B.H. Alizadeh et al. / European Journal of Medicinal Chemistry 45 (2010) 5979e5984
5983
-OMe), 3.92anti (t, 1H, J ¼ 8.5 Hz, -H5), 3.98
(dd, J ¼ 7.0 Hz,
(m, 1H, -H4), 2.85 (dd, 1H, J ¼ 7.2 Hz, J ¼ 8.2 Hz, -H3), 3.00 (brs, 1H,
-OH), 3.94 (t 1H, J ¼ 8.5 Hz, -H5), 4.33 (t 1H, J ¼ 8.5 Hz, -H5), 5.70 syn
(s, 1H, -H7), 5.90 (s, 1H, -O-CH2-O), 6.24 (s, 1H, Ar), 6.29 (d, 1H,
J ¼ 7.7 Hz, Ar), 6.60 (d, 1H, J ¼ 7.7 Hz, Ar), 7.29 (m, 3H, Ph), 7.37
(m, 1H, Ph), 7.74 (d, 1H, J ¼ 7.5 Hz, Ph). anti diasteromer: 2.09 (dd,
1H, J ¼ 5.1 Hz, J ¼ 13.8 Hz, -H6), 2.18 (dd, 1H, J ¼ 9.9 Hz, J ¼ 13.8 Hz,
-H6), 2.64 (m, 1H, -H4), 2.83 (m, 1H, -H3), 3.01 (brs, 1H, -OH), 3.90
(t, 1H, J ¼ 8.8 Hz, -H5), 4.26 (t, 1H, J ¼ 8.8 Hz, -H5), 5.45 (d, J ¼ 8.4 Hz,
-H7), 5.92 (s, 1H, -O-CH2-O), 6.37 (d, 1H, J ¼ 7.8 Hz, Ar), 6.40 (s, 1H,
Ar), 6.68 (d,1H, J ¼ 7.8 Hz, Ar), 7.29 (m,1H, Ph), 7.37 (m, 2H, Ph), 7.43
syn
J ¼ 9.0 Hz, -H5), 4.09 (brs, -OH), 4.17anti (t, J ¼ 8.5 Hz, -H5), 4.39syn
(d, J ¼ 8.2 Hz, -H7), 4.81 anti (d, J ¼ 8.0 Hz, -H7), 5.26 syn (s, -H7), 5.92
and 5.95 (s, 1H, -O-CH2-O), 6.23 (s, Ph), 6.33 (m, Ph), 6.48 (s, Ph),
6.60 (d, J ¼ 7.8 Hz, Ar), 6.65 (m, Ph). FT-IR (KBr)
n 3437 (OH),
1771 cmꢀ1 (lactone). MS m/z (%): 416 (Mþ, 26), 398 (5), 356 (4), 279
(4), 257 (18), 243 (11), 221 (15), 197 (100), 169 (52), 150 (28), 137
(49), 123 (15), 109 (17), 84 (58), 57 (38). Anal. Calcd for C22H24O8:
C, 63.45; H, 5.81. Found: C, 63.25; H, 4.96.
6.1.9. (3S,4R)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-((S)-hydroxy
(4-nitrophenyl)methyl)- dihydrofuran-2(3H)-one (6d)
(d, 1H, J ¼ 7.7 Hz, Ph), 7.65 (d, 1H, J ¼ 7.7 Hz, Ph). FT-IR (KBr)
n 3456
(OH), 1744 cmꢀ1 (lactone). MS m/z (%): 362 (Mþþ2, 6), 361 (Mþþ1,
10), 360 (Mþ, 30), 284 (9), 257 (8), 220 (21), 191 (10), 165 (18), 135
(100), 115 (15), 85 (30), 77 (48), 57 (23). Anal. Calcd for C19H17ClO5:
C, 63.25; H, 4.75. Found: C, 63.48; H, 4.69.
