Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity

J. Med. Chem. 2005, 48, 4931-4946

4931

Synthesis and Structure-Activity Relationships of a New Series of

Retinoid-Related Biphenyl-4-ylacrylic Acids Endowed with Antiproliferative

and Proapoptotic Activity

Raffaella Cincinelli,^#Sabrina Dallavalle,^#Raffaella Nannei,^#Serena Carella,^#Daniele De Zani,^#Lucio Merlini,*^,#

Sergio Penco, Enrico Garattini,^†Giuseppe Giannini, Claudio Pisano, Loredana Vesci, Paolo Carminati,

Valentina Zuco,^‡Chiara Zanchi,^‡and Franco Zunino^‡

Dipartimento di Scienze Molecolari Agroalimentari, Universita` di Milano, Via Celoria 2, 20133 Milano, Italy,

Sigma-tau, R&D, Pomezia, Italy, Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche “Mario Negri”,

Milano, Italy, and Unita` di Farmacologia Antitumorale Preclinica, Istituto Nazionale per lo Studio e la Cura dei Tumori,

Milano, Italy

Received July 15, 2004

Atypical retinoids (AR) represent a class of proapoptotic agents with promising potential in

the treatment of neoplastic diseases. In the present work 4′-hydroxybiphenyl-4-ylacrylic acids

were studied as a novel series of AR. The synthesized compounds were evaluated for their

antiproliferative activity in a human promyelocytic leukemia cell line (NB4) and in an ovarian

carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-

resistant subline, IGROV-1/Pt-1. The presence of a bulky lipophilic group at position 3′

(adamantan-1-yl being the best) and the E configuration of the acrylic moiety appear essential

for activity below 1 µM. No substitution on the rings or on the double bond improved the activity.

A qualitative correlation between the log P and molecular volume of the 3′-substituent and

the antiproliferative activity was found. From the study of a few selected compounds, it appears

that the presence of the carboxylic group is an essential requirement for apoptogenic properties

but not for antiproliferative activity, this being maintained in amide derivatives. On the other

hand, compounds able to induce apoptosis produced a detectable level of genotoxic damage.

This observation supports the hypothesis that the genotoxic stress is a critical event mediating

apoptosis induction by compounds of this class. Among the compounds investigated, E-3-(3′-

adamantan-1-yl-4′-hydroxybiphenyl-4-yl)acrylic acid (2) was chosen for further investigation.

Introduction

The best known compound of this series is 1 (AHPN or

CD437), which was initially developed as a selective

The treatment of neoplastic diseases with chemo-

therapeutic agents is still largely unsatisfactory; the

development of innovative agents and/or novel combina-

tions is needed to improve the therapeutic effectiveness.

Recent advances in molecular biology of tumor cells

have identified a number of cellular targets as a basis

for the development of novel treatment approaches.

Apoptosis or programmed cell death (PCD) is considered

the most important process of cell killing activated by

cytotoxic agents. Apoptosis is a very complex phenom-

enon, and the pathways involved depend largely on the

cell type and the nature of stress. Defects in apoptosis

or alterations in critical pathways have been found in

several human malignancies.¹These defects provide

malignant cells with a selective growth advantage by

extending the cell life span and allowing survival even

under stress conditions. As more information on the

apoptotic process becomes available, novel and poten-

tially exploitable molecular targets are discovered and

characterized.¹

retinoic acid receptor γ (RARγ) agonist.^3,4However,

RARγ itself does not seem to mediate AR apoptotic

activity in most neoplastic cell types.⁵

1 is an effective apoptotic agent in vitro,⁶showing

activity in preclinical models of leukemia and carcinoma

both in vitro and in vivo. The apoptogenic activity of 1

was also found in retinoid-resistant cells and in RARγ-

negative cells, thus supporting a receptor-independent

mechanism of cell death activated by CD437.^7,8Other

1 analogues that lack receptor-selective effects were

found to be potent inducers of apoptosis.⁹On the other

hand, several signaling pathways, including mitogen-

activated protein kinases (MAPK), have been found to

be implicated in receptor-independent induction of

apoptosis.¹⁰Other studies have implicated the mito-

chondrion as a critical target of activity of this class of

compounds because it controls the intracellular homeo-

stasis of calcium, a cation modulating many aspects of

the process of apoptosis.^11,12Several lines of evidence

support the concept that atypical retinoids induce

In recent years the so-called atypical retinoids (AR)

(or retinoid-related molecules (RRMs)²) have been de-

veloped as a promising class of apoptotic compounds.

