Design and synthesis of 4-(4-benzoylaminophenoxy)phenol derivatives as androgen receptor antagonists

Article abstract of DOI:10.1021/ml4001744

We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC₅₀ 0.75 μM), LNCaP cell line bearing T877A-mutated AR (IC₅₀ 0.043 μM), and 22Rv1 cell line bearing H874Y-mutated AR (IC₅₀ 0.22 μM). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.

Full text of DOI:10.1021/ml4001744

Letter
pubs.acs.org/acsmedchemlett
Design and Synthesis of 4‑(4-Benzoylaminophenoxy)phenol
Derivatives As Androgen Receptor Antagonists
Ayumi Yamada, Shinya Fujii,* Shuichi Mori, and Hiroyuki Kagechika
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo
101-0062, Japan
S
* Supporting Information
ABSTRACT: We report the design and synthesis of novel 4-(4-
benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR)
ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound
22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-
promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 μM), LNCaP cell
line bearing T877A-mutated AR (IC50 0.043 μM), and 22Rv1 cell line bearing
H874Y-mutated AR (IC50 0.22 μM). Structure−activity relationship studies
confirmed that the pharmacophore of these novel AR antagonists is distinct from
the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR
antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.
KEYWORDS: Androgen receptor (AR), AR antagonist, prostate cancer, pharmacophore, 4-(4-benzoylaminophenoxy)phenol
ndrogen receptor (AR) is a member of the nuclear
Areceptor superfamily of ligand-dependent transcriptional
factors.1,2 AR is activated by binding of endogenous androgens,
such as testosterone and its activated form, dihydrotestosterone
(DHT), and regulates numerous physiological processes,
including growth, maintenance of the male reproductive
system, and homeostasis of bone and muscle.3,4 Because AR
plays an important role in progression of prostate cancer, AR
antagonists are used clinically for treatment of prostate cancer.
However, chronic administration of AR antagonists often leads
to development of resistance, so-called castration-resistant
prostate cancer (CRPC),5,6 and mutation of AR is thought to
be the main cause.7−9 For example, a representative non-
steroidal AR antagonist, flutamide (1), and its activated
metabolite, hydroxylflutamide (2), act as agonists of AR
Figure 1. Structures of nonsteroidal AR antagonists.
bearing T877A, the most common mutation of AR in CRPC
and consequently exacerbate the cancer.10
All the nonsteroidal AR antagonists currently in clinical use
are derivatives of flutamide bearing a nitrophenyl or a
cyanophenyl group as the pharmacophore (Figure 1),11 and
these antagonists are often ineffective for mutated ARs.12
Intensive studies based on flutamide derivatives have been
investigated, and recently, novel flutamide derivative MDV3100
(5) was developed as a potent AR antagonist effective for
CRPC.13 Another possible approach to overcome CRPC would
be to develop AR antagonists bearing a novel pharmacophore,
different from those of flutamide analogues. For example,
nicotinamide derivative DIMN (6) was developed as novel type
of nonsteroidal AR antagonists.14
that is the key structure of potent nonsteroidal AR antagonists
so far developed. Structurally, curcumin (7) consists of two
phenolic groups linked by an unsaturated 1,3-diketone (or its
enol form), which would be chemically and metabolically
reactive.17 Therefore, we assumed that at least one phenolic
group of 7 was essential for the AR antagonistic activity and
that the overall structural framework of 7 could be replaced by
stable, drug-like structures. Our previous studies on retinoids
suggested that benzanilide is a versatile structure for replacing
conjugated polyene substructure.18,19 Recent studies by us and
others also suggested that a Ph−X−Ph skeleton, such as
diphenylmethane (X = carbon),20 diphenyl ether (X =
With the aim of developing novel AR antagonists, we focused
on the structure of the natural pigment curcumin (7, Figure 2).
