Synthesis and biological evaluation of 2,3,4-triarylbenzopyran derivatives as SERM and therapeutic agent for breast cancer

Article abstract of DOI:10.1016/j.bmc.2009.08.034

A novel class of 2,3,4-triarylbenzopyrans has been synthesized and were evaluated for their selective estrogen receptor modulation activity and as a therapeutic agent for breast cancer. Among the compounds synthesized, compounds 11a and 12c exhibited 73.9

Full text of DOI:10.1016/j.bmc.2009.08.034

Bioorganic & Medicinal Chemistry 17 (2009) 6832–6840
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological evaluation of 2,3,4-triarylbenzopyran derivatives
as SERM and therapeutic agent for breast cancer q
Shailesh Kumar a, Shreekant Deshpande a, Vishal Chandra b, Shakti Kitchlu b, Anila Dwivedi b,
Vadithe Lakshma Nayak b, Rituraj Konwar b, Yenamandra S. Prabhakar a, Devi Prasad Sahu a,
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
b Endocrinology Division, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of 2,3,4-triarylbenzopyrans has been synthesized and were evaluated for their selective
estrogen receptor modulation activity and as a therapeutic agent for breast cancer. Among the com-
pounds synthesized, compounds 11a and 12c exhibited 73.91% and 69.24% inhibition as estrogen antag-
Received 29 May 2009
Revised 15 August 2009
Accepted 18 August 2009
Available online 21 August 2009
onistic activity, respectively. Compound 12a showed the lowest IC50 at 6.97
showed the lowest IC50 value of 5.6 M against MDA-MB-231 cell line in spite of their low receptor bind-
ing affinity implicating these compounds probably act through ER independent mechanism.
Ó 2009 Elsevier Ltd. All rights reserved.
lM against MCF-7 and 11f
l
Keywords:
SERMs
Therapeutic agent for breast cancer
Estradiol
2,3,4-Triarylsubstituted dihydrobenzopyran
4-Acetoxy-2,3–diaryldihydrobenzopyran
1. Introduction
ein, and coumestrol exhibit a moderate selectivity for ERb and pos-
sess a common benzopyran motif. Further exploitation of the
chroman scaffold has also provided some non-subtype selective,
potent chromenes I,11 II,12 and III13 as SERMs of commercial inter-
est (Fig. 1).
Estrogens are known to play an important role in the regulation
of the development and maintenance of the female reproductive
system, in particular of the uterus, ovaries and breast. Moreover,
estrogens are involved in the growth and/or function of several
other tissues such as the bone, liver, brain, and the cardiovascular
system.1 More recently their involvement in the estrogen deficient
syndrome such as osteoporosis, Alzheimer, and cardiovascular dis-
eases in females as well as males has also been established.2–4
By definition, selective estrogen receptor modulators (SERMs)
are ligands that exert estrogen agonist action in some target tissues
while acting as estrogen antagonists in others tissues.5 In this light,
at first tamoxifen,6 and later a second generation compounds with
an agonist/antagonist behavior7 were developed and among them,
raloxifene8 was the first selective estrogen receptor modulator
SERM approved for the treatment and prevention of osteoporosis
(Fig. 1). The efforts to obtain compounds with a better activity pro-
file led to a third generation of SERMs characterized by improved
potency and absence of adverse effects, such as those on breast
and the cardiovascular system.9 In medicinal chemistry the benzo-
pyran/chroman scaffold are present in wide variety of biologically
active molecules.10 The naturally occurring leads genistein, daidz-
A number of 2,3-disubstituted and 3,4-disubstituted benzopy-
ran derivatives10a,11,12 have been reported as potential estrogen
antagonists/SERMs. CDRI-85/28714 and EM-65215 among 2,3-
disubstituted benzopyrans, are potent estrogen antagonists. Orme-
loxifene (centchroman), a 3,4-disubstituted benzopyran derivative
is an oral contraceptive and anti-breast cancer agent. The stereo-
specific presence of different aryl substituents in the pyran ring
was also found to affect the activity. Based upon the above find-
ings, and to extend the scope of ER ligands through introducing
an additional phenolic ether basic side chain, it was envisaged that
a hybrid of 2,3-diaryl and 3,4-diaryldihydrobenzopyran, that is,
2,3,4-triarylbenzopyran would have superior SERM activity. We
herein present synthesis and invitro anti-breast cancer activity of
a novel class of trans, trans-2,3,4-triarylsubstituted benzopyran
IV and related diaryl benzopyran (Fig. 2). The rationale to design
stereospecifically substituted 2,3,4-triarylbenzopyran was to build
a scaffold with stereospecific alignment of three aryl substituents
based on precedented ligands or leads. Structural resemblance of
2,3,4-triarylsubstituted benzopyran of prototype IV in ring A, B,
D, and E to ormeloxifene, and in ring A, B, D, and F to CDRI 85/
287 and EM 652 prompted us to explore this pharmacophore as
potential lead for developing new estrogen receptor ligands.
q
CDRI Communication No. 7778.
* Corresponding author. Tel.: +91 522 2612415x4378; fax: +91 522 2623405.
E-mail addresses: dpsahuin@yahoo.com, dp_sahu@cdri.res.in (D.P. Sahu).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.08.034

S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
6833
N
O
O
N
OH
O
O
O
OH
HO
HO
S
OH
WS-7528
Raloxifene
Tamoxifen
O
N
OCH3
OH
O
OH
O
R4 R5
HO
Z
HO
O
III CHF 4227
HO
O
O
N
N
I
II
Z = CO, S
Figure 1. Structures of some important SERMs.
R
O
OH
E
D
D
F
D
A
B
O
B
A
B
O
A
R
O
HO
F
O
N
N
O
O
Ormeloxifene
EM 652
CDRI 85/287
R
O
D
C
E
A
B
D
F
HO
B
O
A
estradiol
R
O
IV
Figure 2. Structural resemblance of 2,3,4-triaryl benzopyrans I to potential SERMs.
non-polarity of the compound so as to make it soluble in non po-
lar solvents commonly used for aluminum chloride catalyzed
reactions. Herein, we used benzene–hexane mixture (3:1) as an
optimal reaction solvent for the deacetylative arylation of phe-
nols. The diacetylated benzopyran 5 was regio-selectively arylat-
ed by phenol in stereospecific manner in the presence of
anhydrous aluminum chloride to obtain trans, trans-2,3,4-trisub-
stituted-2,3-dihydro-4H-1-benzopyran, (2,3,4-triarylchroman), 6
in quantitative yield. This route was much more facile and gave
the optimal yield, compared to arylation of phenol with monohy-
droxy chroman 7, dihydroxy compound 8 or monoacetylated
chromene 9 (Scheme 2). Compound 10 was obtained by basic
hydrolysis of 6.
