9-cis-Retinoic acid analogues with bulky hydrophobic rings: New RXR-selective agonists

Article abstract of DOI:10.1016/j.bmcl.2004.08.072

Stille cross-coupling of aryltriflates 10 and dienylstannane 11, oxidation and Horner-Wadsworth-Emmons reaction afforded stereoselectively retinoates 15. Saponification provided the carboxylic acids 8a and 8b, retinoids that incorporate a bulky hydrophobic ring while preserving the 9-cis-geometry of the parent system. In contrast to the pan-RAR/RXR agonistic profile of the lower homologue of 8a, compound 7 (LG100567), retinoids 8 showed selective binding and transactivation of RXR, devoid of significant RAR activation. In PLB985 leukemia cells that require RXR agonists for differentiation compounds 8 induced maturation in the presence of the RAR-selective pan-agonist TTNPB; this effect was blocked by an RXR-selective antagonist.

Full text of DOI:10.1016/j.bmcl.2004.08.072

Bioorganic & Medicinal Chemistry Letters 14 (2004) 6117–6122
9-cis-Retinoic acid analogues with bulky hydrophobic rings:
new RXR-selective agonists
a
Rosana Alvarez, M. Jesu´s Vega, Sabrina Kammerer, Aurelie Rossin, Pierre Germain,
a
b
b
b
´
Hinrich Gronemeyerb and Angel R. de Leraa,*
a
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, Universidade de Vigo, 36200 Vigo, Spain
b
´ ´
´
Department of Cell Biology and Singal Transduction, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC),
1 rue Laurent Fries, BP 10142, 67404 Illkirch, France
Received 30 July 2004; accepted 30 August 2004
Abstract—Stille cross-coupling of aryltriflates 10 and dienylstannane 11, oxidation and Horner–Wadsworth–Emmons reaction
afforded stereoselectively retinoates 15. Saponification provided the carboxylic acids 8a and 8b, retinoids that incorporate a bulky
hydrophobic ring while preserving the 9-cis-geometry of the parent system. In contrast to the pan-RAR/RXR agonistic profile of the
lower homologue of 8a, compound 7 (LG100567), retinoids 8 showed selective binding and transactivation of RXR, devoid of sig-
nificant RAR activation. In PLB985 leukemia cells that require RXR agonists for differentiation compounds 8 induced maturation
in the presence of the RAR-selective pan-agonist TTNPB; this effect was blocked by an RXR-selective antagonist.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
strated by the response of a large number of cancer
cell lines in culture to retinoids and the therapeutic suc-
cess of trans-retinoic acid 1 in the treatment of acute
promielocytic leukemia (APL).5
The hormone action of retinoic acid 1 and its 9-cis-iso-
mer 2 in multicellular organisms is expressed through
the activation of genetic networks governed by the
binding of the ligand–cognate receptor complexes1 to
promoter regions of DNA. The retinoid families of
nuclear proteins (RARs-retinoic acid receptors- and
RXRs-retinoid X receptors-, both comprising isotypes
a,b,c) act as ligand-inducible transcription factors, regu-
lating physiological processes essential for embryonic
development as well as for cell growth, differentiation,
and death. trans-Retinoic acid (1) is the natural ligand
for RAR, and its isomer 9-cis-retinoic acid (2) has high
affinity for, and activates, both RAR and RXR. It is be-
lieved that RARs and RXRs act mainly as RAR–RXR
heterodimers, the functional units that also affect other
cell signaling pathways, albeit RXR can also function
autonomously.2
Concerns about secondary effects of retinoid therapy
(retinoic acid syndrome, teratogenicity) has stimulated
the search for novel retinoids incorporating structural
modifications at the hydrophobic ring and/or the side
chain, and these modifications oftentimes contribute to
improve chemical stability.4 Commonly the trimethylcy-
clohexenyl ring is replaced by the lipophilic bioisostere
5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. In
addition, the presence of aryl rings as substitutes of ter-
minal dienes imparts greater stability in some of the
most active analogues, thus increasing the chances for
therapeutical application. LGD1069 (bexarotene, Tar-
gretinꢁ) 3 is the first synthetic RXR-selective agonist
(rexinoid) approved for the treatment of cutaneous T-
cell lymphoma.6
The ability of retinoids3,4 to regulate cell growth and in-
duce differentiation throughout life has been demon-
Another common substitute of the hydrophobic ring is a
3,5-di-tert-butylbenzene, and this structure is present in
some selected antiproliferative retinoids (Fig. 1).7 Amide
4 and chalcone 5 are selective RAR ligands, and show
induction of differentiation on the HL-60 promyelocytic
cell line.
Keywords: 9-cis-Retinoic acid; RXR agonist; Nuclear receptor.
*
Corresponding author. Tel.: +34 986812316; fax: +34 986812556;
e-mail: qolera@uvigo.es
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.08.072