Several curcumin analogues possess antiandrogenic activity,15,16
and 7 does not possess the cyanophenyl or nitrophenyl group
Received: May 10, 2013
Accepted: August 18, 2013
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
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a
Scheme 1. Synthesis of 8, 12a−p, and 15
Figure 2. Design of novel AR antagonists bearing phenol substructure.
oxygen),21 diphenylamine (X = nitrogen),22 or diphenylsilane
(X = silane),23 is a suitable hydrophobic substructure for
nuclear receptor ligands.
a
Reagents and conditions: (a) hydroquinone, NaOH, DMSO−H2O,
50 °C, 56%; (b) Pd−C, H2, MeOH, rt, 92−98%; (c) method A, aroyl
chloride, THF, rt, 55−86%; method B, aroyl chloride, pyridine, rt, 50−
60%; method C, (i) (COCl)2, DMF, CH2Cl2, rt; (ii) 11, THF, rt, 39−
84%; method D, (i) (COCl)2, DMF, CH2Cl2, rt; (ii) 11, pyridine,
THF, rt, 46%; (d) BBr3, CH2Cl2, 40 °C, 50%; (e) K2CO3, MeOH−
H2O, rt, 95%; (f) NaOEt, EtOH, rt, 30%; (g) phenol, K2CO3, DMF,
40 °C, 90%.
On the basis of those findings, we designed the
phenoxybenzanilide core structure as a candidate scaffold of
AR antagonists, and we initially synthesized the parent
compound 8 (Figure 2). Biological evaluation revealed that 8
exhibited significant AR antagonistic activity, being a potent
inhibitor of androgen-dependent SC-3 cell24 proliferation (IC50
= 9.4 μM). Here, we report the synthesis and biological activity
of 8 and its derivatives (general formula shown in Figure 2) as
candidate new-generation AR antagonists bearing a novel
pharmacophore distinct from those of conventional flutamide
analogues.
group and deprotection of the benzyl group by catalytic
hydrogenation afforded amines 28 and 29, and then, amide
condensation gave the target compounds 30 and 31.
Compound 8 and 4-phenoxyphenols 12a−p were synthe-
sized as shown in Scheme 1.25 SNAr reaction using 4-
fluoronitrobenzene (9) and hydroquinone gave diphenyl
ether 10, and then reduction of the nitro group afforded
primary amine 11. Amide bond formation of 11 with benzoic
acid or benzoyl chloride derivatives gave compounds 8 and
12a−p. Compounds 12c, 12f, and 12h were synthesized from
the corresponding O-monomethyl (for 12c) or O-monoacetyl
(for 12f and 12h) derivatives by removal of the O-substituent.
Diphenyl ether 15 without a phenolic hydroxyl group was also
prepared for investigation of the significance of the phenolic
hydroxyl group. SNAr reaction using 7 and phenol gave
diphenyl ether 13, and then reduction of the nitro group
afforded primary amine 14. Amide bond formation of 14 using
benzoyl chloride gave compound 15 (Scheme 1).
Scheme 2 shows the synthesis of compounds 22 and 23
bearing methyl group(s) at the central benzene ring and the
synthesis of heterocyclic analogues 30 and 31. SNAr reaction
using hydroquinone and fluoronitrobenzene 16 or 17 gave
diphenyl ethers 18 and 19, respectively. Reduction of the nitro
group gave amine 20 and 21, and following amide formation
afforded the target compounds 22 and 23. Compounds bearing
pyridine or pyrimidine as the central aromatic ring were also
similarly synthesized. Reaction of 2-chloro-5-nitropyridine 24
or 2-chloro-5-nitropyrimidine 25 with 4-benzyloxyphenol gave
diaryl ethers 26 and 27, respectively. Reduction of the nitro
The antiandrogenic activity of the synthesized compounds
was initially evaluated by assay of growth-inhibitory activity
toward SC-3.24 SC-3 cells have wild-type AR and proliferate
androgen-dependently. None of the synthesized compounds
promoted growth of SC-3 cells. Table 1 shows the inhibitory
potency of the test compounds toward DHT-promoted cell
growth of SC-3. Compound 12b exhibited the most potent
antiandrogenic activity among the synthesized compounds, and
12l also exhibited potent antiandrogenic activity exceeding that
of the lead compound 8. Deletion of the phenolic hydroxyl
group (compound 15) resulted in significant loss of potency
(20% inhibition at the concentration of 10 μM). Ohtsu et al.
reported that the phenolic hydroxyl group was not essential for
its AR antagonistic activity,15 and therefore, the importance of
this hydroxyl group is intriguing. Interestingly, compounds 12i,
12j, and 12k bearing a nitrophenyl group did not exhibit
significant antiandrogen activity. The nitrophenyl group is a
common pharmacophore of conventional nonsteroidal AR
antagonists, and this result suggested that the 4-(4-
benzoylaminophenoxy)phenol derivatives are a novel class of
AR antagonists bearing a unique pharmacophore, different from
those of AR antagonists so far known. Bisphenol compound 12f
and compounds bearing a pyridine ring 12n and 12o exhibited
moderate activity similar to that of 8. These results indicate that
the 3-methoxybenzoyl group of 12b was the most suitable as
the terminal functionality.