* To whom correspondence should be addressed. Phone: +39

0250316812. Fax: +39 0250316801. E-mail: lucio.merlini@unimi.it.

^#Universita` di Milano.

Sigma-tau, R&D.

^†Istituto di Ricerche Farmacologiche “Mario Negri”.

^‡Istituto Nazionale per lo Studio e la Cura dei Tumori.

Published on Web 06/24/2005

4932 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

genotoxic stress.¹³These DNA lesions could activate

apoptotic stimuli which likely integrate other signals

involving mitochondrial response. The integration of

several proapoptotic stimuli may therefore represent the

basis of cell death induction by these agents.^14,15Al-

though the mechanism of apoptosis induction by the

atypical retinoids remains unclear, the therapeutic

potential of the novel agents is supported by the wide

spectrum of antiproliferative activity, the unique mech-

anism of action, and the pharmacological profile. The

proapoptotic activity of atypical retinoids detected in a

wide variety of tumor cells is a promising feature

because reduced susceptibility to apoptosis is recognized

as a relevant mechanism implicated in the resistance

of tumor cells to conventional agents.¹Synthetic retin-

oid-related compounds with distinct and more specific

features may have additional advantages in terms of

improved tolerability because the side effects of classical

retinoids is likely to be related to their ability to bind

the cognate nuclear receptors.¹⁶

To identify potent and well-tolerated RAR-indepen-

dent inducers of apoptosis, we designed and synthesized

novel atypical retinoids. An assumption we made at the

beginning of this study was to keep the relatively rigid

structure of 1 and therefore to maintain the distance

between the carbon bearing the adamantyl group and

the carboxylic group. This led to compound 2 (ST 1926),

endowed with potent antiproliferative and proapoptotic

activity, reported in our preliminary communication,¹⁷

which became the lead compound of a new series. The

present study was designed to explore the putative key

portions of the molecule, i.e., the carboxylic group, the

double bond, and the adamantan-1-yl moiety, by intro-

ducing substituents or structural modifications in these

regions and evaluating the effects of the changes on the

activity of the derivatives obtained on appropriate

cellular and molecular models. A better definition of the

critical requirements for activity and understanding of

the cellular determinants of the novel compounds may

be useful for improving the pharmacological potential

of AR.

Heck reaction with acrylonitrile. Condensation of 2 with

4-aminophenol and 1,2-phenylenediamine in the pres-

ence of WSC and HOBT led to the corresponding amides

7a and 7b (Scheme 1). Replacement of the carboxylic

group with a phosphonic acid was achieved starting

from 2-(adamantan-1-yl)-4-bromophenol 12a, prepared

from 4-bromophenol according to the procedure de-

scribed by Charpentier.⁴Palladium-catalyzed Suzuki

coupling of 12a with 4-formylbenzeneboronic acid led

to the aldehyde 13a, which was subjected to Horner-

Wittig condensation with tetraethylmethylene diphos-

phonate to afford the phosphonate 14a, in turn con-

verted into the acid 14b with trimethylsilyl bromide in

dichloromethane (Scheme 2).

To check the importance of the double bond in

determining the spatial position of the carboxylic moi-

ety, the ester 5 was hydrogenated to obtain, after

hydrolysis, the more flexible saturated acid 11. Com-

pound 15, with a triple bond instead of the double bond,

was obtained by Wittig condensation of the aldehyde

13b with ethoxycarbonyliodomethyltriphenylphosphorane

and subsequent elimination accompanied by hydrolysis.

The double bond was replaced by a cyclopropyl moiety

in compound 18, which was obtained as a mixture of

diastereoisomers by palladium-catalyzed condensation

of 12b with p-vinylbenzeneboronic acid, followed by

cyclopropanation reaction with ethyl diazoacetate and

rhodium tetraacetate. The double bond was completely

removed in compound 16, obtained by a KMnO₄oxida-

tion of the aldehyde 13b (Scheme 2).