2. Chemistry
The titled compounds were synthesized by selective deacetyla-
tive direct arylation of arene 5 with phenol by aluminum chloride
catalyzed C–H and C–OAc bond functionalization (Scheme 2). The
diacetylated compound 5 was prepared by successive reduction
and acetylation of compound 2. Dihydrobenzopyran-4-one 2 was
prepared by base catalyzed condensation of 4-hydroxybenzalde-
hyde with 20-hydroxy-2-phenylacetophenone 1 by a known meth-
od.16 Chalcone 3 as side product was also formed along with
compound
2
and could be easily separated by column
chromatography.
The 4-hydroxy-2,3-dihydro-4H-1-benzopyran 4 was prepared
from dihydrobenzopyran-4-one 2 by sodium borohydride reduc-
tion in mixture of methanol–THF (1:1). (Scheme 1).
The trans, trans geometry in compound 6 was confirmed by the
1H NMR experiment. The appearance of a proton triplet at d 3.24 is
assigned for H-3 (J = 10.8 Hz) and two doublets at
d 4.46
trans-2,3-Disubstituted-2,3-dihydro-4H-1-benzopyran-4-ol
4
(J = 11.2 Hz) and d 5.24 (J = 10.4 Hz) for H-4 and H-1, respectively,
was further acetylated by acetic anhydride to the diacetylated
compound 5. The purpose of acetylation was to increase the
is a characteristic features in the 1H NMR spectrum of compound 6.

6834
S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
O
CHO
O
O
O
benzene, piperidine
reflux, 48h
+
+
OH
OH
1
OH
2
OH
OH
3
NaBH4, MeOH:THF mixture (1:1)
0 ºC, 3h
OH
O
4
OH
O
O
O
O
O
5
Scheme 1.
OH
OH
3
O
O
O
O
7
O
4
PhOH, AlCl3 (1.2mmol),
3
2
O
benzene-hexane
(3:1)
O
O
O
1
O
6
5
O
OH
OH
PhOH
AlCl3 (1.2mmol),
benzene; 10%
O
OH
8
O
O
O
OH
10
9
O
Scheme 2.
The J values together indicated the trans, trans relationship be-
tween these three protons.
3. Results and discussion
A series of compounds 11a–f, 13, and 14 with different basic
ether side chains were prepared in the usual manner by alkylation
of the phenol 6, 2, and 4, respectively, with corresponding ammo-
nium hydrochloride in presence of potassium carbonate in acetone
(Scheme 3). Basic hydrolysis of compound 11a, c, and d afforded
12a–c (Scheme 4).
In order to prepare compounds 13 and 14 with basic ether side
chains at position 4 of 2-hydroxy phenyl ring of dihydrobenzopy-
ran-4-one 2 and its reduced product 4, compounds 2 and 4 were
alkylated with the corresponding amine hydrochloride under the
similar conditions as mentioned above (Scheme 5 and 6).
The biological activities results are shown in Table 1. The com-
pounds 11a, c, e, and f administered orally showed an average
estrogenic activity of >100% gain except compound 11b with estro-
gen-like activity of 41.2%. The same compounds 11a, c, e, and f also
possessed estrogen antagonistic activity >30% to a highest value of
73.91% shown by compound 11a, but the compound 11a possessed
the estrogenic activity of 146.6% compared to centchroman. The
compounds 12a–c with free hydroxyl group in the phenyl ring
at position 2, showed enhanced estrogen antagonistic activity
from 51.47% to 69.24% with a decrease in estrogenic activity
from 28.20% to 11.25% for compounds 12b and 12c, respectively.

S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
6835
OH
R
O
O
R-Cl.HCl (1mmol), K2CO3 (2 mmol)
acetone, reflux, 5h.
O
O
O
O
O
6
11
R =
N
N
N
N
N
N
d
c
f
e
a
b
Scheme 3.
R
R
O
O
activity of 124.5% (14) to 13.17% (13). Compounds 6 and 10 with-
out basic ether side chain in any of the phenyl rings possessed
higher estrogenic activity compared to compounds with basic
ether side chains.
O
O
KOH, methanol
reflux, 3 h.
In order to rationalize the anti-estrogenic profile of the benzo-
pyran derivatives (Table 1), molecular docking studies were per-
formed involving 12b and other known structurally related
molecules namely, centchroman, and EM-652.17 The reference pro-
tein coordinates of crystal structures of ligand binding domains
(LBDs) of estrogen receptor complexed with 4-hydroxytamoxifen
(pdb code: 3ERT) and 17b-estradiol (pdb code: 1ERE) were used
for the docking experiments. The docking study was carried out
in molecular operating environment MOE.18 The starting confor-
mations of 12b, centchroman, and EM-652 were generated in
MOE using systematic conformational search with energy minimi-
zation (forcefield, MMFF94x). These conformations were flexibly
docked into the protein coordinates (3ERT and 1ERE) to take their
final shapes. The docking orientation and interactions of the 12b,
O
O
OH
11 a, c, d
12
R =
N
N
N
12b
12a
12c
Scheme 4.
centchroman, and EM-652 within the LBD of ERa are shown in Fig-
Compound 13 with a carbonyl function and compound 14 with a 2°
hydroxyl group at position 4 of benzopyran ring together with an
ethoxy pyrrolidine side chain at position 4 of 2-substituted phenyl
ring were tested, and it was found that the estrogen antagonistic
activity of compound 13 (45.39%) is comparatively higher than
14 (29.01%). There is also a remarkable decrease in estrogenic
ure 1 along with 4-hydroxy tamoxifen and 17b-estradiol. In the
docking study, the core skeleton benzopyran and its 3- and 4-aryl
rings have favorably positioned similar to 4-hydroxy tamoxifen
(Fig 1a). Also, centchroman, and EM-652 have docked in ERa as ex-
pected for their anti-estrogenic property (Fig. 1a). However, in the
O
O
R-Cl.HCl (1mmol),
K2CO3 (2 mmol), acetone, reflux, 5h.
O
O
R
13
O
2
OH
N
R =
Scheme 5.
OH
O
OH
O
R-Cl.HCl (1mmol),
H
K2CO3 (2 mmol), acetone, reflux, 5h.
H
R
14
O
OH
4
R =
Scheme 6.
