an
equivalent of tri-n-butyl phosphine. Then, the b-alkoxy-
Figure 1. Proposed diastereoisomeric control for the formation of cis-
b-alkoxy-c-alkyl-c-lactone 3.
acrylate 2 is reacted with n-octanal promoted by SmI to
2
1
0
give the corresponding c-lactone 3 in modest yields.
The spectral data of selected c-lactones 3 are given.
Interestingly, the stereochemistry of the substituents
on the ring is cis. Traces of the corresponding trans
isomer are not detected. According to this methodology
a series of derivatives were prepared and the results ob-
tained are given in Table 1.
1
1
compound. In the latter, a steric hindrance can be pres-
1
2
ent between R and R groups. The destabilizing effect
may account for the diastereoisomeric control observed
in this reaction.
1
2
The in vitro antiproliferative activity was evaluated
1
using the National Cancer Institute (NCI) protocol.
3
We propose a chelation-control model such as illustrat-
ed in Figure 1 for the reaction of b-alkoxyacrylates 2
with aldehydes. The ketyl radical generated from the
reduction of aldehydes can coordinate with the Sm(III)
cation. Subsequent chelation of the carbonyl oxygen
atom of the b-alkoxyacrylate 2 forms a complex, where
two nearly alternated approaches of the ketyl radical to
the double bond are possible. The A approach provides
the cis-c-lactone 3 and the B approach gives the trans
We screened growth inhibition and cytotoxicity against
the panel of human solid tumor cell lines A2780,
SW1573, and WiDr after 48 h of drug exposure using
the sulforhodamine B (SRB) assay. The growth inhibi-
tion data are listed in Table 2. The results allow us to
classify the compounds according to their activity pro-
file. Taken as a whole, compounds 3a and 3e–f appear
as the most active products from the series with similar
performance against the three tumor cell lines. Thus,
1
4
Table 1. b-Alkoxyacrylates 2a–h and cis-b-alkoxy-c-alkyl-c-lactones 3a–f
ROH
b-Alkoxyacrylate
CO Me
Yield (%)
Lactone (racemic)
Yield (%)
n
-C
7
H
15
O
OH
2
O
O
O
O
O
6
7
9
2
52
1
a
2
a
3
a
n
-C
7
H
15
O
CO Me
OH
2
O
24
1b
2
b
3
b
n
7 15
-C H
O
CO Me
2
OH
O
O
O
7
5
0
1
15
35
1
c
2
c
3
c
n-C
7
H
15
O
CO Me
OH
2
O
O
O
1d
2
d
3
d
n
-C
7
H
15
O
CO Me
OH
2
O
O
O
6
7
0
2
20
11
1e
2
e
3
e
n-C
7
H
15
O
CO Me
OH
2
O
O
O
1f
2
f
3
f

20
O. J. Donadel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 18–21
a
Table 2. In vitro antiproliferative activity of cis-b-alkoxy-c-alkyl-c-lactones against human solid tumor cells
Compound
A2780
TGI
SW1573
TGI
WiDr
TGI
GI50
LC50
GI50
LC50
GI50
LC50
3
3
3
3
3
3
a
b
c
d
e
f
16 (±3.1)
84 (±27)
63 (±13)
48 (±14)
19 (±6.4)
22 (±3.2)
31 (±4.5)
61 (±5.7)
18 (±2.3)
23 (±4.1)
52 (±7.9)
33 (±12)
27 (±2.3)
32 (±7.1)
36 (±2.8)
49 (±8.7)
71 (±6.5)
95 (±8.3)
16 (±3.8)
50 (±24)
44 (±9.0)
39 (±13)
27 (±8.2)
32 (±12)
33 (±5.1)
71 (±9.2)
83 (±30)
78 (±27)
83 (±30)
42 (±12)
51 (±23)
88 (±15)
80 (±18)
96 (±8.3)
97 (±4.5)
81 (±34)
86 (±25)
97 (±5.0)
a
Values are given in lM and are means of two to four experiments, standard deviation is given in parentheses. GI50 represents 50% growth
inhibition, TGI total growth inhibition, and LC50 50% cell killing. TGI and LC50 values are given only if they are less than 100 lM, which is the
maximum concentration test.
GI50 and TGI values were in the range 16–32 and 31–
6 lM, respectively. These lactones were able to show
LC50 values within the experimental range with the
nanced by the European Regional Development Fund
(CTQ2005-09074-C02-01/BQU) and the Canary Islands
Government. O.J.D. thanks the Canary Islands Govern-
ment for a postdoctoral fellowship.
8
exception of compound 3f against WiDr cells.
