Conformationally defined retinoic acid analogues. 5. Large-scale synthesis and mammary cancer chemopreventive activity for (2E,4E,6Z,8E)-8-(3′,4′-dihydro-1′(2′H) -naphthalen-1′-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30)

Article abstract of DOI:10.1021/jm030095q

Retinoids that activate the nuclear retinoid X receptors (RXRs) display potential for chemoprevention of breast cancer. We previously reported that 9cUAB30 (1) is an RXR-selective retinoid. To explore its in vivo chemopreventive activity, multigram quantities of 1 were needed. Here, we describe a modified synthesis that yields up to 100 g of 1. We further demonstrate that 1 is very effective in the prevention of N-methyl-N-nitrosourea induced mammary cancers in rats without signs of toxicity.

Full text of DOI:10.1021/jm030095q

3766
J . Med. Chem. 2003, 46, 3766-3769
Con for m a tion a lly Defin ed Retin oic Acid An a logu es. 5. La r ge-Sca le Syn th esis
a n d Ma m m a r y Ca n cer Ch em op r even tive Activity for (2E,4E,6Z,8E)-8-
(3′,4′-Dih yd r o-1′(2′H)-n a p h th a len -1′-ylid en e)-3,7-d im eth yl-2,4,6-octa tr ien oic Acid
(9cUAB30)
Venkatram R. Atigadda,† Kimberly K. Vines,† Clinton J . Grubbs,‡ Donald L. Hill,‡ Samuel L. Beenken,‡
Kirby I. Bland,‡ Wayne J . Brouillette,*,† and Donald D. Muccio*,†
Departments of Chemistry and Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294
Received February 26, 2003
Retinoids that activate the nuclear retinoid X receptors (RXRs) display potential for chemo-
prevention of breast cancer. We previously reported that 9cUAB30 (1) is an RXR-selective
retinoid. To explore its in vivo chemopreventive activity, multigram quantities of 1 were needed.
Here, we describe a modified synthesis that yields up to 100 g of 1. We further demonstrate
that 1 is very effective in the prevention of N-methyl-N-nitrosourea induced mammary cancers
in rats without signs of toxicity.
In humans, the estrogen receptor antagonist Tamox-
ifen is used as adjuvant therapy for high-risk patients,1
and currently it is the only chemopreventive agent for
breast cancer approved by the Food and Drug Admin-
istration. Even though the benefits of Tamoxifen are
substantial, long-term administration is not without
risks. Women who undergo Tamoxifen therapy have
higher levels of endometrial cancers, since Tamoxifen
acts as an agonist rather than an antagonist in the
endometrium.2 Other chemopreventive agents that can
be used alone or in combination with Tamoxifen are
needed. Since retinoids are capable of inducing apoptosis
and cell differentiation, these agents have been explored
for their chemopreventive effects. The efficacy of retin-
oids as chemopreventive agents has been demonstrated
for numerous animal models of carcinogenesis including
skin, breast, oral cavity, lung, hepatic, gastrointestinal,
prostatic, and urinary bladder cancers.3
inoid, 1,7 which is a conformationally constrained
analogue of 9-cis-retinoic acid that locks the tetraene
chain in a defined conformation. The retinoid 1 binds
to RXRs and efficiently induces transcription mediated
by these receptors over retinoic acid receptors (RARs).
To evaluate the effectiveness of this retinoid in reducing
the MNU-initiated mammary cancers in rats, multi-
gram quantities of 1 were required. Here, we report a
new synthesis of 1 suitable for the efficient preparation
of multigram quantities and the results of mammary
cancer chemopreventive assays and toxicity in rats.