N

6836
S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
Table 1
Estrogen agonistic and antagonistic activities of triarylbenzopyrans and their anti-proliferative activities
Entry Compd Dose (oral) (mg/kg/day) Estrogen antagonistic activity18 Estrogen agonistic activity18 RBA17 (% of E2) Anti-proliferative activity19 (IC50 in
lM)
Uterine
weighta
(mg)
Inhibitionb (%) Uterine
Gainc (%)
MCF-7
MDA-MB-231
HEK-293
weighta
(mg)
1
2
Control
EE
11a
Control
EE
11b
Control
EE
11c
Control
EE
11e
Control
EE
11f
Control
EE
12a
Control
EE
12b
Control
EE
12c
Control
EE
13
Control
EE
14
Control
EE
6
Control
EE
10
15.2 1.24
113.68
15.2 1.24
113.68
0.02
10
40.77 0.59
33.8 0.97
112.5 2.50
65.8 1.20
14.48 0.88
104.82 1.64
64.62 1.11
14.48 0.88
104.82 1.64
85.42 0.79
15.02 1.24
113.68
41.14 1.51
14.48 0.88
104.82 1.64
47.06 1.76
33.8 0.97
112.5 2.50
72.0 1.54
33.8 0.97
112.5 2.50
58.0 1.09
16.68 0.51
96.75 1.25
60.38 1.97
15.02 1.24
113.68
73.91
59.3
37.0 0.59
33.8 0.97
112.5 2.50
47.8 0.97
14.48 0.88
104.82 1.64
39.32 1.29
14.48 0.88
104.82 1.64
30.17 3.13
15.02 1.24
113.68
32.63 4.76
14.48 0.88
104.82 1.64
47.01 1.76
33.8 0.97
112.5 2.50
36.6 2.40
33.8 0.97
112.5 2.50
37.6 0.68
16.68 0.51
96.75 1.25
38.66 0.42
15.02 1.24
113.68
146.6
41.2
0.01
0.184
0.083
0.15
0.15
0.1
Inactive
11.66
Inactive
Inactive
14
ND
0.02
10
16.11
29.79
88.63
13.99
20.47
38.3
3
0.02
10
51.41
30.61
58.4
171.4
108.3
117.2
225
16.84
4
0.02
10
Inactive
10.95
Inactive
5.61
5
0.02
10
6
0.02
10
68.97
51.47
69.24
45.39
29.01
4.2
6.97
7.48
7
0.02
10
28.2
0.53
0.25
0.109
NIL
7.79
8.65
8
0.02
10
11.25
13.17
124.5
105.18
142.9
164.3
208.8
18.36
17.75
Inactive
Inactive
Inactive
Inactive
ND
36.27
34.02
ND
9
0.02
10
Inactive
Inactive
Inactive
Inactive
ND
10
11
12
13
14
0.02
10
86.22 1.85
21.2 0.80
85.0 1.0
84.7 1.89
21.2 0.80
85.0 1.0
71.5 1.91
17.4
101.23
33.73 0.42
21.2 0.80
85.0 1.0
43.5 0.87
21.2 0.80
85.0 1.0
51.5 0.96
17.4
101.23
0.02
10
0.07
0.09
5.24
2.33
>100
>500
0.02
10
21.2
Control
EE
0.02
Cent.d 10
Control
36.0
77.9
46.0
15.0 0.57
66.35 0.44
52.3 5.3
15.0 0.57
66.35 0.44
46.32 2.92
EE
3
TAMe
27.4
7.65
9.86
EE = 17
a
-ethynylestradiol; E2 = 17b-estradiol; ND: not done.
a
Values represent means SEM of a minimum of six observations in each group.
Percent of 17a-ethynylestradiol per se treated group.
Percent of vehicle control group.
b
c
d
e
Centchroman.
Tamoxifen.
LBD of 1ERE, the 12b, centchroman, and EM-652 have docked in
different postures when compared to that of estradiol (Fig 1b).
The absence of 7-hydroxyl on benzopyran scaffold made all the dif-
ference in the docking posture of these analogues. In docking
dynamics a 7-hydroxyl group on benzopyran scaffold may have
fulfilled the 2-OH role of estradiol. This may explain the weak
estrogenic property of these compounds (Fig. 3).
All the above compounds were also evaluated for anti-prolif-
erative activity. Two compounds 12a and 12b were found to pos-
sessed significant anti-proliferative activity similar to that of
tamoxifen against MCF-7 and MDA-MB-231 cancer cell lines.
Compounds having estrogenic activity are usually considered to
have promoting activity in breast cancer. From estrogenicity re-
sults compound 12a (225%) appeared to have higher estrogen-
like activity than 12b (28.2%). Therefore, though compound 12a
devoid of high estrogenicity. Compound 12b (0.53%) showed
highest RBA followed by 12c (0.25%). Compounds 11c (0.083%),
11e and 11f (0.15%), 13 (0.109%) and 6 (0.07%) and 10 (0.09%)
showed very low affinity for estrogen receptor whereas com-
pound 14 is completely devoid of affinity for estrogen receptor.
From RBA results, it appears that the compound 12b may interact
with estrogen receptor with moderate affinity and thereby, there
is possibility that its anti-proliferative activity may be mediated
by such interaction. Interestingly, 12a although exhibited reason-
ably higher anti-breast cancer activity and estrogenic activity
(225%), the compound failed to interact significantly with estro-
gen receptor (Table 1). Compound 12c which exhibited marginal
anti-proliferative activity, however, showed highest anti-estro-
genic activity (69.24%) and moderately low estrogen-like activity
(11.25%).
has better anti-proliferative activity with IC50 6.971
l
M
and
The compounds were also tested for their non-specific cyto-
toxicity in non-cancer originated cell line HEK-293. The results
7.482 M against MCF-7 and MDA-MB-231, respectively, 12b is
l

S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
6837
was added into each tube, which was briefly vortexed and allowed to
stand for 15 min. DCC was precipitated by centrifugation
(800g ꢀ 10 min) and the supernatants counted for radioactivity in
5 mL of a dioxane-based scintillation fluid. RBA of the test compound
was computed from a graph plotted between percent bound radio-
activities versus log concentration of the test substance. At 50% inhi-
bition, log of the competitor concentration relative to that of
estradiol gave the affinity of the test compound to estrogen receptor
relative to estradiol. This when multiplied with 100 gave the per-
centage value designated as RBA.
4.2. Estrogen agonistic activity20
Twenty-one-day-old immature female Sprague–Dawley rats
were bilaterally ovariectomized under light ether anesthesia and
after post-operative rest for 7 days were randomized into different
treatment groups. Each rat received the compound once daily for
three consecutive days by oral route. A separate group of animals
received only the vehicle for similar duration served as control.
At autopsy 24 h after the last treatment on day 31 of age, vaginal
smear of each rat was taken and uterus was carefully excised,
gently blotted, and weighed. Premature opening of vagina, cornifi-
cation of vaginal epithelium, and increase in uterine fresh weight
were taken as parameters for evaluation of estrogen agonistic
activity in comparison to rats of vehicle control group. The objec-
tive was to evaluate estrogen agonistic effect of the compounds
on the uterus and vagina.