B
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a
Scheme 2. Synthesis of 22, 23, 30, and 31
a
Reagents and conditions: (a) hydroquinone, NaOH, DMSO−H2O, 50 °C to rt, 66% (18), 55% (19); (b) for 20, Pd−C, H2, MeOH, rt, 94%: for
21, Pd−C, H2, THF, rt, 90%; (c) for 22, m-anisoyl chloride, THF, rt, 63%; for 23, m-anisoyl chloride, pyridine, THF, rt, 67%; (d) for 26, 4-
benzyloxyphenol, t-BuOK, DMF, rt, 46%; for 27, p-benzyloxyphenol, K2CO3, DMF, rt, 38%; (e) Pd−C, H2, THF, rt, quant (28), 80% (29); (f) m-
anisoyl chloride, THF, rt, 76% (30), 79% (31).
Table 1. AR Antagonistic Activity of Synthesized
Table 2. Androgen Antagonistic Activity of Synthesized
Phenol Derivatives by Means of SC-3 Assay, Binding
Affinity, and Reporter Assay
Compounds by Means of Inhibition of DHT-Promoted SC-3
a
Cell Proliferation
compd
R
X
IC50 (μM)
a
b
c
SC-3 assay binding affinity luciferase assay
2
0.37
9.4
compd
Z1
Z2
IC50 (μM)
IC50 (μM)
% inhibition
8
Ph
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
2
0.37
2.0
7.1
20
60
6
12a
12b
12d
12f
12c
12h
12i
12j
12k
12l
12m
12n
12o
12p
15
2-MeO−Ph
3-MeO−Ph
4-MeO−Ph
2-HO−Ph
3-HO−Ph
4-HO−Ph
2-NO2−Ph
3-NO2−Ph
4-NO2−Ph
3-NMe2−Ph
4-NMe2−Ph
2-pyridyl
>10
2.0
12b
22
23
30
31
CH
CMe
CMe
N
CH
CH
CMe
CH
N
0.75
2.9
9.2
5.4
>10
66
69
>10
8.8
d
b
7.2
n.d.
n.d.
d
b
N
5.9
>10
n.d.
n.d.
a
b
>10
>10
>10
3.0
Cell growth was promoted by 1 nM DHT. Competitive binding
c
assay using hAR-LBD and 3H-labeled DHT (4 nM). Inhibition (% of
control) of luciferase activity by 10 μM test compound using MDA-
Kb2 cell line. The concentration of DHT was 0.1 nM. Inhibition was
not detected at the concentration of 10 μM.
d
6.7
8.7
line26 also supported the idea that the AR antagonistic activities
of compounds 22 and 23 are due to their AR-modulating
activity.
3-pyridyl
9.7
4-pyridyl
>10
>10
Ph
a
b
SC-3 cell growth was promoted by 1 nM DHT. Inhibition was not
Then, we investigated the antiandrogenic activity of the
selected compounds toward human prostate cancer cell lines
LNCaP and 22Rv1, which have mutation in the AR ligand-
binding domain. The LNCaP cell line expresses T877A AR,
which is the most frequently detected mutation of AR in
castration-resistant prostate cancer.27,28 Hydroxyflutamide (2)
and some other AR antagonists act as agonists toward T877A
AR,10 and therefore, we use 4 as positive control of this assay.
The 22Rv1 cell line expresses H874Y AR.29 None of the
compounds examined promoted growth of these prostate
cancer cell lines, and all of them exhibited significant inhibitory
activity toward DHT-induced proliferation of these cell lines
(Table 3). Among them, compound 22, which was the most
potent AR antagonist in SC-3 assay, exhibited the most potent
antiandrogenic activity toward LNCaP cell line (IC50 = 0.043
μM). Compound 22 also exhibited potent antiandrogenic
activity toward 22Rv1 cell line (IC50 = 0.22 μM). The
antiandrogenic activities of compound 22 are more potent than
those of bicalutamide (4), one of the most effective
detected at the concentration of 10 μM.
