Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

Article abstract of DOI:10.1016/j.bmcl.2008.11.086

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially

Full text of DOI:10.1016/j.bmcl.2008.11.086

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1001–1003
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type
RXR agonists favors switch towards antagonist activity
Ken-ichi Morishita a, Nobumasa Yakushiji a, Fuminori Ohsawa a, Kayo Takamatsu a,
Nobuyasu Matsuura b, Makoto Makishima c, Masatoshi Kawahata d, Kentaro Yamaguchi d,
Akihiro Tai e, Kenji Sasaki a, Hiroki Kakuta a,
*
a Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan
b Faculty of Science, Okayama University of Science, 1-1, Ridai-cho, Okayama 700-0005, Japan
c Division of Biochemisty, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
d Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
e Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara 727-0023, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2008
Revised 12 November 2008
Accepted 18 November 2008
Available online 27 November 2008
Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activ-
ity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and
allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molec-
ular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRa-preferential agonist, and
we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain
or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benze-
nesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful
approach for addressing the lack of structure diversity of RXR antagonists.
Keywords:
Retinoid X receptor
RXR
Antagonists
Molecular design
Sulfonamide
Ó 2008 Elsevier Ltd. All rights reserved.
Retinoid X receptors (RXRs) are members of the nuclear recep-
tor family of ligand-dependent transcription factors. RXRs work as
homodimers or heterodimers with FXR, LXR, PPAR, RAR, etc., to
control gene expression.1–3 They are activated by 9-cis retinoic
acid, an endogenous ligand.4 This compound also activates retinoic
acid receptors (RARs),5 but several RXR-selective ligands have been
developed (Fig. 1).2,3,6–9 The first RXR-selective agonist, LGD1069,
has been approved as a treatment for cutaneous T-cell lymphoma
by the Food and Drug Administration (FDA) in the United States of
America. In addition, RXR agonists are reported to be effective
against tamoxifen-resistant breast cancer, taxol-resistant lung can-
cer and metabolic syndrome.2,3,10,11
dronaphthyl hydrophobic domain of the corresponding RXR ago-
nists (Fig. 1).
We were therefore interested in a new molecular design ap-
proach to RXR antagonists. For this purpose, we focused on the sul-
fonamide-type RXR agonist 5a: 4-[N-methanesulfonyl-N-(5,5,8,8-
tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid
(Fig. 1).6 The X-ray structure of 5a is shown in Figure 2 and Table
1. Comparing the structure with those of existing RXR antagonists
7: HX53113 and 8: UVI300314, we thought that replacement of the
methyl group of the methanesulfonamide moiety of 5a with a long
alkyl chain or a steric bulky aromatic ring might produce RXR
antagonist activity. This is because the longer the alkyl-chain on
the tetramethyltetrahydronaphthyl group, the more likely com-
pounds are to show RXR antagonistic activity, according to Na-
houm et al.14
Sulfonamide compounds were synthesized according to Scheme
1. Amine 9 was prepared according to reference18 and coupled
with methyl 6-chloronicotinate under acidic conditions to give
intermediate 10. Introduction of a sulfonamide group into 10
was performed by with sulfonyl chloride after treatment of 10 with
sodium hydride in DMF. Deprotection of the methyl ester group
was performed under alkaline conditions to afford the desired
compounds 5b–5j. The RXR agonistic activity of these compounds
Several RXR antagonists, 6: LG10075412
, , 8:
7: HX53113
UVI300314, and PA45215, have also been developed (Fig. 1) and
some of them show anti-allergic activity via inhibition of Th2 dif-
ferenciation16 and anti-diabetic action via RXR-PPAR heterodimer
modulation.17 RXR antagonists are expected to be useful tools for
studying the functions of RXR or RXR agonists. However, currently
available RXR antagonists, except HX531 (7), are structurally
rather similar, with a long alkyl chain on the tetramethyltetrahy-
* Corresponding author. Tel./fax: +81 86 251 7977.
E-mail address: kakuta@pharm.okayama-u.ac.jp (H. Kakuta).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.086