4.3. Estrogen antagonistic activity20
Twenty-one-day-old immature female Sprague–Dawley rats
were bilaterally ovariectomized under light ether anesthesia and
after post-operative rest for 7 days were randomized into different
treatment groups. Each rat received the compound of the invention
and 0.02 mg kgꢁ1 dose of 17
a
-ethynylestradiol in 10% ethanol–dis-
tilled water once daily for three consecutive days by oral route. A
separate group of animals receiving only 17 -ethynylestradiol
a
(0.02 mg kgꢁ1) in 10% ethanol–distilled water for similar duration
were used for comparison. At autopsy on day 31 of age, vaginal
smear of each rat was taken and uterus was carefully excised,
gently blotted, weighed, and fixed for histology. Inhibition in eth-
ynylestradiol induced cornification of vaginal epithelium and in-
crease in uterine fresh weight were taken as parameters for
evaluation of estrogen antagonistic effect of the compounds.
Figure 3. Superimposed docking poses of 12b, centchroman (backbone carbons in
green) and EM-652 (cyan) with (a) 4-OH-tamoxifen (brown) in 3ERT coordinates
and with (b) 17b-estradiol (megenta) in 1ERE coordinates of LBD of ERa.
revealed that compound 10 showed lowest cytotoxicity
(>500 M) followed by 6 (>100 M) and 11f (13.99 M). Also,
the compound 12a (20.47 M) appeared to be more toxic than
l
l
l
4.4. Anti-proliferative activity
l
12b (38.30 lM).
4.4.1. Cell lines
MCF-7 is a breast cancer cell line derived from pleural effusion
and most commonly used cell line for screening of anti-cancer
breast agents (Soule et al., 1973), whereas MDA-MB-231 is an ER
negative model of aggressive breast cancer.
4. Biology
4.1. Estrogen receptor binding affinity19
The relative binding affinity (RBA) of the compounds for the
estrogen receptor was determined15 by competition assay, employ-
ing radiolabeled estradiol 3H-[E2] as the reference compound. The
test ligands and 3H-[E2] were incubated (4 °C) with cytosol estrogen
receptors obtained from immature 20–21-day-old rat uteri. Aliquots
4.4.2. Assay for anti-proliferative activity
The anti-proliferative activities21 of the compounds were deter-
mined using MTT assay 1 ꢀ 104 cells/well were seeded in 100
lL
DMEM, supplemented with 10% FBS in each well of 96-well micro
culture plates and incubated for 24 h at 37 °C in a CO2 incubator.
Compounds, diluted to the desired concentrations in culture med-
ium, were added to the wells with respective vehicle control. After
of the uterine cytosol (100 lL) prepared in TEA buffer (10 mM Tris,
1.5 mM EDTA, and 0.02% sodium azide, pH 7.4) were incubated in
triplicate with a fixed concentration of radiolabeled estradiol with
or without various concentrations of the competitor substance dis-
solved in 30 lL of the TEA buffer containing DMF as co-solvent (final
concentration of DMF in the incubation medium never exceeded 5%)
for 18 h at 4 °C. At the end of this period, dextran-coated charcoal
(DCC) (2.5% Norit 0.25% dextran) suspension in 100 lL of TEA buffer
48 h of incubation, media were removed and to each well 100 lL
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bro-
mide) (5 mg/mL) was added and the plates were further incubated
for 4 h. Then the supernatant from each well was carefully re-
moved, formazon crystals were dissolved in 100
absorbance at 540 nm wavelength were recorded.
lL of DMSO and

6838
S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
128.32 (CH), 128.68 (CH), 128.69 (CH), 129.84 (CH), 136.38 (C),
5. Experimental
137.33 (C), 150.48 (C), 154.82 (C), 169.34 (CO), 171.04 (CO); mmax
(KBr, cmꢁ1) 1761, 1729, 1223, 1010, 764; ES-MS (m/z) 403 [M+H]+;
5.1. Preparation of 2-(4-hydroxyphenyl)-3-phenylchroman-4-
one (2)
½
a 2D0
ꢂ
ꢁ1.73, (c 0.337, CHCl3).
To a solution of 20-hydroxydesoxybenzoin 1 (26.5 g, 0.125 mol)
and 4-hydroxybenzaldehyde (15.3 g, 0.125 mol) in dry benzene
(300 mL) was added dry piperidine (0.01 mol, 1 mL). The mixture
was heated under reflux for 48 h, while water was removed azeo-
tropically. After completion of reaction, the reaction mixture was
cooled, and washed with water (30 mL ꢀ 3) and then with brine
and dried over sodium sulfate and concentrated. The residue was
purified on silica gel column chromatography using 10% EtOAc–
hexane as eluent, to furnish the dihydrobenzopyran-4-one 2
(12 g) which was recrystallized from EtOAc–hexane.
5.4. Typical procedure for preparation of acetic acid 4-[4-(4-
hydroxy-phenyl)-3-phenyl-chroman-2-yl]-phenyl ester (6)
To a cooled solution of phenol (2.4 g, 25 mmol) and aluminum
chloride (0.158 g, 1.2 mmol) in 100 mL benzene–hexane mixture
(3:1) at 0–5 °C, a mixture of compound 5 (10 g, 24.8 mmol) and
phenol (2.5 g, 25 mmol) in 100 mL benzene–hexane mixture
(3:1) was added dropwise in 30 min. The reaction mixture was al-
lowed to stir at this temperature during the addition, and then al-
lowed to stir at room temperature for the completion of reaction
(3 h). The reaction mixture was concentrated to 100 mL. To the
resulting mixture crushed ice (100 mL) was added with continuous
stirring for 15 min and then was extracted with EtOAc (50 mL ꢀ 3).
The organic layer was washed with water, brine and dried over so-
dium sulfate and concentrated. The crude product obtained was
further purified by column chromatography using 5–10% EtOAc–
hexane mixture as white solid (9.9 g).