For further structural development of these novel AR
antagonists, the structure−activity relationship of the central
aromatic ring was investigated. Compounds bearing phenol and
methoxybenzoyl groups as terminal aromatic rings and different
center rings were synthesized, and their activities were
compared by means of antiandrogen activity assay with SC-3
cells, competitive AR binding assay, and luciferase assay (Table
2). Compound 22 bearing a methyl group at the center ring
exhibited the most potent activity toward SC-3 cells, and the
potency (IC50 = 0.75 μM) of this compound was of the same
order as that of hydroxyflutamide (2). Dimethylated derivative
23 also exhibited similar potency to 12b, whereas heterocyclic
compounds 30 and 31 exhibited lower potency than 12b in SC-
3 assay. Compounds 22 and 23 exhibited strong binding affinity
for wild-type AR, whereas heterocyclic derivatives 30 and 31
did not. The results of luciferase assay using MDA-Kb2 cell
C
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Notes
Table 3. Antiandrogenic Activity and Cytotoxicity of
Selected Phenol Derivatives toward Three Human Prostate
Cancer Cell Lines
The authors declare no competing financial interest.
REFERENCES
■
LNCaP (T877A-AR)
22Rv1 (H874Y-AR)
PC-3
(1) Evans, R. M. The steroid and thyroid hormone receptor
superfamily. Science 1988, 240, 889−894.
a
a
b
compd
IC50 (μM)
IC50 (μM)
IC50 (μM)
(2) McEwan, I. J. Gene regulation through chromatin remodeling by
members of the nuclear receptor superfamily. Biochem. Soc. Trans.
2000, 28, 369−373.
4
0.94
0.29
0.043
2.4
4.6
>10
5.6
12b
22
23
1.9
0.22
5.7
(3) Mooradian, A. D.; Morley, J. E.; Korenman, S. G. Biological
actions of androgens. Endocr. Rev. 1987, 8, 1−28.
1.3
>10
a
b
Cell growth was promoted by 10 nM DHT. IC50 values for
androgen-independent cell proliferation.
(4) Bagatell, C. J.; Bremner, W. J. Androgens in men; uses and
abuses. N. Engl. J. Med. 1996, 334, 707−714.
(5) Taplin, M.-E. Androgen receptor: Role and novel therapeutic
prospects in prostate cancer. Expert Rev. Anticancer Ther. 2008, 8,
1495−1508.
nonsteroidal AR antagonists. These results suggest that
compound 22 is a potent AR antagonist active toward both
wild-type and mutant AR. We also examined the effect of
compounds toward androgen-independent prostate cancer cell
line PC-3. Compound 12b and 22 exhibited cell-growth
inhibiting potency at micromolar concentrations. This result
indicates that these compounds possess anticancer or cytotoxic
activity independent to AR antagonistic activity, though the
effective concentrations are comparatively higher than that of
antiandrogenic activities. It was reported that curcumin and its
derivatives have various physiological activities and antiprolif-
eration activity toward prostate cancer by interfering with many
transcription pathways.30−33 The compounds developed in this
study certainly bind to AR ligand-binding domain and exhibit
AR antagonistic activity; however, these compounds probably
possess another biological activity other than AR modulation
like curcumin.
In summary, we have developed a new class of nonsteroidal
AR antagonists without the nitrophenyl or cyanophenyl
substructure of known AR antagonists. We designed and
synthesized a series of 4-phenoxyphenol derivatives as AR
antagonist candidates. We found that the 4-(4-
benzoylaminophenoxy)phenol skeleton serves as a novel core
structure of AR antagonists. Compound 22 is one of the most
potent of these non-nitrophenyl and non-cyanophenyl type
nonsteroidal AR antagonists and exhibited antiandrogenic
activity toward several prostate cancer cell lines, including
two with mutated ARs. This novel non-flutamide derivative
type AR antagonist is a promising candidate for antiandrogen
therapy of prostate cancer.
(6) Ross, R. K.; Pike, M. C.; Coetzee, G. A.; Reinchardt, J. K. V.; Yu,
M. C.; Feigelson, H.; Stanczyk, F. Z.; Kolonel, L. N.; Henderson, B. E.
Androgen metabolism and prostate cancer: Establishing a model of
genetic susceptibility. Cancer Res. 1998, 58, 4497−4504.