Aldehyde 13b was used as a starting material for the

introduction of substituents on the double bond. Com-

pound 17a, with a methyl group in a position R to the

carboxylic group, was prepared by Wittig condensation

with the corresponding ylide, whereas the derivative 9

with the methyl group in position â was obtained by

Heck condensation of 4 with crotonic acid. The E

configuration of compound 17a was established on the

basis of the chemical shift of the vinylic proton.¹⁹In the

case of 9, the E configuration is a consequence of the

mechanism of the reaction because it has been reported

that Heck alkylation with crotonic acid gives exclusively

or in a great excess the E diastereoisomer.²⁰Moreover,

the chemical shift of the â-methyl group is consistent

with the diagnostic data reported.²¹The two isomeric

R-fluoroacrylic acids 17b and 17c were obtained by

Wittig-Horner reaction with triethyl 2-fluoro-2-phospho-

noacetate. The ethyl ester of the E acid 17b was

obtained by working at -78 °C,²²whereas operating at

reflux temperature²³afforded an equilibrium mixture

of E and Z isomers, from which the ester of the Z acid

17c could be separated. The E vs Z configuration of the

two stereoisomers was assigned on the basis of the

vicinal H-F coupling constants.²⁴Wittig reaction of 13b

with methyl triphenylphosphoranylideneacetate fol-

lowed by hydrolysis with LiOH constituted an alterna-

tive synthesis of ester 5 and acid 2 (Scheme 2).

Chemistry

The biphenyl scaffold of all compounds was built via

a Suzuki-Miyaura reaction,¹⁸or the commercially

available 4′-bromobiphenyl-4-ol (3) was used as a start-

ing material. Compound 4 was prepared by alkylation

of 3 with adamantan-1-ol in the presence of H₂SO₄/

AcOH, 1:9, conditions being accurately chosen to avoid

the unwanted formation of small amounts of the 2,6-

bis-adamantan-1-yl derivative. Heck reaction with meth-

yl acrylate in the presence of palladium(II) acetate, tri-

o-tolylphosphine, and Et₃N gave the methyl ester 5,

which was hydrolyzed with LiOH in THF/H₂O, 1:1

(Scheme 1). This sequence afforded compound 2 with a

greater than 98% purity without chromatographic sepa-

rations and could be scaled up to 50 g.

To elucidate the role of the lipophilic function on the

phenolic ring, the bulky adamantan-1-yl group was

changed into a 1-methylcyclohexyl (8b), tert-butyl (8c),

and 1-methylcyclododecyl (8d), all compounds being

prepared by alkylation of 3 with the corresponding

tertiary alcohols in acid medium, followed by Heck

alkylation with methyl acrylate and hydrolysis of the

To elucidate the structural requisites for activity, we

planned to explore three key portions of the structure

of 2: the carboxylic group, the double bond, and the

lipophilic adamantan-1-yl moiety. First, we considered

derivatives in which the carboxylic moiety was modified.

The methyl ester 5 was reduced with LiAlH₄in THF to

afford the alcohol 10. Nitrile 6 was obtained from 4 via

Retinoid-Related Acrylic Acids

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4933

Scheme 1^a

^a(a) Adamantan-1-ol, H₂SO₄/AcOH; (b) methyl acrylate, TOTP, Pd(OAc)₂, TEA; (c) LiOH‚H₂O, THF/H₂O; (d) WSC, HOBT, 4-aminophenol

or 1,2-phenylenediamine, CH₃CN/THF; (e) nothing or 1-methylcyclohexanol or t-BuOH or 1-methycyclododecanol, H₂SO₄, CH₂Cl₂; (f)

crotonic acid, Pd(OAc)₂, Et₃N, TOTP; (g) acrylonitrile, TOTP, Pd(OAc)₂, TEA; (h) LiAlH₄, THF; (i) H₂/PtO₂, AcOEt.

ester. For the introduction of a phenyl group, 2-phen-

ylphenol (20) was used as a starting material, with a

sequence of iodination (21), Suzuki coupling (22), Wittig

condensation, and hydrolysis affording the acid 23

(Scheme 3). The chloroderivative 30 was prepared

(Scheme 4) via Suzuki reaction of 2-chloro-4-bromophe-

nol with methyl 4-bromocinnamate. Compound 8a, pre-

pared from 3 by Heck reaction and subsequent hydroly-

sis of the resulting ester, is devoid of any lipophilic

substituent on the phenol ring.