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R. Alvarez et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6117–6122
Figure 2.
Figure 1.
10b,15 and completing the polyene chain with
the Horner–Wadsworth–Emmons condensation.16 The
pseudohalides 10 were obtained from 9 in virtually
quantitative yield by treatment with N-phenyltriflimide
and Et3N (Scheme 1).14 The coupling of aryltriflates to
stannanes is considered to require LiCl in order to stabi-
lize the oxidative addition products and avoid the for-
mation of catalytically inactive Pd species.17 In the
presence of LiCl, coupling of 10 and known12f 11 took
place at 60ꢂC in NMP under the mediation of
Pd2(dba)3/AsPh3 to afford dienols 12 in 56% and 47%
2. Design and synthesis of novel 9-cis-retinoic acid
analogues with bulky hydrophobic rings
Within the group of 3,5-di-tert-butylbenzene-based reti-
noids, ALRT1550 (6) is receiving increased attention,
because it is a highly potent and selective activator of
the RARs in binding and cotransfection assays, and
inhibits proliferation of human cervical carcinoma
cells.8 Although less active than the E isomer in inhibit-
ing the proliferation of ME-180 cervical tumor, the Z
isomer
7 (LG100567), a pan-RAR/RXR agonist,
showed a ca. 25 times greater potency than 9-cis-retinoic
acid 2 (cf. 6 is 300 times more potent than trans-retinoic
acid 1). The pan-RAR/RXR agonistic profile of retinoid
7 is likely due to its flexibility,9 that allows the conform-
ational adaptation to the topologically distinct binding
pockets of both RARs9 and RXRs,10 in a manner simi-
lar to 9-cis-retinoic acid 2. We considered that this con-
formational adaptability could be challenged by the
incorporation of an additional ethenyl group to the side
chain of 7 (compound 8a). Binding of 8a to the more
elongated I-shaped binding pocket of RAR9 would be
disfavored, whereas the ability to fit into the L-shaped
LBP of RXR10 would be preserved. In addition, ana-
logue 8b, having a 6-tert-butyl-1,1-dimethylindanyl
group as a bioisostere of the retinoid hydrophobic
cyclohexenyl ring,11 was anticipated to exhibit RXR
selectivity, since the indanyl ring forces the bending of
the side-chain relative to the ring, a structural feature
observed in the crystal structure of 9-cis-retinoic acid 2
bound to RXR10 (Fig. 2).
We report herein stereoselective approaches to retinoids
8 using metal-catalyzed cross-coupling reactions12 and
confirm the structure-based predictions by transactiva-
tion studies and rexinoid-dependent leukemia cell differ-
entiation assays.
Scheme 1. Reagents and reaction conditions: (a) N-phenyltriflimide,
Et3N, CH2Cl2, 48h (10a: 98%; 10b: 98%); (b) 11, Pd2(dba)3 (cat),
AsPh3, LiCl, NMP, 60ꢂC (12a: 56%; 12b: 47%); (c) TPAP (cat)/NMO,
CH2Cl2, 0ꢂC (13a: 71%; 13b: 60%); (d) i. n-BuLi, 14, DMPU, 0ꢂC; ii.
aldehyde 13, À78ꢂC (15a: 86%; 15b: 74%); (e) 5M KOH, MeOH,
80ꢂC, 2h (8a: 93%; 8b: 81%).
We envisioned a stepwise construction tactic to retinoid
polyene side-chains12 starting with the Stille coupling
reaction13 of geometrically homogeneous dienylstann-
ane 1112h and the triflate14 derived from 3,5-di-tert-
butylphenol 10a or 6-tert-butyl-1,1-dimethylindanol

