Brief Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 1 415
MgSO4, and concentrated to dryness. Purification by flash chro-
matography (Et2O/MeOH: 70/30) provided 221 mg (44%) of
the desired amines 17a and 17b as an inseparable mixture in a
(3) Su, B. N.; Chai, H.; Mi, Q.; Riswan, S.; Kardono, L. B.; Afriastini,
J. J.; Santarsiero, B. D.; Mesecar, A. D.; Farnsworth, N. R.;
Cordell, G. A.; Swanson, S. M.; Kinghorn, A. D. Activity-guided
isolation of cytotoxic constituents from the bark of Aglaia
crassinervia collected in Indonesia. Bioorg. Med. Chem. 2006, 14,
960–972.
(4) Hausott, B.; Greger, H.; Marian, B. Flavaglines: a group of
efficient growth inhibitors block cell cycle progression and induce
apoptosis in colorectal cancer cells. Int. J. Cancer 2004, 109,
933–940.
(5) Zhu, J. Y.; Lavrik, I. N.; Mahlknecht, U.; Giaisi, M.; Proksch, P.;
Krammer, P. H.; Li-Weber, M. The traditional Chinese herbal
compound rocaglamide preferentially induces apoptosis in leuke-
mia cells by modulation of mitogen-activated protein kinase
activities. Int. J. Cancer 2007, 121, 1839–1846.
1
30:70 ratio. H NMR (CDCl3): 2.02-2.12 (1H, m), 2.43-2.49
(1H, m), 3.57 (1H, dd, J=5.9, 14.4 Hz), 3.79 (6H, s), 3.82 (1H,
m), 6.06 (1H, d, J=2 Hz), 6.21 (1H, d, J=2.0 Hz), 7.02 (2H, d,
J =8.7 Hz), 6.99-7.11 (5H, m), 7.19 (2H, d, J =8.7 Hz). 13C
NMR (CDCl3): 36.9, 52.0, 55.7, 55.8, 57.0, 86.4, 88.9, 92.5,
101.9, 112.1, 121.0, 126.6, 128.0, 128.1, 129.5, 130.2, 135.9,
138.3, 157.6, 159.7, 163.4.
N-(3a-(4-Bromophenyl)-8b-hydroxy-6,8-dimethoxy-3-phenyl-
2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl)formamide
(18a and 18b). A 3:7 mixture of amines 17a and 17b (130 mg,
0.27 mmol) was heated under reflux for 12 h in THF (2 mL),
ethyl formate (0.35 mL, 4.31 mmol), and a drop of acetic acid.
Concentration and purification by flash chromatography
(Et2O/AcOEt: 6/4) afforded formamides 18a (11 mg, 8%) and
18b (60 mg, 44%) as white solids.
€
(6) Thuaud, F.; Bernard, Y.; Turkeri, G.; Dirr, R; Aubert, G.; Cresteil,
T.; Baguet, A.; Tomasetto, C.; Svitkin, Y; Sonenberg, N.; Nebigil,
ꢀ
C.; Desaubry, L. Synthetic analogue of rocaglaol displays a potent
and selective cytotoxicity in cancer cells: involvement of apoptosis
inducing factor and caspase-12. J. Med. Chem. 2009, 52, 5176–
5187.
18a. 1H NMR (CDCl3): 2.09 (1H, m), 2.82 (1H, m), 3.84 (7H,
m), 4.98 (1H, m), 6.08 (1H, d, J=2.0 Hz), 6.21 (1H, d, J=2.0
Hz), 6.90-7.10 (7H, m), 7.15 (2H, d, J=8.7 Hz), 8.07 (1H, s).
13C NMR (CDCl3): 34.1, 53.7, 55.4, 55.5, 58.3, 88.9, 92.4, 92.6,
102.4, 106.4, 121.1, 126.4, 127.9 (2C), 128.3 (2C), 129.4 (2C),
129.8 (2C), 135.0, 138.6, 157.6, 161.0, 161.9, 163.9. IR (thin
film): 3338, 2928, 1673, 1596, 700 cm-1. LC-MS: calculated,
509.1; found, 492.0 (M þ H - H2O)þ.
(7) Taylor, R. J. K.; Davey, A. E.; Schaeffer, M. J. Synthesis of the
novel anti-leukaemic tetrahydrocyclopenta[b]benzofuran, rocagla-
mide and related synthetic studies. J. Chem. Soc., Perkin Trans. 1
1992, 2657.
(8) Lee, S. K.; Cui, B.; Mehta, R. R.; Kinghorn, A. D.; Pezzuto, J. M.
Cytostatic mechanism and antitumor potential of novel 1H-
cyclopenta[b]benzofuran lignans isolated from Aglaia elliptica.
Chem.-Biol. Interact. 1998, 115, 215–228.
(9) Bordeleau, M. E.; Robert, F.; Gerard, B.; Lindqvist, L.; Chen,
S. M.; Wendel, H. G.; Brem, B.; Greger, H.; Lowe, S. W.; Porco,
J. A., Jr.; Pelletier, J. Therapeutic suppression of translation
initiation modulates chemosensitivity in a mouse lymphoma mod-
el. J. Clin. Invest 2008, 118, 2651–2660.