Ch em istr y
Our previously reported7 synthesis of 1 is shown in
Scheme 1. In this procedure, a Reformatsky reaction
between R-tetralone (2) and ethyl 4-bromo-3-methyl-2-
butenoate (3) directly provided the acid 5 (86%). Reduc-
tion of the acid to the alcohol 6 (67%) [1:1 (9Z) to (all-E)
mixture], followed by oxidation, provided the aldehyde
(9Z)-7 (69%) [1:1 (9Z) to (all-E) mixture; pure (9Z)
isomer obtained by flash chromatography]. A Horner-
Emmons condensation between aldehyde (9Z)-7 and
triethyl phosphonosenecioate (8) provided the ester 9
(78%) as a 2:1 mixture of (9Z) and (9Z,13Z) isomers.
These isomers were separated by HPLC, and the desired
(9Z)-9 was hydrolyzed under basic conditions (98% yield)
to give 1.
While satisfactory for a small scale, this methodology
was not amenable for large-scale synthesis of multigram
quantities needed for the chemoprevention studies. The
oxidation of the alcohol to the aldehyde required the use
of large amounts of MnO2 and molecular sieves, and the
purification became extremely tedious at larger scale.
Oxidation of 100 g of alcohol 6 would require 1 kg of
MnO2 and 0.5 kg of powdered molecular sieves. Separa-
tion of the product would require washing the MnO2
with about 15 L of solvent, and during this process, a
considerable amount of aldehyde decomposes. At this
scale, the yield of the aldehyde is expected to be
considerably lower than 69%. Furthermore, the Hor-
ner-Emmons reaction resulted in a 2:1 mixture of
Anzano et al.4 showed that 9-cis-retinoic acid is a
potent retinoid for the prevention of N-methyl-N-ni-
trosourea (MNU) induced mammary carcinogenesis.
However, since the effective dose is near the toxic dose,
this agent may not be suitable for long-term adminis-
tration needed in chemoprevention. The all-trans-ret-
inoic acid is much less effective in these assays, sug-
gesting that retinoids that activate the retinoid X
receptors (RXRs) may be more efficacious in mammary
cancer chemoprevention. Gottardis et al.5 demonstrated
that Targretin, an RXR-selective ligand, prevented the
appearance of MNU-induced rat mammary tumors.
Furthermore, this retinoid had less toxicity than 9-cis-
retinoic acid. When either 9-cis-retinoic acid or Targre-
tin was used in combination with Tamoxifen, increased
chemopreventive efficacy was observed over either agent
alone.6 Recently we reported a new RXR-selective ret-
* To whom correspondence should be addressed. Address for W.J .B.
and D.D.M.: Department of Chemistry, 901 South 14th Street,
Birmingham, AL 35294. Phone for W.J .B. and D.D.M.: (205) 934-8285.
Fax for W.J .B. and D.D.M.: (205) 934-2543. E-mail for W.J .B.:
wbrou@uab.edu. E-mail for D.D.M.: muccio@uab.edu.
† Department of Chemistry.
‡ Department of Surgery.
10.1021/jm030095q CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/23/2003

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3767
Sch em e 1
F igu r e 1. Average tumor formation versus days after MNU
administration for female rats fed a 4% Teklad diet with
9cUAB30 (200 mg/kg diet, diamond; 100 mg/kg diet, triangle),
with 9-cis-retinoic acid (100 mg/kg diet, circle), or without
retinoid (MNU control, square).
(9Z)-9 and (9Z,13Z)-9. This is another problematic step
because the separation of the two isomers requires
HPLC, which is impractical for large scales, and because
one-third of the aldehyde 7 is wasted by conversion to
the undesired di-Z ester 9. These limitations prompted
us to develop an alternative synthetic methodology more
amenable for a large-scale synthesis.
in the diet continuously after MNU injection, beginning
at 53 days of age (3 days after the carcinogen). The
compounds were incorporated into the diet using a
Patterson-Kelly liquid-solid blender. Stability of the
retinoids during feeding was verified by HPLC. The
groups were as follows: group 1, 1 (200 mg/kg diet);
group 2, 1 (100 mg/kg diet); group 3, 9-cis-retinoic acid
(100 mg/kg diet); group 4, diet only. The rats were
weighed once per week, palpated for mammary tumors
twice per week, and checked daily for signs of toxicity.