A second group comprises derivatives 3b–d, which
showed modest activity against A2780 ovarian and
WiDr colon cancer cells with GI50 values in the range
References and notes
3
9–84 lM. For these drug-cell line combinations TGI
1. (a) Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 255; (b)
Devon, T. K.; Scott, A. I.. In Handbook of Naturally
Occurring Compounds; Academic: New York, 1975; 1; (c)
Fischer, N. H.; Olivier, E. J.; Fischer, H. D. Fortschr.
Chem. Org. Nat. 1979, 38, 47; (d) Brown, H. C.; Kulkarni,
S. K.; Racherla, U. S. J. Org. Chem. 1994, 59, 365; (e)
Rodr ´ı guez, A. D.; Pi n˜ a, I. C.; Barness, C. L. J. Org. Chem.
and LC50 values could not be reached at the maximum
test concentration, that is, 100 lM. Interestingly, differ-
ences in activity were observed for lactones 3b–d against
lung cancer cells. While compound 3c showed a compa-
rable modest activity in all cell lines, derivatives 3b and
3
d exerted larger activity against lung cancer cells. The
1
995, 60, 8096.
activity profile of compound 3b was better, showing
specificity for SW1573 cells comparable to those of 3a
and 3e–f.
2
. (a) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem.
2005, 243, 43; (b) Collins, I. J. Chem. Soc. Perkin Trans. 1
1999, 1377; (c) Collins, I. J. Chem. Soc. Perkin Trans. 1
1
998, 1869; (d) Rodr ´ı guez, C. M.; Mart ´ı n, T.; Ram ´ı rez, M.
A.; Mart ´ı n, V. S. J. Org. Chem. 1994, 59, 4461.
. For reports on the synthesis of cis-b,c-disubstituted-c-
lactones, see: (a) Bystr o¨ m, S.; H o¨ gberg, H.-E.; Norin, T.
¨
Tetrahedron 1981, 37, 2249; (b) Nubbemeyer, U.; Ohrlein,
R.; Gonda, J.; Ernst, B.; Bellus, D. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1465; (c) Ferreira, J. T. B.; Marques, J. A.;
Marino, J. P. Tetrahedron: Asymmetry 1994, 5, 641; (d)
Brecht-Forster, A.; Fitremann, J.; Renaud, P. Helv. Chim.
Acta 2002, 85, 3965; (e) Wu, Y.; Shen, X.; Tang, C.-J.;
Chen, Z.-L.; Hu, Q.; Shi, W. J. Org. Chem. 2002, 67, 3802.
Even though the experiments are preliminary, we found
that these synthetic derivatives considerably induced
growth inhibition or even cytotoxicity in human solid
tumor cells. Taking as a whole, the results are consistent
with considering c-lactones as an essential structure with
the substituents on the ring modulating the biological
activity. The outcome of the assay brings up a dual
behavior for derivative 3b. While this c-lactone may be
considered as a lead for further development of tradi-
tional cytotoxic agents for lung cancer, a new strategy
can be foreseen for colon and ovarian cancer cells: com-
pound 3b may be considered as a cytostatic drug against
these cancer cells.
3
4. (a) Doyle, M. P.; Zhou, Q.-L.; Dyatkin, A. B.; Ruppar, D.
A. Tetrahedron Lett. 1995, 36, 7579; (b) Fukuzawa, S.;
Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem. Soc.
1
997, 119, 1482; (c) Kerrigan, N. J.; Hutchison, P.;
Heightman, C. T. D.; Procter, D. J. Chem. Commun.
003, 1402; (d) Ramachandran, P. V.; Padiya, K. J.;
2
In conclusion, we have reported a samarium(II) iodide
promoted method for the synthesis of cis-b-alkoxy-c-al-
kyl-c-lactones from linear precursors. This general
methodology allows the quick production of a variety
of c-lactones that are anticipated to be useful for the dis-
covery of novel bioactive compounds. On the basis of
growth inhibition parameters, a structure–activity rela-
tionship was obtained.
Rauniyar, V.; Reddy, M. V. R.; Brown, H. C. Tetrahedron
Lett. 2004, 45, 1015.
. (a) Kagan, H.; Namy, J. L. In Lanthanides Chemistry and
Use in Organic Synthesis, Ed. Kobayashi, S., Springer,
Heidelberg, 1999, p. 155; (b) Edmonds, D. J.; Johnston,
D.; Procter, D. J. Chem. Rev. 2004, 104, 3371.
. (a) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S.
Chem. Commun. 1986, 624; (b) Otsubo, K.; Inanaga, J.;
Yamaguchi, M. Tetrahedron Lett. 1986, 27, 5763; (c)
Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S.