18b. 1H NMR (CDCl3): 2.25 (1H, m), 2.70 (1H, m), 3.56 (1H,
m), 3.76 (3H, s), 3.80 (3H, s), 4.69 (1H, m), 6.06 (1H, d, J=2.0 Hz),
6.21 (1H, d, J=2.0 Hz), 6.96 (2H, m), 7.02-7.08 (5H, m), 7.19 (2H,
d, J=8.8 Hz), 8.24 (1H, s). 13C NMR (CDCl3): 35.4, 53.7, 53.9,
55.1, 55.3, 86.2, 88.6, 92.0, 101.7, 110.6, 120.7, 126.3, 127.5 (2C),
127.7 (2C), 129.3 (2C), 129.7 (2C), 135.1, 137.5, 157.6, 159.2, 161.6,
ꢀ
(10) Cencic, R.; Carrier, M.; Galicia-Vazquez, G.; Bordeleau, M. E.;
Sukarieh, R.; Bourdeau, A.; Brem, B.; Teodoro, J. G.; Greger, H.;
Tremblay, M. L.; Porco, J. A., Jr.; Pelletier, J. Antitumor activity
and mechanism of action of the cyclopenta[b]benzofuran, silvestrol.
PLoS One 2009, 4, e5223.
163.5. IR (thin film): 3585, 3386, 2944, 2839, 1666, 1694, 698 cm-1
.
LC-MS: calculated, 509.1; found, 492.0 (M þ H - H2O)þ.
(11) Gerard, B.; Jones, Ii, G.; Porco, J. A., Jr. A biomimetic approach to
the rocaglamides employing photogeneration of oxidopyryliums
derived from 3-hydroxyflavones. J. Am. Chem. Soc. 2004, 126,
13620–13621.
(12) Bohnenstengel, F. I.; Steube, K. G.; Meyer, C.; Quentmeier, H.;
Nugroho, B. W.; Proksch, P. 1H-cyclopenta[b]benzofuran lignans
from Aglaia species inhibit cell proliferation and alter cell cycle
distribution in human monocytic leukemia cell lines. Z. Natur-
forsch., C: J. Biosci. 1999, 54, 1075–1083.
(13) Cui, B.; Chai, H.; Santisuk, T.; Reutrakul, V.; Farnsworth, N. R.;
Pezzuto, J. M.; Kinghorn, A. D. Novel cytotoxic 1H-cyclopenta-
[b]benzofuran lignans from Aglaia elliptica. Tetrahedron 1997, 53,
17625–17632.
(14) Chumkaew, P.; Kato, S.; Chantrapromma, K. Potent cytotoxic
rocaglamide derivatives from the fruits of Amoora cucullata. Chem.
Pharm. Bull. 2006, 54, 1344–1346.
Acknowledgment. Generous financial support for this
work was provided by the Association pour la Recherche
sur le Cancer (ARC, grant nos. 3940 and A09/5/5036 to L.D.
and C.G.), Conectus (L.D.), INCA (C.G.), and the Ligue
contre le Cancer (C.G.). We also thank ARC (N.R.) and
MNESR (F.T.) for fellowships.
Supporting Information Available: Supplementary biological
data, in vitro neuronal toxicity, cytotoxicity on 3LL cells, and
acute toxicity of 18b, cytotoxicity against cancer cell lines (IC50
with standard deviations), synthesis of compounds 1b, 6c, 7a,
8a, 9a, 9b, and 7b, and supplementary biological assay methods.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(15) Sioka, C.; Kyritsis, A. P. Central and peripheral nervous system
toxicity of common chemotherapeutic agents. Cancer Chemother.
Pharmacol. 2009, 63, 761–767.
(16) Meng, X.; Leyva, M. L.; Jenny, M.; Gross, I.; Benosman, S.;
ꢀ
Fricker, B.; Harlepp, S.; Hebraud, P.; Boos, A.; Wlosik, P.;
Bischoff, P.; Sirlin, C.; Pfeffer, M.; Loeffler, J. P.; Gaiddon, C. A
ruthenium-containing organometallic compound reduces tumor
growth through induction of the endoplasmic reticulum stress gene
CHOP. Cancer Res. 2009, 69, 5458–66.
References
(1) Kim, S.; Salim, A. A.; Swanson, S. M.; Kinghorn, A. D. Potential
of cyclopenta[b]benzofurans from Aglaia species in cancer che-
motherapy. Anticancer Agents Med. Chem. 2006, 6, 319–345.
(2) Proksch, P.; Edrada, R.; Ebel, R.; Bohnenstengel, F.; Nugroho, B.
Chemistry and biological activity of rocaglamide derivatives and
related compounds in Aglaia species (Meliaceae). Curr. Org. Chem.
2001, 5, 923–938.
(17) Zhu, J. Y.; Giaisi, M.; Kohler, R.; Muller, W. W.; Muhleisen, A.;
Proksch, P.; Krammer, P. H.; Li-Weber, M. Rocaglamide sensi-
tizes leukemic T cells to activation-induced cell death by differential
regulation of CD95L and c-FLIP expression. Cell Death Differ.
2009, 16, 1289–99.