1002
K. Morishita et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1001–1003
Figure 1. Chemical structures of known RXR agonists and antagonists.
Table 1
Crystallographic data for compound 5a
Formula
Crystal system
Space group
Temperature
a (Å)
C21H26N2O4S
Triclinic
P-1
90 K
8.8310(13)
10.8501(16)
11.9915(18)
75.853(2)
71.405(2)
69.786(2)
1010.2(3)
2
b (Å)
c (Å)
a
(ꢀ)
b (ꢀ)
c
(ꢀ)
v (Å3)
Z
D (g/cm3)
1.323
No. of obsd. reflns.
R1; wR2
6218
0.0680; 0.1975
Figure 2. ORTEP drawing of compound 5a.
was evaluated by means of luciferase-reporter gene assay in COS-1
cells using 1 M LGD1069 (RXR-pan-agonist) as a reference. As
shown in Figure 3, the longer the alkyl chain on the sulfonamide
group, the weaker the RXR agonistic activity. Compounds 5e–5j
bearing an aromatic sulfonamide group also did not show RXR ago-
nistic activity. We judged that the decreasing RXR agonistic activ-
ity represented a shift from agonist to antagonist activity, and
therefore evaluated the RXR antagonistic activity.
RXR antagonistic activity of the compounds was evaluated in
terms of inhibition of the agonistic activity of LGD1069 at 10 nM
(see Table 2). Whereas the alkyl-sulfonamide derivatives did not
l
show RXR antagonistic activity below 10 lM, some benzenesulfo-
Scheme 1. Reagents and conditions: (a) i—6-chloronicotinic acid, MsOH, dioxane; ii—MeOH, H2SO4; (b) RSO2Cl, NaH, DMF; (c) NaOH, MeOH, then HCl.