J. Chem. Soc. Perkin Trans. 1 1988, 1669.
5
6
Acknowledgments
7
. Kerrigan, N. J.; Upadhyay, T.; Procter, D. J. Tetrahedron
Lett. 2004, 45, 9087.
This research was supported by the EU INTERREG
IIIB-MAC initiative (05/MAC/2.5/C14 BIOPOLIS),
the Ministerio de Educaci o´ n y Ciencia of Spain, co-fi-
8
. (a) Donadel, O. J.; Mart ´ı n, T.; Mart ´ı n, V. S.; Villar, J.;
Padr o´ n, J. M. Bioorg. Med. Chem. Lett. 2005, 15, 3536; (b)
Padr o´ n, J. M.; Tejedor, D.; Santos-Exp o´ sito, A.; Garc ´ı a-

O. J. Donadel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 18–21
21
Tellado, F.; Mart ´ı n, V. S.; Villar, J. Bioorg. Med. Chem.
Lett. 2005, 15, 2487.
. (a) Garc ´ı a, C.; Mart ´ı n, T.; Mart ´ı n, V. S. J. Org. Chem.
(m, 4H), 2.53 (dd, J = 16.9, 1.9 Hz, 2H), 2.62 (dd, J = 16.9,
4.9 Hz, 2H), 3.46 (m, 2H), 4.15 (ddd, J = 4.2, 4.2, 1.9 Hz,
2H), 4.37 (m, 2H), 5.07 (m, 4H), 5.75 (m, 2H); C NMR
1
3
9
2
001, 66, 1420; (b) Mart ´ı n, T.; Soler, M. A.; Betancort, J.
M.; Mart ´ı n, V. S. J. Org. Chem. 1997, 62, 1570.
0. General procedure for the SmI promoted synthesis of cis-
b-alkoxy-c-alkyl-c-lactones: to solution of
0.405 mmol) in dry THF (4 mL, 0.1 M) at 0 ꢁC were
added sequentially under nitrogen atmosphere n-octanal
(75 MHz, CDCl ): d 13.8 (q), 18.7 (q), 20.3 (q), 22.4 (t), 25.1
3
(t), 25.3 (t), 28.3 (t), 28.9 (t), 29.2 (t), 31.5 (t), 36.5 (t), 37.1 (t),
40.4 (t), 41.1 (t), 72.8 (d), 73.6 (d), 73.8 (d), 74.7 (d), 84.2 (d),
84.4 (d), 117.2 (t), 134.1 (d), 175.3 (s).
1
2
a
2
1
(
Compound 3e: H NMR (300 MHz, CDCl
3
): d 0.88 (m,
6H), 1.15–1.92 (m, 19H), 2.35 (m, 1H), 2.54 (dd, J = 17.3,
2.2 Hz, 1H), 2.64 (dd, J = 17.3, 5.3 Hz, 1H), 3.67 (m, 1H),
4.14 (ddd, J = 5.3, 5.3, 2.2 Hz, 1H), 4.37 (m, 1H), 5.19 (m,
(
(
0.405 mmol), dry MeOH (1.22 mmol), and SmI2
1.22 mmol, 0.1 M in THF). The resultant mixture was
1
3
stirred at 0 ꢁC for 1 h, after which time it was diluted with
EtOAc (25 mL) and a saturated solution of sodium
thiosulfate was added (50 mL). The aqueous phase was
extracted with EtOAc (3· 25 mL), the combined organic
3
2H), 5.67 (m, 1H); C NMR (75 MHz, CDCl ): d 14.0 (q),
24.8 (t), 25.3 (t), 25.6 (t), 28.5 (t), 28.7 (t), 28.9 (t), 29.0 (t),
29.1 (t), 29.4 (t), 29.5 (t), 31.6 (t), 31.7 (t), 35.4 (t), 37.6 (t),
74.5 (d), 76.6 (d), 79.5 (d), 82.7 (d), 84.5 (d), 117.2 (d), 118.1
layers were dried under anhydrous MgSO
4
, filtered, and
(d), 138.2 (t), 139.5 (t), 175.5 (s).
Compound 3f: H NMR (300 MHz, CDCl
1
the solvent was removed under reduced pressure. The
residue was purified by chromatography on silica gel
3
): d 0.90 (t,
J = 6.9 Hz, 12 H), 1.22–1.52 (m, 38H), 1.59 (bs, 2H), 1.72
(m, 4H), 1.81 (m, 4H), 2.44 (d, J = 1.8 Hz, 1H), 2.49 (d,
J = 1.8 Hz, 1H), 2.49 (dd, J = 17.7, 1.7 Hz, 2H), 2.62 (dd,
J = 17.7, 4.7 Hz, 2H), 4.06 (ddd, J = 4.7, 4.7, 1.7 Hz, 2H),
(
1. Compound 3a: H NMR (300 MHz, CDCl
EtOAc/hexane, 1:9) to give c-lactone 3.