Compounds substituted on one or the other aromatic

ring were prepared following similar procedures (Scheme

4). The acids 27a and 27b were synthesized from 24a

and 24b by Heck reaction, followed by Suzuki coupling

with 12a and 12b and hydrolysis. The synthesis of the

chloroderivative 27b has been recently reported by

another group.²⁵For the synthesis of the phenanthrene

analogue 29 the intermediate aldehyde 26a was sub-

jected to the Wittig reaction to give the methoxyvinyl-

derivative 28, which after ring closure with methane-

sulfonic acid²⁶and hydrolysis gave 29. The ester obtained

by the ring closure contained only a small amount of

the isomer coming from the ring closure ortho to the

adamantyl ring. The structure of 29 was established

from the absence of an ortho coupling constant for the

proton adjacent to the OH, easily assigned on the basis

of the high-field chemical shift. From the substituted

bromophenol 12c, compound 17d was obtained after

Suzuki condensation with 4-formylbenzeneboronic acid,

Wittig reaction, and hydrolysis, while a Suzuki coupling

of 12a with 4-bromo-2-fluorocinnamate and hydrolysis

led to compound 19 (Scheme 2).

Compound 33, where the adamantyl group and the

OH were interchanged, was prepared as described in a

patent (Scheme 5).²⁷Compound 37 was prepared by a

general method of synthesis of 3,5-disubstituted phe-

nols,²⁸by addition-elimination of acetylmethylpyri-

dinium bromide onto the chalcone 34 (Scheme 6).²⁹

However, under the conditions of the literature, i.e.,

with bases such as triethylamine or sodium acetate, the

reaction stopped at a stage of one of the possible

intermediates. Only the use of a stronger base, such as

DBU, induced the cyclization.

Antiproliferative Activity

The antiproliferative activity of the synthesized com-

pounds was tested in an ovarian carcinoma cell

line, IGROV-1, carrying a functional wild-type p53,³⁰in

a cisplatin resistant ovarian carcinoma cell line,

IGROV-1/Pt-1, and in a human promyelocytic leukemia

cell line, NB₄.

4934 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

Scheme 2^a

^a(a) 4-Formylbenzeneboronic acid, Pd tetrakis, Na₂CO₃, toluene; (b) TBDMSCl, Et₃N, DMAP, DMF; (c) tetraethylmethylene diphosponate,

KF/Al₂O₃, THF; (d) (CH₃)₃SiBr, CH₂Cl₂; (e) Ph₃PdCH(I)COOEt, K₂CO₃, MeOH; (f) KOH, MeOH; (g) KMnO₄, H₂O/acetone; (h) LiOH‚H₂O,

DMF; (i) Ph₃PdC(R′′)COOEt/CHCl₃/BuLi/THF; (l) EtOCOCHFPO(OEt)₂/BuLi/THF; (m) p-vinylbenzeneboronic acid, Pd(Ph₃P)₄, Na₂CO₃,

toluene; (n) rhodium tetraacetate bihydrate, ethyl diazoacetate, CH₂Cl₂; (o) KF/Al₂O₃, dimethoxyethane, then LiOH‚H₂O, THF/H₂O; (p)

bis(pinacolato)diboron, KOAc, PdCl₂(dppf), methyl 4-Br-2-F-cinnamate, Na₂CO₃.

Scheme 3^a

^a(a) NaI, chloramine T, DMF; (b) p-formylbenzeneboronic acid, Pd tetrakis, Na₂CO₃, toluene; (c) Ph₃PdCHCOOCH₃, CHCl₃; (d)

LiOH‚H₂O, THF/H₂O.

Results and Discussion

and of a leukemia, i.e., the cell line IGROV-1, the

cisplatin-resistant subline IGROV-1/Pt1, and the human

promyelocytic leukemia cell line NB₄. In the case of

IGROV-1, the parental cell line, characterized by the

expression of a wild-type p53, was appreciably more

A cell growth inhibition assay was used to deter-

mine the antiproliferative activity of the compounds

synthesized. The cell systems selected for this study

were representative of a solid tumor (ovarian carcinoma)

Retinoid-Related Acrylic Acids

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4935

Scheme 4^a

^a(a) Methyl acrylate, Pd(OAc)₂, TOTP, TEA; (b) C₆H₅N(SO₂CF₃)₂, TEA, CH₂Cl₂, 0-5 °C; (c) bis(pinacolato)diboron, KOAc, PdCl₂(dppf),

12a or 12b, Na₂CO₃; (d) CH₃OCH₂PPh₃⁺Cl^-, BuLi, THF, 0 °C; (e) LiOH‚H₂O, THF/H₂O, 1:1; (f) methanesulfonic acid, CH₂Cl₂, 0 °C; (g)

bis(pinacolato)diboron, KOAc, PdCl₂(dppf), methyl 4-Br-cinnamate, Na₂CO₃.