Yield 32%; mp 195–196 °C; 1H NMR (300 MHz, CDCl3) d 4.17 (d,
1H, J = 11.5 Hz), 5.51 (d, 1H, J = 11.5 Hz), 6.72 (d, 2H, J = 8.5 Hz),
6.97–7.00 (m, 2H), 7.04–7.09 (m, 4H), 7.16–7.22 (m, 3H), 7.49–
7.56 (m, 1H), 7.97 (dd, 1H, J = 8.2 and 1.7 Hz), 8.49 (s, 1H, OH); 13C
NMR (75 MHz, CDCl3 + DMSO-d6) d 59.02 (CH), 84.27 (CH), 115.11
(CH), 117.84 (CH), 120.64 (C), 121.24 (CH), 126.87 (CH), 127.11
(CH), 128.05 (C), 128.11 (CH), 128.27 (CH), 129.37 (CH), 135.00 (C),
Yield 92%; mp 156–158 °C; 1H NMR (300 MHz, CDCl3) d 2.22 (s,
3H), 3.24 (t, 1H, J = 10.8 Hz), 4.46 (d, 1H, J = 11.2 Hz), 4.74 (s, 1H),
5.24 (d, 1H, J = 10.4 Hz), 6.57–6.59 (m, 2H), 6.77–6.84 (m, 6H),
6.88–6.91 (m, 2H), 6.96–7.06 (m, 4H), 7.14–7.19 (m, 3H); 13C NMR
(50 MHz, CDCl3) d 21.34 (CH3), 49.55 (CH), 55.19 (CH), 82.31 (CH),
115.33 (CH), 117.03 (CH), 121.01 (CH), 121.22 (CH), 126.77
(CH),126.82 (C), 127.86 (CH), 128.41 (C), 128.51 (CH), 128.81 (CH),
130.36 (CH), 130.39 (CH), 135.37 (C), 137.29 (C), 139.55 (C), 150.33
(C), 154.23 (C), 155.32 (C), 169.44 (CO); mmax (KBr, cmꢁ1) 3362,
1762, 1720, 1194, 759; ES-MS (m/z) 437 [M+H]+.
135.92 (CH), 157.26 (C), 160.98 (C), 192.70 (CO); mmax (KBr, cmꢁ1
3380, 1670, 1601, 1190; ES-MS (m/z) 317 [M+H]+.
)
5.2. Preparation of 2-(4-Hydroxy-phenyl)-3-phenyl-chroman-
4-ol (4)
To a solution of dihydrobenzopyran-4-one 2 (20 g, 0.06 mol) in
methanol–THF (1:1) (200 mL), cooled in an ice bath. Sodium boro-
hydride (6.8 g, 0.18 mol) was added in four portions at 5-min inter-
vals. The reaction mixture was then stirred for 4 h. The reaction
mixture was concentrated to 100 mL and the resulting solution
was neutralized with saturated NH4Cl solution and extracted with
ethyl acetate (50 mL ꢀ 3). The organic layer was washed with brine
and dried over sodium sulfate and concentrated. The solid residue
obtained was further crystallized from EtOAc–hexane to obtain
pure 4 (19.6 g).
5.5. General procedure for preparation of ethers (11a–f), (13)
and (14)
A mixture of compound 6 (1 mmol) for 11a–f or 2 (1 mmol) for
13 or 4 (1 mmol) for 14 and corresponding 1-(2-chloroethyl) alkyl
amine hydrochloride (1 mmol), anhydrous potassium carbonate
(2 mmol) in dry acetone (15 mL) was refluxed for 5 h. The reaction
mixture was then cooled to rt and the solid material was filtered
off and washed with acetone (5 mL ꢀ 3). The combined filtrate
was concentrated and the residue was purified by silica gel column
chromatography using 2% methanol–chloroform mixture.
Yield 98.3%; mp 165–167 °C; 1H NMR (300 MHz, CDCl3 + DMSO-
d6) d 3.22 (t, 1H, J = 10.5 Hz), 3.51 (br s, 1H, OH), 5.10–5.17 (m, 2H),
6.62 (d, 2H, J = 8.5 Hz), 6.87–6.89 (m, 1H), 6.94–7.04 (m, 5H), 7.08–
7.22 (m, 4H), 7.57 (d, 1H, J = 7.5 Hz), 8.43 (s, 1H); 13C NMR
(75 MHz, CDCl3 + DMSO-d6) d 54.03, 70.47, 81.66, 115.17, 116.21,
120.64, 126.13, 126.74, 127.44, 128.41, 128.64, 128.82, 129.57,
139.01, 139.04, 154.31, 156.73;
m
max (KBr, cmꢁ1) 3375, 1611, 1224,
ꢂ ꢁ1.56, (c 0.105, CHCl3).
5.5.1. Acetic acid 4-{4-[4-(2-diisopropylaminoethoxy) phenyl]-
3-phenylchroman-2-yl}phenyl ester (11a)
755; ES-MS (m/z) 319 [M+H]+; ½a D20
Yield 89.2%; mp 132–134 °C; 1H NMR (300 MHz, CDCl3) d 1.01 (d,
12H, J = 6.5 Hz), 2.22 (s, 3H), 2.75 (t, 2H, J = 7.5 Hz), 2.96–3.05 (m,
2H), 3.26 (t, 1H, J = 10.9 Hz), 3.78 (t, 2H, J = 7.6 Hz), 4.46 (d, 1H,
J = 11.2 Hz), 5.24 (d, 1H, J = 10.4 Hz), 6.64–6.67 (m, 2H), 6.78–6.85
(m, 6H), 6.88–6.91 (m, 2H), 6.96–7.06 (m, 4H), 7.13–7.19 (m, 3H);
13C NMR (75 MHz, CDCl3) d 20.97 (CH3 ꢀ 4), 21.31 (CH3), 44.64
(CH2), 49.49 (CH), 49.85 (CH), 55.07 (CH), 69.19 (CH2), 82.29 (CH),
114.29 (CH), 116.95 (CH), 120.95 (CH), 121.19 (CH), 126.69
(CH), 126.93 (C), 127.77 (CH), 128.36 (CH), 128.48 (CH), 128.78
(CH), 130.14 (CH), 130.37 (CH), 134.96 (C),137.26 (C), 139.55 (C),
5.3. Preparation of acetic acid 2-(4-acetoxy-phenyl)-3-phenyl-
chroman-4-yl ester (5)
A mixture of compound 4 (10 g, 0.03 mol) and acetic anhydride
(0.05 mol, 4.6 mL) in pyridine (50 mL) was refluxed for 4 h, and
during this period the reaction was monitered by TLC. After com-
pletion of the reaction, pyridine was distilled off and the resulting
reaction mixture was poured into crushed ice (300 mL). The reac-
tion mixture was extracted with EtOAc (50 mL ꢀ 3), and the organ-
ic layer was washed with brine and dried over sodium sulfate and
concentrated. The solid residue obtained was further crystallized
from EtOAc–hexane to obtain pure 5 (12 g).
150.28 (C), 155.25 (C), 157.60 (C), 169.30 (CO); mmax (KBr, cmꢁ1
)
2360, 1756, 1508, 1216, 760; ES-MS (m/z) 564 [M+H]+. HRMS-EI:
found 563.7297, calcd 563.7291. Microanalysis: C37H341 NO4.