The study was terminated 140 days after MNU treat-
ment. All mammary tumors were histologically classi-
fied as adenocarcinomas.
The modified synthetic methodology is also depicted
in Scheme 1. As shown, the first step also involved a
Reformatsky reaction between 1-tetralone (2) and ethyl
4-bromo-3-methyl-2-butenoate (3) in the presence of Zn
and Cu(OAc)2 in THF.8 However, conditions were used
to favor the formation of the intermediate δ-lactone 4.
This reaction was performed on a 100 g scale to yield
approximately 100 g (70%) of 4. Another major change
was the controlled reduction of 4 by DIBAH, followed
by ring opening and elimination, to provide the aldehyde
7 (75%) [5:1 (9Z) to (all-E)]. The isomers were readily
separated on flash silica, and triethyl phosphonosene-
cioate 8 was used to olefinate (9Z)-7 under modified
Horner-Emmons conditions to produce the ester 9.
Under these conditions, the use of excess HMPA as the
solvent resulted in the desired ester 9 as a 9:1 mixture
of (9Z,13E)-9 and (9Z,13Z)-9, which were separated by
selective crystallization. Pure (9Z,13E)-9 was hydrolyzed
under basic conditions to give the pure acid 1 in 78%
yield.
Resu lts a n d Discu ssion
1 and 9-cis-retinoic acid were tested in the MNU-
induced mammary cancer model currently used by the
National Cancer Institute to evaluate the efficacy of
chemopreventive agents.4 At termination of the study,
the average number of mammary cancers per rat for
the control group was 2.6. 1 at the 200 and 100 mg/kg
diet dose levels reduced the number of mammary
cancers by 63% and 29%, respectively (Figure 1). The
use of 9-cis-retinoic acid at the 100 mg/kg diet dose level
(a level just below the toxic dose for this compound)
decreased the multiplicity of cancers by 65%. Both the
high dose of 1 and 9-cis-retinoic acid greatly delayed
the time of appearance of the mammary cancers (Figure
1). As shown in Table 1, retinoid 1 did not alter body or
liver weights of the rats significantly at either dose level.
Other signs of retinoid clinical toxicity were not ob-
served. Since mammary cancers are highly sensitive to
ovarian hormone changes, we measured the weight of
the ovaries and uterus at the end of the study and
Biology
Female Sprague-Dawley rats were obtained from
Harlan Sprague-Dawley, Inc., at 23 days of age. The
animals were housed five per cage and maintained on
a Teklad (4%) rodent diet throughout the study. At 50
days of age, the rats received one intravenous injection
of MNU via the jugular vein. MNU was purchased from
the NCI Chemical Repository. The animals (n ) 20 per
group) were administered with 1 or 9-cis-retinoic acid
Ta ble 1
organ weight (g) per 100 g of body weight
retinoid
final body weight (g)
liver
uterus
ovaries
MNU control
1 (100 mg/kg diet)
1 (200 mg/mg diet)
9-cis-retinoic acid (100 mg/kg diet)
269 ( 9a
271 ( 3
272 ( 9
254 ( 7
3.22 ( 0.05
2.96 ( 0.07
3.11 ( 0.09
3.48 ( 0.09
0.18 ( 0.03
0.16 ( 0.01
0.21 ( 0.02
0.18 ( 0.01
0.046 ( 0.002
0.046 ( 0.002
0.052 ( 0.005
0.040 ( 0.003
a
Values are the mean ( SEM; N ) 5. Statistical differences between groups were not observed.

3768 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17
Brief Articles
(2Z,4E)-4-(3′,4′-Dih yd r o-1′(2′H)-n a p h th a len -1′ylid en e)-
3-m eth yl-2-bu ten a l (7). To a flame-dried three-neck, round-
bottomed flask fitted with a nitrogen inlet, addition funnel,
and rubber septum was added lactone 4 (20.0 g, 87.6 mmol).