Scheme 5^a

^a(a) Adamantan-1-ol, H₂SO₄/AcOH; (b) bis(pinacolato)di boron, KOAc, PdCl₂(dppf), methyl 4-Br-cinnamate, Na₂CO₃; (c) LiOH, THF/

H₂O.

Scheme 6^a

^a(a) DBU, EtOH, 42%; (b) methyl acrylate, Pd(OAc)₂, tri-o-tolylphosphine, Et₃N, 50%; (c) LiOH, THF/H₂O, 80%.

responsive to the lead compound 2 than the cisplatin-

resistant subline carrying a mutant p53.³⁰Since atypical

retinoids are able to activate apoptosis through p53-

dependent and p53-independent pathways and the

relative susceptibility to apoptosis likely reflects a

cooperation between these pathways, the reduced apo-

ptotic response in the cisplatin-resistant cells could be

the consequence of loss of p53 function.¹³Indeed, the

differential sensitivity of the two cell lines to the

antiproliferative activity reflected the relative suscep-

4936 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

Table 1. Antiproliferative Activity of Selected Compounds on

tance of a bulky lipophilic group ortho to the phenolic

OH, with the lipophilicity and/or size of adamantyl being

approximately the best.

IGROV-1, IGROV-1/Pt1, and NB₄Cellular Lines^a

IC₅₀(µM)

compd

IGROV-1

IGROV-1/Pt1

NB4

Replacing the carboxylic group with a phosphonic acid

(14b) or its diethyl ester (14a) again resulted in a

substantial reduction of biological effects (IC₅₀g 20 µM).

Similarly, a marked reduction of antiproliferative activ-

ity was found following conversion of the carboxylic

moiety to the corresponding nitrile 6 or alcohol 10. In

the case of the methyl ester 5, good activity is main-

tained only in the IGROV-1 line. This may reflect a

different rate of hydrolysis of the ester. Examples of in

vivo hydrolysis of esters are well-known.³¹Because the

4-hydroxyphenylamide of retinoic acid (fenretinide) is

endowed with antiproliferative and apoptogenic activ-

ity,³²the corresponding amide (7a) of compound 2 was

prepared, but this modification did not lead to an

increase of activity. A similar result was given by

amidation with 1,2-phenylenediamine to give 7b. Modi-

fications involving the double bond, e.g., reduction to

the propionic acid 11, cyclopropanation (18), or the

introduction of a methyl substituent on each carbon of

the double bond (9 and 17a, respectively) resulted in a

marked reduction of potency. In contrast, the presence

of a small-size substituent such as fluorine caused only

a marginal effect on activity provided that the E

configuration of 2 was maintained (17c). Conversely, the

activity was reduced in the isomer with the Z configu-

ration (17b). These data emphasize the importance of

the optimal geometry of the chain containing the car-

boxylic group for the activity. In the compound with a

triple bond (15) only a marginal reduction of antipro-

liferative activity was observed, in accordance with the

small changes in the spatial position of the COOH group

(the distance between C-1 of the adamantyl group and

the carbon of the carboxyl is 11.69 Å in 15, whereas it

is 11.48 Å in 2). Contrarily, a substantial decrease of

activity was observed when the carboxylic group was

directly linked to the ring (16). Derivatives with sub-

stituents in the rings that could force the biphenyl

moiety to assume a more twisted conformation (17d,

27a, 27b) or where the system was rigidified in a plane

as in the phenanthrene derivative 29 were also pre-

pared. The activity of 27b is still high and comparable

with that of 2 and 19, whereas the methyl derivative

17d and the aldehyde 27a, which bear a bulky ortho

substituent on one or the other of the aromatic rings,

are less active. However, MM2 and AM1 calculations

show a value of the dihedral angle between the two

rings for all the three compounds 17d, 27a, 27b of

around 50-55°, whereas it is 35-40° for 2 and for 19,

where the F atom ortho to the acrylic chain does not

influence the twisting of the biphenyl system. Therefore,

the twisting of the biphenyl rings does not seem to be

an important factor for activity. Similarly, the phenan-

threne derivative 29 was not better than 2. Here, it is

difficult to ascribe the decrease in activity to the

complete planarity of the compound or to the presence

of an additional group within the rings that could

interfere with the putative receptor.