1
1
3
): d 0.88 (t,
J = 7.0 Hz, 3H), 1.25–1.51 (m, 16H), 1.60–1.87 (m, 6H),
1
3
2
1
4
.54 (dd, J = 17.4, 2.1 Hz, 1H), 2.64 (dd, J = 17.4, 5.2 Hz,
H), 3.25 (m, 1H), 4.17 (ddd, J = 5.0, 5.0, 2.1 Hz, 1H),
.37 (m, 1H); C NMR (75 MHz, CDCl ): d 14.0 (q), 22.6
3
4.48 (m, 2H), 4.48 (m, 2H); C NMR (75 MHz, CDCl ): d
3
14.1 (q), 22.6 (t), 24.9 (t), 25.0 (t), 25.1 (t), 25.6 (t), 28.4 (t),
28.6 (t), 29.1 (t), 29.2 (t), 29.4 (t), 29.5 (t), 31.7 (t), 35.6 (t),
36.0 (t), 37.2 (t), 67.3 (d), 70.4 (d), 72.8 (d), 74.3 (d), 74.5 (d),
75.7 (d), 83.0 (s), 84.3 (d), 84.4 (d), 175.2 (s).
13
(
(
(
t), 23.7 (t), 23.8 (t), 25.4 (t), 25.6 (t), 28.5 (t), 29.1 (t), 29.4
t), 31.4 (t), 31.7 (t), 33.0 (t), 37.1 (t), 72.9 (t), 76.6 (d), 84.5
d), 175.5 (s).
12. The cis relative stereochemistry for c-lactone 3 was
determined by nOe studies and H– H coupling constants.
1
1
1
Compound 3b: H NMR (300 MHz, CDCl
J = 7.0 Hz, 3H), 1.18–2.03 (m, 18H), 2.57 (dd, J = 17.5,
3
): d 0.89 (t,
2
4
5
1
2
7
1
.4 Hz, 1H), 2.67 (dd, J = 17.5, 5.4 Hz, 1H), 3.84 (m, 1H),
.24 (ddd, J = 5.4, 5.4, 2.4 Hz, 1H), 4.39 (m, 1H), 5.69–
1
3
.74 (m, 1H), 5.87 (m, 1H); C NMR (75 MHz, CDCl ): d
3
4.1 (q), 18.8 (t), 22.6 (t), 25.1 (t), 25.2 (t), 25.4 (t), 28.1 (t),
8.6 (t), 29.1 (t), 29.4 (t), 31.7 (t), 37.0 (t), 37.2 (t), 71.7 (d),
2.1 (d), 73.3 (d), 84.5 (d), 126.2 (d), 127.3 (d), 131.6 (d),
32.0 (d), 176,0 (s).
1
3. 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
1
Compound 3c: H NMR (300 MHz, CDCl
3
): d 0.89 (t,
J = 6.6 Hz, 3H), 1.18–1.51 (m, 9H), 1.74–1.91 (m, 3H), 2.63
dd, J = 17.6, 5.0 Hz, 1H), 2.70 (dd, J = 17.6, 2.3 Hz, 1H),
.17 (ddd, J = 5.0, 5.0, 2.3 Hz, 1H), 4.40 (m, 1H), 4.41 (d,
J = 11.9 Hz, 1H), 4.61 (d, J = 11.9 Hz, 1H), 7.29 (m, 5H);
(
4
(
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, M. R. J. Natl. Cancer Inst. 1990, 82,
1
3
3
C NMR (75 MHz, CDCl ): d 13.8 (q), 22.4 (t), 25.2 (t),
2
8
8.3 (t), 28.9 (t), 29.2 (t), 31.5 (t), 35.5 (t), 71.1 (t), 74.8 (d),
4.1 (d), 127.4 (d), 127.8 (d), 128.3 (d), 136.9 (s), 174.9 (s).
1
Compound 3d: H NMR (300 MHz, CDCl
J = 7.0 Hz, 6H), 1.11 (d, J = 6.0 Hz, 3H), 1.13 (d,
J = 6.0 Hz, 3H), 1.20–1.45 (m, 20H), 1.72 (m, 4H), 2.18
3
): d 0.89 (t,
1107.
4. Miranda, P. O.; Padr o´ n, J. M.; Padr o´ n, J. I.; Villar, J.;
Mart ´ı n, V. S. ChemMedChem 2006, 1, 323.
1