To this was added 400 mL of THF (freshly distilled from Na/
benzophenone). The resulting solution was cooled to -78 °C
in a dry ice/acetone bath. The reaction mixture was treated
with diisobutylaluminum hydride (88.0 mL, 87.6 mmol, 1 N
solution in THF, Aldrich) dropwise over a period of 45 min.
After 2 h of stirring at -78 °C, an additional amount of DIBAH
(8.80 mL, 8.76 mmol) was added dropwise. After an additional
3 h of stirring, more DIBAH (8.80 mL, 8.76 mmol) was added
dropwise, and stirring continued at -78 °C for an additional
20 h. The reaction mixture was quenched with 20 mL of water,
and the dry ice bath was removed. After reaching room
temperature, the mixture was warmed to about 35 °C in a
water bath and 60 mL of 18% HCl was added. The mixture
was stirred for 10 min at 35-40 °C. The reaction mixture was
diluted with ether (200 mL), washed with water (3 × 100 mL)
and brine (2 × 100 mL), dried (Na2SO4), and evaporated
(rotary evaporator, water bath temperature of <35 °C) to give
18 g of an oil, which was purified by column chromatography
(silica gel, 40 cm × 7 cm, 1:6 ether/hexanes, all column solvents
purged with nitrogen) to give 10 g of (9Z)-7 (Rf ) 0.3) and 2.5
g of (all-E)-7 (Rf ) 0.25) (75% combined yield). The (9Z)-7 was
crystallized from hexanes/ether: mp 65-66 °C; IR 1662 (Cd
O), 1609 (CdC) cm-1; UV λmax 295 (ꢀ 6000); MS m/z 213 (M+
+ H); 1H NMR (CDCl3) δ 9.64 (d, 1H), 7.64 (m, 1H), 7.13-
7.25 (m, 3H), 6.57 (s, 1H), 6.0 (d, 1H), 2.86 (t, 2H), 2.50 (t,
2H), 2.09 (s, 3H), 1.82-1.90 (m, 2H).
(2E,4E,6Z,8E)-Eth yl 8-(3′,4′-Dih yd r o-1′(2′H)-n a p h th a -
len -1′-ylid en e)-3,7-d im eth yl-2,4,6-octa tr ien oa te (9). So-
dium hydride (60% suspension in mineral oil, 2.95 g, 73.8
mmol) was placed in a flame-dried three-neck, round-bottomed
flask fitted with a nitrogen inlet, addition funnel, and rubber
septum. Freshly distilled THF (from Na/benzophenone, 400
mL) was added, followed by freshly distilled 8 (19.45 g, 73.67
mmol). The resulting brown mixture was stirred for 15 min,
and freshly distilled HMPA (50 mL) was introduced through
a syringe. The flask was covered with aluminum foil, and
stirring was continued for 15 min. The aldehyde 7 (14.20 g,
66.98 mmol) in 100 mL of dry THF was added dropwise from
the addition funnel (covered with aluminum foil). The reaction
mixture was stirred for an additional 2.5 h, was quenched with
50 mL of water, and then diluted with 500 mL of ether. The
aqueous layer was separated and washed with 100 mL of
ether. The combined organic layers were washed with brine
(2 × 150 mL), dried (Na2SO4), and evaporated to give a crude
oil (35 g), which was suspended in methanol (75 mL, degassed
with nitrogen). Ether was added until the mixture was
homogeneous (about 20 mL), and the solution was cooled
overnight at 0 °C to give a crystalline solid. This solid was
filtered, washed with methanol, and dried to give 14 g of pure
product (9Z)-9 as one isomer: mp 64-65 °C; IR 1706 (CdO),
1602 (CdC) cm-1; UV λmax 328 nm (ꢀ 29 300); MS m/z 323 (M+
+ H); 1H NMR (CDCl3) δ 7.62-7.68 (m, 1H), 7.11-7.22 (m,
3H), 6.65 (dd, 1H), 6.5 (s, 1H), 6.23 (d, 1H), 6.1 (d, 1H), 5.75
(s, 1H), 4.15 (q, 2H), 2.85 (t, 2H), 2.40 (dt, 2H), 2.22 (s, 3H),
1.97 (s, 3H), 1.78-1.87 (m, 2H), 1.27 (t, 3H).