1

0.35 ( 0.04

0.23 ( 0.08

0.61 ( 0.2

8.3 ( 1.4

6.6 ( 0.5

2.1 ( 0.15

89 ( 11

2.58 ( 0.2

30

0.62 ( 0.24

0.40 ( 0.08

3.5 ( 1.6

12.7 ( 0.5

10.50

0.4 ( 0.05

0.082 ( 0.005

18.2 ( 0.2

14.3 ( 0.2

2 ( 0.02

1.8 ( 0.006

78.7 ( 7.4

2.2 ( 0.01

42.3 ( 3.4

nd

6.7 ( 0.02

9.1 ( 0.08

63.6 ( 11.7

1.7 ( 0.3

>200

1.2 ( 0.1

35.2 ( 4.5

2.3 ( 0.3

22.4 ( 0.9

0.081 ( 0.002

1.7 ( 0.05

39.4(0.5

0.17 ( 0.02

45.3 ( 3.9

1.05 ( 0.1

0.20 ( 0.01

1.5 ( 0.01

nd

2

5

6

7a

7b

8a

8b

8c

8d

9

2 ( 0.07

156 ( 2

2.3 ( 0.1

30

3.57 ( 0.4

9.97 ( 1.32

10.8

nd

16.65 ( 9.92

10.6

10

11

14a

14b

15

16

17a

17b

17c,

17d

18

19

23

27a

27b

29

30

33

37

48.42 ( 0.88

19.7

44.50 ( 0.28

>20

1.15

1.52

>3

7.19 ( 1.27

>3

10.04 ( 3.02

>3

0.37 ( 0.04

1.14 ( 0.2

>20

0.63 ( 0.06

2.92 ( 0.24

>20

0.2 ( 0.08

19.0 ( 2

1.28 ( 0.02

0.58 ( 0.09

2.2 ( 0.3

26 ( 2

0.43(0.13

12.5

2.63 ( 0.24

0.73 ( 0.38

2.10 ( 0.35

nd

6.13 ( 0.4

1.31 ( 0.22

nd

>10

1.2 ( 0.09

^aIC₅₀(µM) is the concentration required for 50% inhibition of

cell growth ((SD).

tibility to apoptosis.¹³After 72 h of exposure, the level

of apoptosis induced by IC₈₀of compound 2 in IGROV-1

was 65%, which is substantially higher than the apop-

tosis induced in the cisplatin-resistant sublines (30%).

The antiproliferative activities (IC₅₀) of the tested

compounds are summarized in Table 1. As said above,

the purpose of this study was to explore the putative

key portions of the molecule, i.e., the carboxylic group,

the double bond, and the adamantan-1-yl moiety, by

introducing substituents or structural modifications in

these regions and evaluating the effects of the changes

on the activity of the derivatives.