Yield 96.0%; mp 160–162 °C; 1H NMR (300 MHz, CDCl3) d 1.88 (s,
3H), 2.25 (s, 3H), 3.47 (t, 1H, J = 9.8 Hz), 5.33 (d, 1H, J = 10.1 Hz), 6.59
(d, 1H, J = 9.6 Hz), 6.92–7.00 (m, 4H), 7.04–7.06 (m, 2H), 7.14–7.20
(m, 6H), 7.24–7.29 (m, 1H); 13C NMR (75 MHz, CDCl3) d 20.95
(CH3), 21.32 (CH3), 51.45 (CH), 71.22 (CH), 81.24 (CH), 117.05 (CH),
121.31 (CH), 121.41 (CH), 121.97 (C), 127.52 (CH), 127.72 (CH),
5.5.2. Acetic acid 4-{4-[4-(2-diethylaminoethoxy)phenyl]-3-
phenylchroman-2-yl}phenyl ester (11b)
Yield89.7%; mp 85–87 °C;1HNMR (300 MHz, CDCl3) d 1.03 (t, 6H,
J = 7.1 Hz), 2.21 (s, 3H), 2.60 (br m, 4H), 2.81 (t, 2H, J = 6.3 Hz), 3.25 (t,
1H, J = 10.9 Hz), 3.94 (t, 2H, J = 6.5 Hz), 4.46 (d, 1H, J = 11.2 Hz), 5.24

S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
6839
(d, 1H, J = 10.5 Hz), 6.65–6.68 (m, 2H), 6.77–6.85 (m, 6H), 6.88–6.91
(m, 2H), 6.96–7.05 (m, 4H), 7.13–7.19 (m, 3H); 13C NMR (75 MHz,
CDCl3) d 11.99 (CH3 ꢀ 2), 21.30 (CH3), 48.02 (CH2 ꢀ 2), 49.53 (CH),
51.87 (CH2), 55.11 (CH), 66.47 (OCH2), 82.28 (CH), 114.37 (CH),
116.96 (CH), 120.95 (CH), 121.18 (CH), 126.69 (CH), 126.89 (C),
127.78 (CH), 128.36 (CH), 128.49 (CH), 128.78 (CH), 130.13 (CH),
130.36 (CH), 135.13 (C), 137.26 (C), 139.55 (C), 150.29 (C), 155.27
(C), 157.55 (C), 169.28 (CO); mmax (KBr, cmꢁ1) 2361, 1762, 1509,
1216, 759; ES-MS (m/z) 536 [M+H]+; HRMS-EI: found 535.2720,
calcd 535.2723.
137.26, 139.53, 140.95, 149.33, 150.31, 155.25, 157.54, 169.30; mmax
(KBr, cmꢁ1) 2360, 1757, 1511, 1216, 760; ES-MS (m/z) 522 [M+H]+;
HRMS-EI: found 521.2548, calcd 521.2566.
5.5.7. 3-Phenyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)
chroman-4-one (13)
Yield 78%; viscous liquid; 1H NMR (300 MHz, CDCl3) d 1.76–1.78
(m, 4H), 2.58–2.60 (m, 4H), 2.83 (t, 2H, J = 5.7 Hz), 3.86 (t, 2H,
J = 5.7 Hz), 3.96 (d, 1H, J = 10.9 Hz), 5.50 (d, 1H, J = 10.9 Hz), 6.73–
6.75 (m, 2H), 6.95–7.00 (m, 2H), 7.01–7.05 (m, 2H), 7.09–7.21 (m,
5H), 7.45–7.53 (m, 1H), 7.96 (dd, 1H, J = 8.1 and 1.6 Hz); 13C NMR
(50 MHz, CDCl3) d 23.59, 54.89, 55.17, 59.62, 67.02, 84.65, 114.51,
118.23, 121.10, 121.76, 127.46, 127.73, 128.61, 130.31, 130.11,
135.11, 136.29, 159.02, 161.31, 192.06; ES-MS (m/z) 414 [M+H]+.
HRMS-EI: found 413.5097, calcd 413.5106. Microanalysis data
agreed: for C27H27 NO3.
5.5.3. Acetic acid 4-{3-phenyl-4-[4-(2-piperidin-1-yl-ethoxy)-
phenyl]-chroman-2-yl}-phenyl ester (11c)
Yield 88.5%; mp 48–50 °C; 1H NMR (300 MHz, CDCl3) d 1.44–1.45
(m, 2H), 1.58–1.65 (m, 4H), 2.22 (s, 3H), 2.43–2.51 (m, 4H), 2.74 (t,
2H, J = 5.94 Hz), 3.25 (t, 1H, J = 10.80 Hz), 4.02 (t, 2H, J = 6.00 Hz),
4.46 (d, 1H, J = 11.28 Hz), 5.24 (d, 1H, J = 10.44 Hz), 6.65–6.71 (m,
2H), 6.77–6.93 (m, 8H), 6.96–7.04 (m, 4H), 7.09–7.19 (m, 3H); 13C
NMR (75 MHz, CDCl3) d 21.32 (CH3), 24.21 (CH2), 25.89 (CH2),
49.49 (CH), 55.09 (CH), 55.17 (CH2), 58.08 (CH2), 65.71 (OCH2),
82.28 (CH), 114.42 (CH), 116.97 (CH), 120.97 (CH), 121.19 (CH),
126.71 (CH), 126.86 (C), 127.79 (CH), 128.37 (CH), 128.48 (CH),
128.77 (CH), 130.14 (CH), 130.36 (CH), 135.27 (C), 137.24 (C),
139.52 (C), 150.28 (C), 155.26 (C), 157.43 (C), 169.30 (CO); mmax
(KBr, cmꢁ1) 2361, 1761, 1509, 1217, 757; ES-MS (m/z) [M+H]+:
548; HRMS-EI: found 547.2722, calcd 547.2723.