Yield 65% as a mixture of diasteromers (syn/anti: 15/85), syn
diasteromer:1H-NMR (500 MHz, CDCl3)
d
: 2.05 (dd, 1H, J ¼ 9.0 Hz,
J ¼ 13.7 Hz, -H6), 2.21 (dd, 1H, J ¼ 9.0 Hz, J ¼ 13.7 Hz, -H6), 2.54
(m, 1H, -H4), 2.67 (t, 1H, J ¼ 8.1 Hz, -H3), 3.92 (t, 1H, J ¼ 8.0 Hz, -H5),
4.03 (brs, 1H, -OH), 4.47 (t, 1H, J ¼ 8.0 Hz, -H5), 5.46 (brs, 1H, -H7),
5.82 and 5.88 (2s, 2H, -O-CH2-O), 6.03 (s, 1H, Ar), 6.33 (d, 1H,
J ¼ 7.5 Hz, Ar), 6.60 (d, 1H, J ¼ 7.5 Hz, Ar), 7.37 (d, 2H, J ¼ 8.2 Hz, Ph),
6.1.12. (þ) (3R,4R)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-benzyl-
dihydrofuran-2(3H)-one (6g)
25
[a
]
þ 4.8ꢁ (c ¼ 0.0013, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d:
D
8.14 (d, 2H, J ¼ 8.2 Hz, Ph). FT-IR (KBr)
n
3440 (OH), 1749 cmꢀ1
2.24 (dd, 1H, J ¼ 6.0 Hz, J ¼ 12.9 Hz, -H6), 2.46 (m, 1H, -H4), 2.56
(sextet, 1H, J ¼ 5.1, Hz, J ¼ 7.5 Hz, J ¼ 10.7 Hz, -H3), 2.95 (dd, 1H,
J ¼ 7.5 Hz, J ¼ 14.0 Hz, -H7), 3.13 (dd, 1H, J ¼ 5.1 Hz, J ¼ 14.0 Hz, -H7),
3.86 (dd, 1H, J ¼ 7.8 Hz, J ¼ 9.2 Hz, -H5), 4.10 (dd, 1H, J ¼ 7.3 Hz,
J ¼ 9.2 Hz, -H5), 5.95 (s, 1H, -O-CH2-O), 6.44 (m, 2H, Ar), 6.69 (d, 1H,
J ¼ 8.3 Hz, Ar), 7.19 (d, 2H, J ¼ 7.0 Hz, Ph), 7.24 (m, 1H, Ph), 7.324
(lactone). MS m/z (%): 371 (Mþ, 8), 279 (20), 257 (85), 243 (42), 229
(21), 213 (21), 167 (35), 149 (100), 135 (52), 115 (47), 97 (34), 83 (55),
69 (100), 55 (85). Anal. Calcd for C19H17NO7: C, 61.45; H, 4.61.
Found: C, 61.38; H, 4.78; anti diasteromer: 1H-NMR (500 MHz,
CDCl3)
d
: 2.23 (dd, 1H, J ¼ 6.0 Hz, J ¼ 13.8 Hz, -H6), 2.35 (dd, 1H,
J ¼ 8.9 Hz, J ¼ 13.8 Hz, -H6), 2.51 (m, 1H, -H4), 2.69 (t, 1H, J ¼ 8.1 Hz,
-H3), 3.96 (dd, 1H, J ¼ 7.8 Hz, J ¼ 9.2 Hz, -H5), 4.02 (brs, 1H, -OH),
4.24 (dd, 1H, J ¼ 8.2 Hz, J ¼ 9.2 Hz, -H5), 5.01 (d, 1H, J ¼ 7.7 Hz, -H7),
5.93 (d, 1H, J ¼ 9.9 Hz, -O-CH2-O), 6.29 (s, 1H, Ar), 6.39 (d, 1H,
J ¼ 7.9 Hz, Ar), 6.69 (d, 1H, J ¼ 7.9 Hz, Ar), 7.59 (d, 2H, J ¼ 8.7 Hz, Ph),
(m, 2H, Ph). FT-IR (KBr) n
1774 cmꢀ1 (C]O). MS m/z (%): 310 (Mþ,
54), 284 (10), 207 (11), 162 (14), 135 (100), 105 (15), 91 (24), 77 (19),
57 (12). Anal. Calcd for C14H18O4: C, 73.53; H, 5.85. Found: C, 73.64;
H, 5.66.
8.26 (d, 2H, J ¼ 8.7 Hz, Ph). FT-IR (KBr)
n
3445 (OH), 1748 cmꢀ1
6.2. Cytotoxic assay [22]
(lactone). MS m/z (%): 371 (Mþ, 10), 341 (10), 306 (10), 279 (17), 257
(87), 243 (42), 229 (21), 213 (21), 185 (15), 161 (35), 149 (95), 135
(52), 115 (49), 97 (38), 83 (59), 69 (100). Anal. Calcd for C19H17NO7:
C, 61.45; H, 4.61. Found: C, 61.55; H, 4.45.
Breast cancer human cell lines including MDA-MB 231, MCF-7
and T47D (human breast duct carcinoma; ATCC HTB-133 estrogen
receptor-positive, ERþ) was obtained from Pasture institute, Tehran
(Iran). Cells were maintained in RPMI 1640 with added 10% FBS,
6.1.10. (3S,4R)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(hydroxy(2-
nitrophenyl)methyl)-dihydrofuran-2(3H)-one (6e)
1% L-Glutamine, and Penicillin-Streptomycin, and then cells were
incubated at 37 ꢁC in a 5% concentration of CO2. Cells were har-
vested by Trypsin-EDTA and re-suspended in fresh medium. Cell
survival was determined by MTT colorimetric assay. Exponentially
growing cells (4 ꢄ 104 cells/well) were seeded in 96-well plates in
RPMI with 10% FBS and incubated for 24 h. After treatment of
cells with different concentrations of test compounds for 24 h at
37 ꢁC, the medium was removed and phenol red-free medium
with FBS was added to cells. Then MTT solution was added to
each well (2 mg/ml), followed by 4 h incubation. The viable cell
number is directly proportional to the production of formazan,
which, following solubilization with isopropyl alcohol, can be
measured spectrophotometrically at 492 nm by an ELISA plate
reader. In each plate, there were control wells (cells without test
compounds) and blank wells (the medium only or 0.1% DMSO). The
percentage of cell viability versus controls was assessed by the
formula [1 e (absorbance of treated cells/absorbance of control
cells)] ꢄ 100.