monitored the estrus cycles of the rats in the various
groups. Since major differences between groups were
not observed, it appeared that 1 modified the carcino-
genic process by a mechanism other than through
hormonal modifications. Anzano et al. reported similar
efficacy for 9-cis-retinoic acid in mammary cancer
chemoprevention using this MNU assay.4
Con clu sion s
Synthetic methodology suitable for generating 1, and
presumably related retinoids, on a multigram scale was
developed. Retinoid 1 was found to be highly active in
the prevention of mammary carcinogenesis in rats and
was completely nontoxic at the highest tested dose when
administered orally. This and related retinoids warrant
further evaluation as potential therapeutic agents in
mammary chemoprevention.
Exp er im en ta l Section
Melting points were obtained on an electrothermal melting
point apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded on a Bruker ARX 300 spectrometer. UV/vis
spectra were recorded on Varian Cary 100 Conc spectropho-
tometer in methanol. IR spectra were recorded using a Bomem
MB series FT IR spectrometer. Mass spectra were recorded
on a MicroMass platform LCZ spectrometer. Atlantic Microlabs
of Atlanta, GA, provided combustion analyses. Solvents and
liquid starting materials were distilled prior to use. Reactions
and purifications were conducted with deoxygenated solvents
under inert gas (N2) and in subdued lighting. Flash chroma-
tography was performed using Selecto Scientific silica gel (40
µm). Ethyl 4-bromo-3-methylbut-2-enoate (3) was prepared by
the reaction of ethyl 3,3-dimethylacrylate with N-bromo-
succinimide.9-11 Triethyl phosphonosenecioate (8) was pre-
pared via the Arbusov reaction.12 Tetrahydrofuran was dis-
tilled from sodium metal/benzophenone ketyl. Diethyl ether,
benzene, and dichloromethane were purchased from Fischer
as anhydrous solvents. HMPA was distilled from calcium
hydride.
7,8-Ben zo-4-m eth yl-1-oxaspir o[5.5]u n dec-3-en -2-on e (4).
A mixture of zinc dust (150 g) (<10 µm, Aldrich, catalog no.
20,998-8) and copper(II) acetate monohydrate (15 g, Acros) in
500 mL of glacial acetic acid was stirred under nitrogen for 1
h in a 1000 mL one-neck, round-bottomed flask. The mixture
was diluted with anhydrous ether (500 mL) and filtered with
suction, and the Zn-Cu complex was washed successively with
anhydrous ether (3 × 300 mL) and dry benzene (3 × 300 mL).
The mixture was then transferred into a flame-dried 2000 mL
three-neck flask fitted with a nitrogen inlet, condenser, and
addition funnel. Freshly distilled THF (distilled from Na/
benzophenone) (200 mL) was added to the flask, which was
heated to about 90 °C in an oil bath. The reaction mixture
was then treated dropwise with a solution of tetralone 2 (100.0
g, 684.9 mmol, freshly distilled) and bromoester 3 (220.0 g,
1063 mmol, freshly distilled) in 400 mL of THF (dry). Vigorous
bubbling occurred during the addition. The mixture was stirred
at reflux for an additional 3.5 h. The reaction mixture was
cooled to room temperature, and water (200 mL) and HCl (2
N, 500 mL) were added. The mixture was diluted with 1000
mL of ether and filtered, and the acid layer was separated.