R. Alvarez et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6117–6122
6119
yield, respectively. Addition of the alcohol 12 to NMO
˚
and 4A MS in CH2Cl2, followed by TPAP at 0ꢂC,
and then stirring at ambient temperature delivered the
aldehydes 13 in 71% and 60% yield, respectively (Scheme
1). The chain was then extended by treatment of these
unstable aldehydes with the anion (n-BuLi, THF,
DMPU, À78ꢂC) of ethyl (E)-3-(ethoxycarbonyl)-2-
methylprop-2-enyl phosphonate 14, as previously re-
ported,16 affording esters 15 (86% for 15a, 74% for
15b). Finally, basic hydrolysis provided the correspond-
ing acids 8a (93% yield) and 8b (81% yield).18
3. Modeling reveals structural basis of RXR selectivity
Crystal structure-based modeling provided initial evi-
dence that compounds 8 could have gained selectivity
compared with the parent 9-cis-retinoic acid. While the
structural details of 9-cis-retinoic acid binding in the lig-
and binding pockets are well understood from the corre-
sponding crystal structures of the 9-cis RA-RARc
ligand binding domain (LBD) complex (PDB ID,
3LBD) and the 9-cis-RXR LBD complex (PDB ID,
1FM6), modeling reveals that 8b cannot be equally
accommodated in the RARc binding pocket (Fig. 3,
top panel; note that one of the two methyl groups at-
tached to the indanyl ring extends outside the cavity,
thus incurring in steric clashes). Similar results were ob-
tained for 8a (data not shown). In contrast, due to the
alternate shape of the RXRa ligand binding pocket 8b
fits well inside (Fig. 3, middle and bottom panels show
two views, the middle panel corresponds to the view of
RARc). Thus, modeling suggests that compounds 8
may have acquired selective RXR binding activity com-
pared to 9-cis-retinoic acid.
4. Biological activity of novel rexinoids
To differentiate RAR and RXR-selective ligand-medi-
ated transactivation we used transient assays with chi-
meric Gal4-receptor fusion proteins and the cognate
reporter gene carrying five Gal4 response elements in
front of the b-globin promoter used to drive the lucif-
erase reporter (schematically illustrated in Fig. 4, top).
No significant transactivation was seen with the rexi-
noids 8, while the pan-RAR/RXR agonist 9-cis-retinoic
acid parent molecule displayed a strong transcriptional
activity (Fig. 4, top panel). In striking contrast, using
the equivalent RXR reporter system both 8a and 8b
activated transcription through RXR with an activity
about 10 times lower than 9-cis-retinoic acid (Fig. 4,
bottom panel). Note, however, that RXR selectivity is
not absolute, as at high concentrations (>1lM) a weak
RAR agonist activity becomes apparent (Fig. 4, top
panel).
Figure 3. Modeling of 8b in the ligand binding pockets of RAR c and
RXRa. The ligands 8 (green), used for docking experiments including
all hydrogen atoms, were built with the QUANTA package using the
force field from CHARMM.19 The protein structures used for the
docking experiments were the X-ray structures of either the 9-cis RA
(red)-RARc LBD complex (PDB ID, 3LBD) or the 9-cis RA (red)-
RXR LBD complex (PDB ID, 1FM6). The cavity volume of the ligand
binding pockets was calculated in the program O820 with VOIDOO21
and used as a guide during the docking process. One of the cavities
calculated by VOIDOO gives the volume accessible to the center of the
˚
probe-sphere (1.4A radius) that is in contact with the protein van der
Competition assays done with all three RARs confirmed
that compounds 8a and 8b do not substantially interact
with RARa and RARb, while there is a weak interac-
tion with RARc at high concentrations (Fig. 5). In all
cases both 8a and 8b act as very weak antagonists with
apparent binding affinities about 1000 times lower than
Waals surface. In this representation of the cavity most of the apolar
heavy atoms should lie inside the calculated volume. The ligands were
then manually fitted in the ligand binding pocket using the 9-cis RA,
the cavity volume and the favored conformations as landmarks. The
force field from the Quanta/CHARMM package was used for the
energy minimization.

