L. G. León et al. / Bioorg. Med. Chem. 17 (2009) 6251–6256
6255
2
9
ꢀ1
7
1
6%). ½
a
ꢂ
ꢀ35.8 (c 1, CHCl
3
); IR (KBr, cm ): 3450, 1710, and
D
620 cm 1; H NMR (CDCl
ꢀ
1
, TMS, 200 MHz), d (ppm): 6.09 (d,
3
J = 1.5 Hz, 1H), 5.51 (s, 1H), 3.70 (s, 3H), 1.07 (s, 3H), 0.86 (s, 3H).
1
3
C NMR (CDCl
4.69, 51.58, 44.25, 43.11, 40.67, 40.16, 34.38, 27.05, 26.21,
2.21, 19.87, 18.48. Anal. Calcd for C16 : 72.14; H, 9.84; 0,
8.02. Found: C. 71.95; H, 9.97; 0, 18.35.
3
, 50.25 MHz) d: 167.71, 145.41, 122.38, 72.14,
5
2
1
24 2
H O
3
.2.4. c-Costic acid methyl esther. Methyl 2-((2R,4aR)-4a,8-
dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)acrylate (7)
The general esterification method was applied to -costic acid
5, 500 mg, 2.13 mmol) to give compound 7 as an oil (428 mg,
c
(
8
1
1%). H NMR (CDCl
3
, TMS, 200 MHz), d (ppm): 6.15 (s, 1H), 5.56
(
s, 1H), 3.75 (br s, 1H), 1.05 (s, 3H), 1.60 (s, 3H), 2.65 (d, 1H),
.69 (br s, 1H), 2.40 (m, 1H), 1.75–1.44 (m, 2H). C NMR (CDCl ,
3
0.25 MHz) d: 167.80, 142.62, 134.24, 125.08, 122.26, 51.68,
1
3
1
5
4
1
2.07, 41.50, 40.10, 34.37, 33.04, 31.32, 27.96, 24.54, 19.24,
+
+
9.00. MS (EI ) calcd for C16
24 2
H O [M ] 248.36, found 248.
3
.2.5. Tessaric acid methyl esther. Methyl 2-((2R,8S,8aR)-8,8a-
dimethyl-6-oxo-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-
yl)acrylate (9)
The general esterification method was applied to tessaric acid
(
(
8, 500 mg, 2.02 mmol) to give compound 9 as a yellow oil
1
417 mg, 79%). H NMR (CDCl
3
, TMS, 200 MHz), d (ppm): 3.76 (s,
3
5
1
1
3
C
H), 1.06 (s, 3H), 0.97 (s, J = 8 Hz 3H), 6.19 (s, 1H), 5.57 (s, 1H),
0
0
.86 (s, 1H), 2.58 (m, 1H), 1.55 (dd, J = 6,6 = 6,7 = 6 ,7 = 14 Hz,
1
3
3
H), 1.72-1.86 (m, 1H). C NMR (CDCl , 50.25 MHz) d: 199.5,
73.86, 167.39, 144.25, 125.65, 123.15, 42.00, 40.26, 39.4, 35.81,
+
2.63, 29.18, 28.85, 19.02, 15.34. 51.86 (OMe). MS (EI ) calcd for
+
16
24
H O
2
[M ] 262.34, found 262.
3
1
.2.6. Methyl 2-((2R,6R,8S,8aR)-6-hydroxy-8,8a-dimethyl-
,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)acrylate (10)
To a stirred solution of 9 (327 mg, 1.25 mmol) in dry THF
(
1
1
10 mL) in an ice-cold bath was added slowly LiAlH
4
(69 mg,
O (70 L),
2
O (2.7 mL) were sequen-
.88 mmol). After 25 min to the reaction mixture H
5% NaOH aqueous solution 70 L) and H
2
l
l
tially added with stirring. The mixture was allowed to reach rt,
dried over MgSO , filtered through a pad of celite, concentrated,
and purified by silica gel column chromatography, to yield 10
4
2
D
0
1
(
(
(
273 mg, 83% yield) as an oil. ½
CDCl , TMS, 200 MHz), d (ppm): 6.12 (s, 1H), 5.54 (s, 1H) y 5.42
s, 1H), 4.27 (m, 1H), 0.93 (s, 3H), 0.87 (d, J = 8.0 Hz, 3H).
, 50.25 MHz) d: 167.61, 148.89, 145.03, 122.53,
19.82, 96.08, 71.52, 40.35, 35.74, 32.85, 32.63, 29.68, 26.07,
a
ꢂ
ꢀ59.8 (c 1, CHCl
3
); H NMR
3
13
C
NMR (CDCl
1
2
3
+
+
1.47, 15.65, 51.69 (OMe). MS (EI ) calcd for C16
24 3
H O [M ]
Figure 5. Representative results of drug schedule 24+24. Cell cycle phase distri-
bution in untreated cells (C) and cells treated with compounds 9 and 10, at low (L)
and high (H) dose concentrations; (a) T-47D and (b) WiDr. Histogram of cells after
264.04, found 264. Anal. Calcd for C16
H
24
O
3
: C, 72.69; H, 9.15; O,
1
8.16. Found: C, 72.63; H, 9.01; O, 18.36.
.3. 2D-QSAR studies
All computational studies were performed using E-DRAGON
exposure to analog 10 at 35 lM: (c) T-47D; (d) WiDr.
3
3
.2.2.
octahydronaphthalen-2-yl)acrylic acid (5)
Compound 5 was obtained according known procedures. 1H
NMR (CDCl , TMS, 200 MHz), d (ppm): 6,37 (s, 1H), 5,71 (s, 1H),
.75 (s, 3H), 2.63 (ddd, 1H), 2,42 (m, 1H), 1.95 (m, 2H), 1.61 (s,
c-Costic acid. 2-((2R,4aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,7-
7
11
3
application for the calculation of molecular descriptors DRAGON.
Six descriptors were used in this study: ALOGP, Ghose-Crippen oct-
anol–water partition coefficient (log P); TPSA, topological polar
surface area; AMR, molar refractivity; Sp, sum of atomic polariz-
abilities (scaled on Carbon atom); nHDon, number of donor atoms
for H-bonds; and nHAcc, number of acceptor atoms for H-bonds.
Molecular structure files with 3D optimized structures were ob-
regression (MLR) was performed with MicrosoftÒ Office Excel
2007 (Microsoft Corporation, WA, USA).
3
1
1
3
C
H), 1,07 (s, 1H), 1 C NMR (CDCl
3
, 50.25 MHz) d: 167.8, 145.6,
3
34.24, 125.08, 122.46, 122.36, 51.68, 42.06, 40.51, 40.10, 34.36,
+
3.05, 31.32, 27.96, 24.54, 19.24, 10.0. HRMS (EI ) calcd for
+
15
H
22
O
2
[M ] 234.1619, found 234.
3
.2.3. Ilicic acid methyl esther. Methyl 2-((2R,4aR,8R)-8-
hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl)acrylate (6)
Ò
The general esterification method was applied to ilicic acid (4,
5
00 mg, 1.98 mmol) to give compound 6 as a yellow oil (404 mg,