5.5.8. 3-Phenyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-
chroman-4-ol (14)
Yield78%;mp138–140 °C;1HNMR(300 MHz, CDCl3)d1.77–1.80
(m, 4H), 2.58 (br m, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.22 (t, 1H,
J = 10.4 Hz), 3.99 (t, 2H, J = 5.9 Hz), 5.18 (d, 1H, J = 10.9 Hz), 5.23 (d,
1H, J = 10.1 Hz), 6.70–6.73 (m, 2H), 6.91–6.93 (m, 1H), 6.98–7.10
(m, 5H), 7.14–7.26 (m, 4H), 7.58 (d, 1H, J = 7.6 Hz); 13C NMR
(75 MHz, CDCl3) d 23.64 (CH2 ꢀ 2), 54.69 (CH), 54.90 (CH2 ꢀ 2),
55.17 (CH2), 67.03 (OCH2), 70.88 (CH), 81.53 (CH), 114.44 (CH),
116.65 (CH), 121.08 (CH), 125.43 (C), 127.32 (CH), 127.42 (CH),
128.72 (CH), 128.94 (CH), 129.19 (CH), 131.00 (C), 138.49 (C),
5.5.4. Acetic acid 4-{3-phenyl-4-[4-(2-pyrrolidin-1-yl-ethoxy)
phenyl]chroman-2-yl}phenyl ester (11d)
154.41 (C), 158.71 (C); m
max (KBr, cmꢁ1) 3398, 1265, 1037, 738; ES-
Yield 95%; mp 54–56 °C; 1H NMR (300 MHz, CDCl3) d 1.99–2.02
(m, 4H), 2.23 (s, 3H), 3.07 (br m, 4H), 3.18–3.29 (m, 3H), 4.26–4.31
(m, 2H), 4.49 (t, 1H, J = 10.83 Hz), 5.23 (t, 1H, J = 9.70 Hz), 6.65–
6.71 (m, 2H), 6.77–6.97 (m, 8H), 6.99–7.08 (m, 4H), 7.10–7.19 (m,
3H); 13C NMR (75 MHz, CDCl3) d 21.33, 23.49, 50.19, 54.36, 54.40,
55.16, 64.57, 82.25, 114.31, 117.09, 121.21, 121.34, 126.79, 127.96,
128.44, 128.72, 128.89, 130.10, 130.34, 130.48, 136.24, 137.19,
139.53, 140.87, 149.36, 155.51, 169.51; mmax (KBr, cmꢁ1) 1759,
1490, 1360, 1216, 758; ES-MS (m/z) [M+H]+ 534; HRMS-EI: found
533.2571, calcd 533.2566.
MS (m/z) [M+H]+ 416. HRMS-EI: found 415.5272, calcd 415.5265.
Microanalysis data agreed: for C27H29 NO3.
5.6. General procedure for preparation of hydroxy-ethers (12a–
c) and (10)
To a solution of compound 11a, c, and d (1 mmol) (for 12) or 6
(1 mmol) (for compound 10) in methanol (10 mL) was added
potassium hydroxide (1.2 mmol) and the mixture was refluxed
for 1 h. The reaction mixture was allowed to cool to rt and then
concentrated to 2–5 mL, and to it was poured ice cooled water
(20 mL). The mixture was then extracted with ethyl acetate
(3 ꢀ 15 mL). The organic layer was washed with brine and dried
over sodium sulfate and concentrated. The crude product was puri-
fied on silica gel column chromatography using 2–5% methanol–
chloroform mixture.
5.5.5. 4-(4-(4-(2-(Azepan-1-yl)ethoxy)phenyl)-3-phenylchro-
man-2-yl)phenyl acetate (11e)
Yield 86.3%; mp 61–63 °C; 1H NMR (300 MHz, CDCl3) d 1.60–1.66
(m, 8H), 2.22(s, 3H), 2.76–2.81(m, 4H), 2.93(t, 2H, J = 6.0 Hz), 3.25(t,
1H, J = 10.9 Hz), 4.00 (t, 2H, J = 6.4 Hz), 4.46 (d, 1H, J = 11.2 Hz), 5.24
(d, 1H, J = 10.5 Hz), 6.65–6.68 (m, 2H), 6.77–6.91 (m, 8H), 6.96–7.06
(m, 4H), 7.12–7.19 (m, 3H); 13C NMR (75 MHz, CDCl3) d 21.31 (CH3),
27.18 (CH2), 27.51 (CH2), 49.47 (CH), 55.05 (CH), 55.92 (CH2), 56.44
(CH2), 65.98 (OCH2), 82.25 (CH), 114.39 (CH), 116.95 (CH), 120.95
(CH), 121.19 (CH), 126.69 (CH), 126.83 (C), 127.79 (CH), 128.35
(CH), 128.47 (CH), 128.75 (CH), 130.13 (CH), 130.35 (CH), 131.69
(C), 135.25 (C), 137.21 (C), 139.49 (C), 150.25 (C), 155.23 (C),
5.6.1. 4-{4-[4-(2-Diisopropylamino-ethoxy)-phenyl]-3-phenyl-
chroman-2-yl}-phenol (12a)
Yield 100%; mp 64–65 °C; 1H NMR (300 MHz, CDCl3) d 1.03 (d,
12H, J = 6.5 Hz), 2.18–2.26 (br s, OH), 2.78 (t, 2H, J = 7.4 Hz), 3.00–
3.09 (m, 2H), 3.28 (t, 1H, J = 8.1 Hz), 3.82 (t, 2H, J = 7.4 Hz), 4.44 (d,
1H, J = 11.2 Hz), 5.19 (d, 1H, J = 10.4 Hz), 6.61–6.67 (m, 4H), 6.77–
6.84 (m, 6H), 6.96–7.08 (m, 7H); 13C NMR (75 MHz, CDCl3) d 20.80
(CH3 ꢀ 4), 44.76 (CH2), 49.87 (CH), 50.20 (CH), 54.96 (CH), 68.84
(OCH2), 82.56 (CH), 114.37, 115.25, 117.02, 120.85, 126.49, 127.02,
127.74, 128.28, 128.84, 128.93, 130.20, 130.42, 131.80, 135.36,
140.10, 155.61, 157.52; mmax (KBr, cmꢁ1) 3427, 1363, 1216, 761;
ES-MS (m/z) [M+H]+ 522; HRMS-EI: found 521.2925, calcd
521.2930.
157.40 (CH), 158.46 (C), 169.33 (CO); m
max (KBr, cmꢁ1) 1750, 1511,
1400, 1206, 777; ES-MS (m/z) 562 [M+H]+. HRMS-EI: found
561.7135, calcd 561.7132.