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R. Alvarez et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6117–6122
Figure 4. Transient transactivation studies to assess RAR or RXR
activity of 8a and 8b. Transiently transfected COS cells expressing
chimeric proteins containing the GAL4 DNA-binding domain (Gal-
DBD) fused to the ligand binding domain (LBD) of either RARa (Gal-
RARa, top panel) or RXRa (Gal-RXRa bottom panel), and a
luciferase gene driven by a pentamer of the Gal4 recognition sequence
(Ô17mÕ) in front of the b-globin promoter, as illustrated at the top. This
reporter system is insensitive to endogenous receptors, which cannot
recognize the GAL4 binding site. Cells were incubated with increasing
concentrations of 9-cis-retinoic acid 2 (closed squares), 8a (closed
diamonds) or 8b (open circles).
Figure 5. Transient transactivation studies to assess RAR antagonist
potential of 8a and 8b. Transiently transfected COS cells expressing
chimeric proteins containing the GAL4 DNA-binding domain (Gal-
DBD) fused to the ligand binding domain (LBD) of either RARa
(Gal-RARa, (a) panel) or RARb (Gal-RARb, (b) panel) or RARc
(Gal-RARc, (c) panel), and the luciferase gene driven by the 17m
sequence in front of the b-globin promoter, as illustrated in Figure 4.
Cells were incubated with 10nM 9-cis-retinoic 2 and increasing
concentrations of the RAR pan-antagonist BMS493 (closed squares),
8a (closed diamonds) or 8b (open circles).
that of the RAR agonist 9-cis-retinoic. As control the
strong RAR pan-antagonist BMS493 is shown for
comparison.
To investigate if the rexinoid activity of 8a and 8b would
suffice to exert a biological activity in intact cells we used
leukemic PLB985 cells that display a strong synergy be-
tween RAR and RXR agonists for induction of differen-
tiation along the granulocyte lineage (our unpublished
observation). We chose conditions (four days exposure
to the indicated ligand concentrations) under which nei-
ther the RAR pan-agonist TTNPB nor compounds 8a
or 8b would induce significant differentiation, as deter-

R. Alvarez et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6117–6122
6121
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2004.08.072.
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Figure 6. Differentiation-inducing activity of rexinoids 8. PLB985
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We thank the European Commission (QLK3-2002-
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02029 ÔAnticancer RetinoidsÕ), the Spanish Ministerio
´
´
de Educacion y Ciencia (Grant SAF01-3288, Ramon y
Cajal Contract to R. Alvarez) and Xunta de Galicia
(Grant PGIDIT02PXIC30108PN) for financial support,
and C.A.C.T.I. (Universidade de Vigo) for NMR and
mass spectra. Work in the laboratory of H.G. was
supported additionally by the Fondation de France,
the Association pour la Recherche sur le Cancer, the
ULP, the INSERM, the CNRS and Bristol-Myers
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(400.13MHz, CDCl3): d 1.29 (s, 6H), 1.38 (s, 9H), 1.98
(t, J = 7.2Hz, 2H), 2.12 (s, 3H), 2.40 (s, 3H), 2.97 (t,
J = 7.2Hz, 2H), 5.85 (s, 1H), 6.19 (d, J = 11.5Hz, 1H),
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(d, J = 15.9Hz, 1H), 7.38 (d, J = 1.5Hz, 1H)ppm. 13C
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2·), 28.8 (t), 31.6 (q, 3·), 34.8 (s), 41.3 (t), 44.0 (s), 117.6
(d), 118.8 (d), 120.9 (d), 125.9 (d), 129.3 (d), 130.1 (d),
130.4 (d), 132.9 (s), 134.8 (d), 138.3 (s), 138.8 (s), 150.2 (s),
153.2 (s), 155.0 (s), 170.5 (s)ppm. FTIR (NaCl): t 3600–
2900 (br, OH), 2956 (s, C–H), 1677 (s, C@O), 1578 (s),
1258 (m)cmÀ1. MS: m/z (%) 379 (M++1, 30), 378 (M+,
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(23). HRMS: calcd for C26H34O2, 378.2559; found,
378.2549. Anal. Calcd C, 82.55; H, 8.98. Found: C,
82.44; H, 9.01.
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before mass spectra were recorded. Data for selected
compounds: 8a: yellow solid (mp 196–198ꢂC, Et2O/
hexane). 1H NMR (400.13MHz, CDCl3): d 1.37 (s,
18H), 2.11 (s, 3H), 2.41 (s, 3H), 5.81 (s, 1H), 6.18 (d,
J = 11.4Hz, 1H), 6.32 (d, J = 15.0Hz, 1H), 6.77 (d,
J = 15.8Hz, 1H), 7.2–7.4 (m, 5H). 13C NMR
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34.8 (s, 2·), 118.3 (d), 121.0 (d, 2·), 122.5 (d), 124.4 (d),
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