(7) Scher, H. I.; Steineck, G.; Kelly, W. K. Hormone-refractory (D3)
prostate cancer: refining the concept. Urology 1995, 46, 142−148.
(8) Miyamoto, H.; Rahman, M. M.; Chang, C. Molecular basis for
the antiandrogen withdrawal syndrome. J. Cell. Biochem. 2003, 91, 3−
12.
(9) Bohl, C. E.; Gao, W.; Miller, D. D.; Bell, C. E.; Dalton, J. T.
Structural basis for antagonism and resistance of bicalutamide in
prostate cancer. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 6201−6206.
(10) Steketee, K.; Timmerman, L.; Ziel-van der Made, A. C.;
Doesburg, P.; Brinkmann, A. O.; Trapman, J. Broadened ligand
responsiveness of androgen receptor mutants obtained by random
amino acid substitution of H874 and mutation hot spot T877 in
prostate cancer. Int. J. Cancer 2002, 100, 309−317.
(11) Gao, W.; Bohl, C. E.; Dalton, J. T. Chemistry and structural
biology of androgen receptor. Chem. Rev. 2005, 105, 3352−3370.
(12) Jung, M. E.; Ouk, S.; Yoo, D.; Sawyers, C. L.; Chen, C.; Tran,
C.; Wongvipat, J. Structure−activity relationship for thiohydantoin
androgen receptor antagonists for castration-resistant prostate cancer
(CRPC). J. Med. Chem. 2010, 53, 2779−2796.
(13) Song, C.-H.; Yang, S. H.; Park, E.; Cho, S. H.; Gong, E.-Y.;
Khadka, D. B.; Cho, W.-J.; Lee, K. Structure-based virtual screening
and identification of a novel androgen receptor antagonist. J. Biol.
Chem. 2012, 287, 30769−30780.
(14) Yang, S. H.; Song, C.-H.; Van, H. T. M.; Park, E.; Khadka, D. B.;
Gong, E.-Y.; Lee, K.; Cho, W.-J. SAR based design of nicotinamides as
a novel class of androgen receptor antagonists for prostate cancer. J.
Med. Chem. 2013, 56, 3414−3418.
(15) Ohtsu, H.; Xiao, Z. Y.; Ishida, J.; Nagai, M.; Wang, H. K.;
Itokawa, H.; Su, C. Y.; Shih, C.; Chiang, T. Y.; Chang, E.; Lee, Y. F.;
Tsai, M. Y.; Chang, C. S.; Lee, K. H. Antitumor agents. 217. Curcumin
analogues as novel androgen receptor antagonists with potential as
anti-prostate cancer agents. J. Med. Chem. 2002, 45, 5037−5042.
(16) Zhou, J.; Geng, G.; Shi, Q.; Sauriol, F.; Wu, J. H. Design and
synthesis of androgen receptor antagonists with bulky side chains for
overcoming antiandrogen resistance. J. Med. Chem. 2009, 52, 5546−
5550.
ASSOCIATED CONTENT
■
S
* Supporting Information
Analytical data and experimental procedures for synthetic
preparation and biological evaluation of compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Esatbeyoglu, T.; Huebbe, P.; Ernst, I. M. A.; Chin, D.; Wagner,
A. E.; Rimbach, G. Curcumin: From molecule to biological function.
Angew. Chem., Int. Ed. 2012, 51, 5308−5332.
(18) Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Himi, T.; Shudo, K.
Retinobenzoic acids. 1. Structure−activity relationships of aromatic
amides with retinoidal activity. J. Med. Chem. 1988, 31, 2182−2192.
(19) Kagechika, H.; Shudo., T. Synthetic retinoids: Recent
developments concerning structure and clinical utility. J. Med. Chem.
2005, 48, 5875−5883.
(20) Boehm, M. F.; Fitzgerald, P.; Zou, A.; Elgort, M. G.; Bischoff, E.
D.; Mere, L.; Mais, D. E.; Bissonnette, R. P.; Heyman, R. A.; Nadzan,
A. M.; Reichman, M.; Allegretto, E. A. Novel nonsecosteroidal vitamin
D mimics exert VDR-modulating activities with less calcium
AUTHOR INFORMATION
Corresponding Author
*(S.F.) E-mail: fujiis.chem@tmd.ac.jp.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the manuscript.