5.5.6. Acetic acid 4-{4-[4-(3-dimethylaminopropoxy) phenyl]-
3-phenylchroman-2-yl}phenyl ester (11f)
Yield 85%; mp 54–56 °C; 1H NMR (300 MHz, CDCl3) d 1.93–2.00
(m, 2H), 2.22 (s, 3H), 2.31 (s, 6H), 2.49–2.56 (m, 2H), 3.21–3.31 (t,
1H, J = 9.9 Hz), 3.91 (t, 2H, J = 6.2 Hz), 4.49 (d, 1H, J = 10.9 Hz), 5.24
(d, 1H, J = 9.9 Hz), 6.64–6.69 (m, 2H), 6.77–6.93 (m, 8H), 6.97–7.05
(m, 4H), 7.09–7.19 (m, 3H); 13C NMR (75 MHz, CDCl3) d 21.32
(CH3), 27.13 (CH2), 45.22 (NCH3 ꢀ 2), 49.48 (CH), 55.00 (CH), 56.45
(CH2), 65.91 (OCH2), 77.45 (CH), 114.23, 116.96, 120.97, 121.19,
126.66, 126.87, 127.79, 128.35, 130.11, 130.36, 131.68, 135.21,
5.6.2. 4-{3-Phenyl-4-[4-(2-piperidin-1-yl-ethoxy)phenyl]-
chroman-2-yl}phenol (12b)
Yield 97.3%; mp 82–84 °C; 1H NMR (300 MHz, CDCl3) d 1.43–1.45
(m, 2H), 1.58–1.60 (m, 4H), 1.99–2.04 (br s, OH), 2.51 (br m, 4H), 2.73
(t, 2H, J = 5.9 Hz), 3.26 (t, 1H, J = 10.8 Hz), 3.99 (t, 2H, J = 6.00 Hz),
4.43 (d, 1H, J = 11.1 Hz), 5.18 (d, 1H, J = 10.3 Hz), 6.58–6.68 (m,

6840
S. Kumar et al. / Bioorg. Med. Chem. 17 (2009) 6832–6840
4H), 6.76–6.83 (m, 7H), 6.97–7.08 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 24.06 (CH2), 25.43 (CH2), 29.90 (CH2), 49.82 (CH), 55.01 (CH2),
57.93 (CH), 65.12 (OCH2), 82.59 (CH), 114.37, 115.43, 115.52,
117.02, 120.81, 126.43, 127.74, 128.24, 128.84, 130.17, 130.40,
binding. Further optimization of these prototype molecules as
anti-cancer agents is in progress.
Acknowledgments
131.16, 135.65, 140.08, 155.58, 156.22, 157.25; mmax (KBr, cmꢁ1
)
3416, 1358, 1217, 760; ES-MS (m/z) 506 [M+H]+. HRMS-EI:
found 505.6503, calcd 505.6497. Microanalysis data agreed: for
C34H35 NO5.
S.K. is thankful to the University GrantsCommission, New Delhi,
for the financial support which is gratefully acknowledged and the
Sophisticated Analytical Instrument Facility, CDRI, Lucknow for
providing spectroscopic data. The authors are also thankful to Min-
istry of Health and Family Welfare, Govt. of India for financial
assistance.
5.6.3. 4-{3-Phenyl-4-[4-(2-pyrrolidin-1-yl-ethoxy) phenyl]
chroman-2-yl}phenol (12c)
Yield 96.8%;mp 88–90 °C;1H NMR (300 MHz, CDCl3) d 1.78 (br m,
4H), 2.65–2.67 (br m, 4H), 2.84–2.89 (m, 2H), 3.19–3.28 (m, 1H), 3.95
(t, 2H, J = 5.70 Hz), 4.40 (t, 1H, J = 11.01 Hz), 5.17 (t, 1H, J = 10.77 Hz),
5.99 (br s, 1H, OH), 6.50–6.60 (m, 4H), 6.70–6.84 (m, 6H), 6.91–6.99
(m, 5H), 7.06–7.16 (m, 2H); 13C NMR (75 MHz, CDCl3) d 23.44, 49.92,
54.67, 54.92, 55.05, 66.19, 82.38, 114.23, 115.57, 116.98, 120.81,
126.42, 127.03, 127.68, 128.24, 128.76, 130.14, 130.27, 130.45,
References and notes
1. Ciocca, D. R.; Vargas Roig, L. M. Endocr. Rev. 1995, 16, 35.
2. Smith, E. P.; Boyd, J.; Frank, G. R.; Takahashi, H.; Cohen, R. M.; Specker, B.;
Williams, T. C.; Lubahn, D. B.; Korach, K. S. N. Eng. J. Med. 1994, 331, 1056.
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K. S.; Simpson, E. R. N. Eng. J. Med. 1997, 337, 91.
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5. Grese, T. A.; Dodge, J. A. Curr. Pharm. Des. 1998, 4, 71.
132.06, 134.48, 135.66, 140.10, 155.54, 158.22; mmax (KBr, cmꢁ1
)
3376, 1449, 1029, 758; ES-MS (m/z) 492 [M+H]+. HRMS-EI: found
491.6237, calcd 491.6230. Microanalysis data agreed: for C33H33
NO5.
6. Wakeling, A. E.; Valcaccia, B. J. Endocr. 1983, 99, 445.
7. Miller, C. P.; Komm, B. S. Ann. Rep. Med. Chem. 2001, 36, 149.
8. Black, L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.; Williams, D. C.;
Cullinan, G. J.; Bendele, R.; Kauffman, R. F.; Bensch, W. R.; Frolik, C. A.; Termine,
J. D.; Bryant, H. U. J. Clin. Invest. 1994, 93, 63.
9. Miller, C. P. Curr. Pharm. Des. 2002, 8, 2089.
5.6.4. 2,4-Di-(4-hydroxyphenyl)-3-phenyldihydrobenzo-pyran
(10)
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Yield 91%; mp 151–153 °C; 1H NMR (200 MHz, CDCl3) d 3.26 (t,
1H, J = 10.8 Hz), 4.43 (d, 1H, J = 11.1 Hz), 4.81 (br s, 1H, OH,
exchangeable with D2O), 4.89 (br s, 1H, OH, exchangeable with
D2O), 5.19 (d, 1H, J = 10.5 Hz), 6.57–6.64 (m, 4H), 6.76–6.83 (m,
6H), 6.95–7.09 (m, 7H); 13C NMR (50 MHz, CDCl3) d 49.80, 54.56,
82.55, 115.23, 115.32, 116.76, 120.56, 126.20, 127.12, 127.47,
128.04, 128.70, 128.73, 130.09, 130.30, 130.62, 134.13, 140.16,
155.29, 155.43, 156.53; mmax (neat) 3475, 1360, 756; ES-MS (m/z)
395 [M+H]+. HRMS-EI: found 394.4633, calcd 394.4642.
6. Conclusion
In conclusion, synthesis of trans, trans-2,3,4-trisubstituted-2,3-
dihydro-4H-1-benzopyran, (2,3,4-triarylchroman), by selective
deacetylative direct arylation of trans-2,3-disubstituted-2,3-dihy-
dro-4H-1-benzopyran with phenol and its further derivatization
with different alkyl amine chains were disclosed. The biological
activity of the synthesized compounds found to sensitive to amino
component in the side chain. Significant estrogenic and anti-estro-
genic activities exhibited by 11a and 12c point to their ability to
bind to estrogen receptor as such or as possible hydroxyl metabo-
lite. In in vitro evaluation of anti-breast cancer activity, 11f and 12a
showed promising activity comparable with that of tamoxifen, in
spite of their poor receptor binding affinity suggests that these
compounds might have different mechanism than through ER