Yield 73% as a mixture of diasteromers (anti/syn: 35/65): 1H-
NMR (500 MHz, CDCl3)
2.35anti (dd, J ¼ 8.4 Hz, J ¼ 13.8 Hz, -H6), 2.38
d
: 2.12anti (dd, J ¼ 7.3 Hz, J ¼ 13.8 Hz, -H6),
(dd, J ¼ 9.8 Hz,
syn
J ¼ 13.6 Hz, -H6), 2.49 syn (dd, J ¼ 5.3 Hz, J ¼ 13.6 Hz, -H6), 2.77anti (m,
-H4), 2.80 anti (dd, J ¼ 6.3 Hz, J ¼ 8.0 Hz, -H3), 2.83 syn (m, -H4), 2.96
syn (dd, J ¼ 2.6 Hz, J ¼ 6.7 Hz, -H3), 3.90anti (t, J ¼ 8.1 Hz, -H5), 3.95 syn
(dd, J ¼ 6.3 Hz, J ¼ 8.8 Hz, -H5), 4.30anti (t, J ¼ 7.6 Hz, -H5), 4.36syn
(t, J ¼ 8.5 Hz, -H5), 5.30 (brs, -OH), 5.53 anti (d, J ¼ 6.3 Hz, -H7), 5.92
(2s, 2H, -O-CH2-O), 6.05 syn (d, J ¼ 2.6 Hz, -H7), 6.20 anti (s, Ar), 6.25
syn (dd, J ¼ 7.9 Hz, Ar), 6.45 syn (s, Ar), 6.55 syn (d, J ¼ 7.9 Hz, Ar), 6.68
anti (d, J ¼ 8.3 Hz, Ar), 7.48 (dd, 1H, J ¼ 7.6 Hz, J ¼ 8.0 Hz, Ph), 7.67 anti
(t, 1H, J ¼ 7.3 Hz, Ph), 7.73
(t, 1H, J ¼ 7.9 Hz, Ph), 7.88
syn
anti
(d, J ¼ 7.7 Hz, Ph), 7.93
(d, J ¼ 8.5 Hz, Ph), 8.03 (m, 1H, Ph). 13
C
syn
NMR (125 MHz, CDCl3) d: 36.5, 38.3, 39.3, 39.3, 40.5, 50.5, 51.6, 67.9,
68.5, 72.0, 72.3, 101.0, 108.2, 108.4, 108.6, 113.8, 121.4, 121.5, 124.2,
125.2, 128.5, 128.7, 129.1, 129.6, 131.2, 133.4, 133.7135.8, 137.0, 146.5,
147.6, 177.5, 177.8. FT-IR (KBr)
n
3425 (OH), 1779 cmꢀ1 (lactone). MS
m/z (%): 371 (Mþ, 10), 341 (10), 306 (10), 269 (12), 257 (20), 236
(25), 219 (25), 185 (12), 161 (30), 149 (38), 137 (30), 111 (30), 97 (30),
91 (80), 69 (100), 55 (85). Anal. Calcd for C19H17NO7: C, 61.45; H,
4.61. Found: C, 61.62; H, 4.56.
Acknowledgement
This research was supported by a grant from Iran National
Science Foundation (INSF). Special thanks to Miss A. Javidnia and
Mr. K. Abdi for their helps in measuring NMR and IR spectra.
6.1.11. (3S,4R)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(hydroxy(2-
chlorophenyl)methyl)-dihydrofuran-2(3H)-one (6f)
References
Yield 70% as a mixture of diasteromers (syn/anti: 38/62), syn
diasteromer:1H-NMR (500 MHz, CDCl3)
J ¼ 13.7 Hz, -H6), 2.35 (dd, 1H, J ¼ 9.0 Hz, J ¼ 13.7 Hz, -H6), 2.63
d
: 2.09 (dd, 1H, J ¼ 6.1 Hz,
[1] Y.-L. Chen, S.-Z. Lin, J.-Y. Chang, Y.-L. Cheng, N.-M. Tsai, S.-P. Chen, W.-
L. Chang, H.-J. Harn, Biochem. Pharmacol. 72 (2006) 308e319.