Removal (8a) or substitution of the lipophilic ada-

mantan-1-yl moiety with a phenyl (23) or a tert-butyl

group (8c) resulted in a dramatic reduction of antipro-

liferative activity. This effect was less marked in

compounds 8b and 8d containing the methylcyclohexyl

and methylcyclododecyl residues, respectively. No direct

correlation of the activity of the whole series of com-

pounds prepared with the calculated log P could be

found because the strongly lipophilic adamantyl group

present in almost all the compounds dominates the log P

value. However, in the restricted series 8a, 30, 23, 8c,

8b, 2, 8d, where only the substituent on the phenol ring

was changed, the trend of activity (e.g., for the IGROV

line IC₅₀(µM) is 89, 26, 19, 30, 2.58, 0.23, 3.57,

respectively) is similar to that of the lipophilicity of the

first six compounds (log P is 3.22, 3.78, 4.89, 4.92, 5.68,

5.67, respectively) or of the molecular volume of the first

six compounds (188.7, 200.6, 254.0, 255.4, 288, 297.7

cm³, respectively), to decreasing again for compound 8d,

where log P and the molecular volume are 7.78 and 377

cm³, respectively. This certainly indicates the impor-

From these data we can conclude that the structural

requirements for optimal activity are rather strict, in

particular that (a) the presence of the carboxylic group

is required for activity, (b) the E configuration of the

Retinoid-Related Acrylic Acids

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4937

Table 2. Comparison of Antiproliferative Proapoptotic Activity

and Production of DNA Damage by Selected Compounds

DNA

acrylic moiety is necessary, (c) no substitution except a

very small one (fluorine) is tolerated on the double bond,

(d) substituents on the biphenyl ring that could force

twisting of the ring do not increase the activity, (e) a

bulky lipophilic substituent in position 3′ is necessary,

adamantan-1-yl being so far the best. These results

suggest that the interaction of the carboxylic group at

the binding pocket is critically dependent on the op-

timal distance and orientation of the bulky adamantyl

group in position 3′. This last statement is sup-

ported by the strong decrease of activity (ca. 6 µM on

IGROV-1) when the adamantyl and the OH groups in

2 are interchanged (33). In this compound the bulky

adamantyl group is shifted far away from the COOH

and occupies a different region of the space with respect

to 2. To exclude that this effect is due to just the change

in the position of the OH group, we prepared compound

37, which shows a much lesser decrease of activity (1.31

µM on IGROV-1).

antiproliferative activity^a

apoptosis^b

(%)

damage^c

(rad

IC₅₀(µM)

compd IGROV-1 IGROV-1/Pt IGROV-1 IGROV-1/Pt equiv)

1

0.35 ( 0.04

0.23 ( 0.08

0.20 ( 0.08

0.62 ( 0.24 38 ( 4

0.40 ( 0.08 65 ( 6

47 ( 3

25 ( 3

30 ( 4

180-210

2

350

19

27b 0.58 ( 0.08

74 ( 4

15

1.15

52 ( 11

27a 1.28 ( 0.02

44 ( 9

7b

8b

33

7a

6

2.1 ( 0.15

2.58 ( 0.2

6.13 ( 0.4

6.6 ( 0.5

8.3 ( 1.4

9.97 ( 1.32

19.0 ( 2

2 ( 0.07

2.3 ( 0.1

8 ( 3

25 ( 3

23 8

0

200

9 ( 1

10.50

2 ( 2

2 ( 1

26 ( 11

7 ( 3

26

0

9

23

11

8a

12.5 ( 1.5

156 ( 2

1

0

48.42 ( 0.88

89 ( 11

3 ( 2

^aIC₅₀, concentration required for 50% inhibition of cell growth

((SD). ^bApoptosis level (% of apoptotic cells) determined after 72

h exposure to IC₈₀.

^cDNA damage in IGROV-1 cells determined

by alkaline elution after 6 h of exposure to IC₈₀

.

mantyl retinoids but not for antiproliferative activity.

An interesting observation of the comparative study of

the antiproliferative activities and proapoptotic effects

of the compounds tested in Table 2 was a moderate or

low induction of apoptosis by compounds characterized

by a low antiproliferative potency (IC₅₀> 5 µM). Since

the study of drug-induced apoptosis was performed at

concentrations that strongly inhibited proliferation

(IC₈₀), this finding of low proapoptotic ability of these

compounds even at concentrations causing a marked

growth inhibition indicates that their cytostatic activity

was substantially more pronounced than their cytotoxic

activity. It is conceivable that the potent antiprolifera-

tive activity reflects the drug’s ability to induce apop-

tosis. The involvement of different biological actions and

therefore of distinct mechanisms of antiproliferative and

apoptotic effects was further supported by the analysis

of the cell cycle perturbation of drug-treated cells

(Figure 1). The pattern of cell cycle distribution indi-

cated minimal changes induced by the antiproliferative

compounds 7a, 7b, 8a, and 23, in contrast to a G1/S

arrest with appearance of sub-G1 cells following treat-

ment with proapoptotic compounds 2 and 8b. Relevant

to this point is the observation that among the tested

retinoids only compounds able to induce apoptosis (2

and 8b) produced a detectable level of genotoxic damage.

Although this observation is limited to few compounds,

it supports the hypothesis that the genotoxic stress is a

critical event mediating apoptosis induction by ada-

mantyl retinoids.