The organic layer was washed with water (2 × 200 mL), NaOH
(1 N, 2 × 250 mL), and brine (2 × 250 mL). It was then dried
(Na2SO4) and evaporated to give an oil. This oil was subjected
to distillation on a high-vacuum pump (0.1 mm) at 60 °C. The
distillate was discarded, and the remaining thick oily residue
solidified upon addition of hexanes. This mixture was cooled,
filtered, and washed with hexanes to give 108 g (69.2%) of 4
(Rf ) 0.3, 50:50 ether/hexane) as a white solid: mp 67-69 °C;
(2E,4E,6Z,8E)-8-(3′,4′-Dih yd r o-1′(2′H )-n a p h t h a len -1′-
ylid en e)-3,7-d im eth yl-2,4,6-octa tr ien oic Acid (9cUAB30,
1). Ester 9 (12.00 g, 37.26 mmol) was suspended in methanol
(640 mL, degassed with nitrogen) and warmed to about 60 °C.
This mixture was treated with KOH solution (20.90 g, 372.7
mmol, in 220 mL of distilled and degassed water). The
resulting mixture was stirred at reflux for 1 h, cooled to 0 °C
in an ice bath, and diluted with 300 mL of ice-cold water. The
mixture was slowly acidified with ice-cold 2 N HCl to about
pH 2. The resulting precipitate was filtered, and the solid was
redissolved in 500 mL of ether. The organic solution was
washed with brine (3 × 150 mL), dried (Na2SO4), and concen-
trated on a rotary evaporator to about 75 mL of volume. The
residual solution was diluted with 100 mL of degassed hexanes
and cooled at 0 °C for about 12 h. The resulting yellow crystals
1
MS m/z 229 (M+); H NMR (CDCl3) δ 7.5-7.54 (m, 1H), 7.2-
7.25 (m, 2H), 7.07-7.1 (m, 1H), 5.92 (s, 1H), 2.7-2.9 (m, 3H),
2.5 (d, 1H), 1.98-2.23 (m, 3H), 2.01 (s, 3H), 1.67-1.78 (m, 1H).

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3769
(5) Gottardis, M. M.; Bischoff, E. D.; Shirley, M. A.; Wagoner, M.
A.; Lamph, W. W.; Heyman, R. A. Chemoprevention of Mam-
mary Carcinoma by LGD 1069 (Targretin): An RXR-Selective
Ligand. Cancer Res. 1996, 56, 5566-5570.
(6) Bischoff, E. D.; Gottardis, M. M.; Moon, T. E.; Heyman, R. A.;
Lamph, W. W. Beyond Tamoxifen: The Retinoid X Receptor-
Selective Ligand LGD 1069 (TARGRETIN) Causes Complete
Regression of Mammary Carcinoma. Cancer Res. 1998, 58, 479-
484.
were filtered and dried to give 8.5 g (78%) of pure (9Z)-1 (9Z-
9cUAB30): mp 175-176 °C; IR 1672 (CdO), 1594 (CdC) cm-1
;
1
UV λmax 328 nm (ꢀ 30 200); MS m/z 295 (M+ + H); H NMR
(CDCl3) δ 11.00 (br, 1H), 7.6-7.67 (m, 1H), 7.15-7.21 (m, 2H),
7.11-7.14 (m, 1H), 6.68 (dd, 1H), 6.47 (s, 1H), 6.25 (d, 1H),
6.12 (d, 1H), 5.77 (s, 1H), 2.85 (t, 2H), 2.40 (dt, 2H), 2.22 (s,
3H), 1.98 (s, 3H), 1.79-1.87 (m, 2H).
Ack n ow led gm en t. We are grateful for financial
support from NIH (Grant RO1 CA73844 to D. D.
Muccio), the Komen Foundation (Grant BCTR 2000 690
to D. D. Muccio), and a Specialized Program of Research
Excellence in Cancer (SPORE) (Grant 1 P50 CA89019
to K. I. Bland).
(7) Muccio, D. D.; Brouillette, W. J .; Breitman, T. R.; Taimi, M.;
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