Funding
This study was partially supported by Grants-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan (Grant No. 21790128
to S.F.).
■
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Letter
mobilization than 1,25-dihydroxyvitamin D3. Chem. Biol. 1999, 6,
265−275.
(21) Mitchell, L. H.; Hub, L.-Y.; Nguyen, M.; Fakhoury, S.; Smith, Y.;
Iula, D.; Kostlan, C.; Carroll, M.; Dettling, D.; Du, D.; Pocalyko, D.;
Wade, K.; Lefker, B. Bioorg. Med. Chem. Lett. 2009, 19, 2176−2178.
(22) Takahashi, B.; Ohta, K.; Kawachi, E.; Fukasawa, H.; Hashimoto,
Y.; Kagechika, H. Novel retinoid X receptor antagonists: Specific
inhibition of retinoid synergism in RXR−RAR heterodimer actions. J.
Med. Chem. 2002, 45, 3327−3330.
(23) Nakamura, M.; Makishima, M.; Hashimoto, Y. Development of
silicon-containing bis-phenol derivatives as androgen receptor
antagonists: Selectivity switching by C/Si exchange. Bioorg. Med.
Chem. 2013, 21, 1643−1651.
(24) Hiraoka, D.; Nakamura, N.; Nishizawa, Y.; Uchida, N.; Noguchi,
S.; Matsumoto, K.; Sato, B. Inhibitory and stimulatory effects of
glucocorticoid on androgen-induced growth of murine shionogi
carcinoma 115 in vivo and in cell culture. Cancer Res. 1987, 47,
6560−6564.
(25) One-pot synthesis of this scaffold was also reported: Chen, W.;
Li, J.; Fang, D.; Feng, C.; Zhang, C. Copper-catalysed one-pot
multicomponent coupling reaction of phenols, amides, and 4-
bromophenyl iodide. Org. Lett. 2008, 10, 4565−4568.
(26) Wilson, V. S.; Bobseine, K.; Lambright, C. R.; Gray, L. E., Jr. A
novel cell line, MDA-kb2, that stably expresses an androgen- and
glucocorticoid-responsive reporter for the detection of hormone
receptor agonists and antagonists. Toxicol. Sci. 2002, 66, 69−81.
(27) Veldscholte, J.; Berrevoets, C. A.; Brinkmann, A. O.;
Grootegoed, J. A.; Mulder, E. Anti-androgens and the mutated
androgen receptor LNCaP cells: Differential effects on binding affinity,
heat-shock protein interaction, and transcription activation. Biochem-
istry 1992, 31, 2393−2399.
(28) Zhou, J.; Liu, B.; Geng, G.; Wu, J. H. Study of the impact of the
T877A mutation on ligand induced helix-12 positioning of the
androgen receptor resulted in design and synthesis of novel
antiandrogens. Proteins 2010, 78, 623−637.
(29) Sramkoski, R. M.; Pretlow, T. G., II; Giaconia, J. M.; Pretlow, T.
P.; Schwartz, S.; Sy, M.-S.; Marengo, S. R.; Rhim, J. S.; Zhang, D.;
Jacobberger, J. W. A new human prostate carcinoma cell line, 22Rv1.
In Vitro Cell. Dev. Biol.-Anim. 1999, 35, 403−409.
(30) Aggarwal, B. B. Prostate cancer and curcumin. Prostate 2001, 47,
293−303.
(31) Singh, R. P.; Agarwal, R. Mechanism of action of novel agents
for prostate cancer chemoprevention. Endocr.-Relat. Cancer 2006, 13,
751−778.
(32) Fuchs, J. R.; Pandit, B.; Bhasin, D.; Etter, J. P.; Regan, N.;
Abdelhamid, D.; Li, C.; Lin, J.; Li, P.-K. Structure−activity relationship
studies of curcumin analogues. Bioorg. Med. Chem. Lett. 2009, 19,
2065−2069.
(33) Shi, Q.; Wada, K.; Ohkoshi, E.; Lin, L.; Huang, R.; Morris-
Natschke, S. L.; Goto, M.; Lee, K.-H. Antitumor agents 290. Design,
synthesis and biological evaluation of a new LNCaP and PC-3
cytotoxic curcumin analogs conjugated with anti-androgens. Bioorg.
Med. Chem. 2012, 20, 4020−4031.
E
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