K. Morishita et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1001–1003
1003
Figure 3. Dose-dependent RXR agonistic activities of compounds 5a–5d against RXR
a, RXRb, and RXR
c
. Open circles, open triangles, open squares, closed circles and closed
triangles indicate compounds 5a, 5b, 5c, 5d, and 5e, respectively. Luciferase activity of LGD1069 at 1
lM was defined as 1.0.
Table 2
ence and technology in the prefectures where nuclear power plants
and other power plants are located.
RXR antagonistic activities of compounds 5d–5j and HX531 (7) against 10 nM
LGD1069 (RXR pan-agonist)a
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.11.086.
References and notes
Compound
R
RXR
IC50
a
(
RXRb
IC50
RXRc
b
b
b
1. Mangelsdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.; Schultz, G.; Umesono,
K.; Blumberg, B.; Kastner, P.; Mark, M.; Chambon, P.; Evans, R. M. Cell 1995, 83,
835.
2. de Lera, A. R.; Bourguet, W.; Altucci, L.; Gronemeyer, H. Nat. Rev. Drug Discov.
2007, 6, 811.
3. Altucci, L.; Leibowitz, M. D.; Ogilvie, K. M.; Lera, A. R. D.; Gronemeyer, H. Nat.
Rev. Drug Discov. 2007, 6, 793.
4. Heyman, R. A.; Mangelsdorf, D. J.; Dyck, J. A.; Stein, R. B.; Eichele, G.; Evans, R.
M.; Thaller, C. Cell 1992, 68, 397.
5. Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; Lera,
A. R. D.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. Pharmacol. Rev. 2006, 58,
760.
6. Takamatsu, K.; Takano, A.; Yakushiji, N.; Morishita, K.; Matsuura, N.;
Makishima, M.; Ali, H. I.; Akaho, E.; Tai, A.; Sasaki, K.; Kakuta, H.
ChemMedChem 2008, 3, 454.
7. Takamatsu, K.; Takano, A.; Yakushiji, N.; Morohashi, K.; Morishita, K.;
Matsuura, N.; Makishima, M.; Tai, A.; Sasaki, K.; Kakuta, H. ChemMedChem
2008, 3, 780.
8. Muccio, D. D.; Brouillette, W. J.; Breitman, T. R.; Taimi, M.; Emanuel, P. D.;
Zhang, X.-K.; Chen, G.-Q.; Sani, B. P.; Venepally, P.; Reddy, L.; Alam, M.; Herren,
L. S.; Hill, D. L. J. Med. Chem. 1998, 41, 1679.
l
M)
(lM)
IC50 (lM)
5d
5e
5f
5g
5h
5i
5j
n-Bu
Ph
>10
>10
>10
>10
3.0 1.4
>10
>10
p-MePh
p-MeOPh
p-ClPh
p-CF3Ph
p-NO2Ph
—
5.2 1.4
2.7 0.4
4.1 1.1
3.2 1.1
>10
3.8 0.2
6.6 0.8
4.5 1.3
2.7 0.9
>10
3.9 2.0
0.87 0.36
0.75 0.46
>10
7: HX531
0.29 0.04
0.044 0.002
0.38 0.14
a
All values represent the standard error of the mean value of at least two sep-
arate experiments with triplicate determinations.
b
IC50 values were determined from full dose–response curves ranging from 10À7
to 10À5 M in COS-1 cells.
nanilide derivatives were found to show RXR antagonistic activity
at single digit micromolar concentrations. Among them, com-
pounds bearing a chloro substituent 5h or trifluoromethyl group
5i at the para-position on the benzenesulfonyl group showed mod-
erate RXR antagonistic activity against RXRb.
9. Umemiya, H.; Fukasawa, H.; Ebisawa, M.; Eyrolles, L.; Kawachi, E.; Eisenmann,
G.; Gronemeyer, H.; Hashimoto, Y.; Shudo, K.; Kagechika, H. J. Med. Chem. 1997,
45, 3327.
10. Grubbs, C. J.; Hill, D. L.; Bland, K. I.; Beenken, S. W.; Lin, T. H.; Eto, I.; Atigadda, V.
R.; Vines, K. K.; Brouillette, W. J.; Muccio, D. D. Cancer Lett. 2003, 201, 17.
11. Yen, W.-C.; Corpuz, M. R.; Prudente, R. Y.; Cooke, T. A.; Bissonnette, R. P.;
Negro-Vilar, A.; Lamph, W. W. Clin. Cancer Res. 2004, 10, 8656.
12. Koch, S. S. C.; Dardashti, L. J.; Hebert, J. J.; White, S. K.; Croston, G. E.; Flatten, K.
S.; Heyman, R. A.; Nadzan, A. M. J. Med. Chem. 1996, 39, 3229.
13. Ebisawa, M.; Umemiya, H.; Ohta, K.; Fukasawa, H.; Kawachi, E.; Christoffel, G.;
Gronemeyer, H.; Tsuji, M.; Hashimoto, Y.; Shudo, K.; Kagechika, H. Chem.
Pharm. Bull. 1999, 47, 1778.
In conclusion, we found that introduction of a bulky substituent
on the sulfonamide group that links the hydrophobic aromatic
group and aromatic carboxylic group of RXR ligands can generate
RXR antagonistic activity. Although the RXR antagonistic activity
of the compounds 5h and 5i prepared in this study is slightly
weaker than that of 7: HX531, this molecular design strategy
should be a useful approach for addressing the lack of structure
diversity of RXR antagonists.
´
´
14. Nahoum, V.; Perez, E.; Germain, P.; Rodrıguez-Barrios, F.; Manzo, F.; Kammerer,
S.; Lemaire, G.; Hirsch, O.; Royer, C. A.; Gronemeyer, H.; de Lera, A. R.; Bourguet,
W. Proc. Natl. Acad. Sci. USA 2007, 104, 17323.
Acknowledgments
15. Takahashi, B.; Ohta, K.; Kawachi, E.; Fukasawa, H.; Hashimoto, Y.; Kagechika, H.
J. Med. Chem. Lett. 2002, 45, 3327.
16. Grenningloh, R.; Gho, A.; di Lucia, P.; Klaus, M.; Bollag, W.; Ho, I.-C.; Sinigaglia,
F.; Bordignon, P. P. J. Immunol. 2006, 176, 5161.
The authors are grateful to the SC-NMR Laboratory of Okayama
University for the NMR experiment. We also thank Dr. Kagechika
(School of Biomedical Science, Tokyo Medical and Dental Univer-
sity) for kindly providing HX531. This research was partially sup-
ported by a Grant-in Aid for Scientific Research on Priority Areas
from the Ministry of Education, Science, Culture and Sports of Ja-
pan (Nos. 17790090 and 20790101), by the subsidy to promote sci-
17. Yamauchi, T.; Waki, H.; Kamon, J.; Murakami, K.; Motojima, K.; Komeda, K.;
Miki, H.; Kubota, N.; Terauchi, Y.; Tsuchida, A.; Tsuboyama-Kasaoka, N.;
Yamauchi, N.; Ide, T.; Hori, W.; Kato, S.; Fukayama, M.; Akanuma, Y.; Ezaki, O.;
Itai, A.; Nagai, R.; Kimura, S.; Tobe, K.; Kagechika, H.; Shudo, K.; Kadowaki, T. J.
Clin. Invest. 2001, 108, 1001.
18. Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Himi, T.; Shudo, K. J. Med. Chem.
1988, 31, 2182.