Retinoids are known to modulate several biological

processes including proliferation, differentiation, and

metabolism.³³Some biological effects of these agents

could be mediated by common molecular mechanism-

(s). These synthetic retinoids are relatively selective for

RARγ (Table 3), as already reported for compounds 1

and 2, which show comparable patterns of interaction

with receptors.^15,34However, in these experiments

compound 2 did not exhibit clear subtype selectivity. It

is noted that the selectivity of compound 1 for RARγ

was more evident at low concentrations (<0.1 µM). The

less potent compounds 8b, 7a, and 7b were apparently

more selective for RARγ than compound 2. In particular,

Among the compounds investigated, E-3-(3′-adaman-

tan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid (2) ap-

peared the most potent, and was therefore chosen for

further investigation.^13,15,17

Atypical retinoids are known to inhibit proliferation

and induce apoptosis in tumor cells in vitro.²The extent

of growth inhibition and apoptosis induction is likely

dependent on the biological context. Using an ovarian

carcinoma cell line carrying wild-type p53 and a plati-

num-resistant p53 mutant subline, we compared the

antiproliferative and proapoptotic activities of selected

compounds carrying specific modifications in critical

positions, i.e., substitution of the adamantan-1-yl moiety

(8a, 8b, 23) or modification of the carboxyl group to give

amide derivatives (7a and 7b) (Table 2). In contrast to

compound 8b, containing the methylcyclohexyl residue

and retaining an appreciable antiproliferative activity

and proapoptotic activity in cells with wild-type p53,

removal of the adamantan-1-yl moiety (8a) or substitu-

tion of the adamantan-1-yl moiety with a phenyl ring

(23) caused a dramatic reduction of antiproliferative

activity and an almost complete loss of apoptotic activ-

ity. Although it is evident that adamantyl retinoids are

able to activate p53-independent pathways of apopto-

sis,¹³as already observed for compound 2, a reduced

induction of apoptosis in p53 mutant cells was observed

with all tested compounds (Table 2). The two amide

derivatives (7a and 7b) exhibited no ability to induce

significant levels of apoptosis, despite retention of

appreciable antiproliferative activity. Thus, the presence

of the carboxylic group appears to be an essential

requirement for the apoptogenic properties of the ada-

4938 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

Figure 1. Cell cycle distribution of IGROV-1 ovarian carcinoma cells treated with equitoxic concentrations of atypical retinoids

(IC₈₀) for the indicated times.

Table 3. Nuclear Retinoic Acid Receptor Specificity of Some

retinoids. Consistent with this interpretation is the

finding that the activity of compounds characterized by

low antiproliferative potency was comparable in cis-

platin-sensitive and -resistant IGROV-1 cells, thus

indicating a p53-independent cytostatic response. In

particular, protein kinases and protein phosphatases

have been implicated as cellular targets for apoptosis

induction by synthetic retinoids.^35,12However, we have

found that MAP kinases, involved in cellular stress

response (e.g., p38 kinase), could be modulated by a

compound (23) devoid of significant proapoptotic activity

(Figure 2). In conclusion, our results support the con-

cept^34,36,37that distinct molecular mechanisms are

responsible for the antiproliferative and apoptotic effects

of atypical retinoids.

Compounds^a

RARR

EC₅₀(µM)

RARâ

EC₅₀(µM)

RARγ

EC₅₀(µM)

compd

2

0.2

(0.1-0.4)

6.4

(4.6-8.9)

20.3

(13.9-29.7)

18.2

0.2

(0.1-0.3)

5.3

(3.9-7.2)

7.7

(6.1-9.8)

17.6

0.1

(0.1-0.3)

0.2

(0.1-0.5)

1.4

(0.8-2.4)

0.9

8b

7a

7b

(5.6-59.1)

>100

(7.5-41.1)

>100

(0.6-1.5)

>100

8a

23

^aCOS-7 cells were transfected with the indicated RAR isoform

and a DR5-tk-CAT reporter construct. Twenty-four hours following

transfection, cells were treated for an additional 24 h with

increasing concentrations of the indicated compound. CAT activity

was measured in cell extracts and normalized for the level of

transfection using a â-galactosidase-based construct. The EC₅₀

values for the transactivation of each RAR isoform are expressed

as the mean value of three independent replicates (the numbers

in parentheses indicate the interval of confidence for each mean

value).

Experimental Section

General Methods. All reagents and solvents were reagent

grade or were purified by standard methods before use.

Melting points were determined in open capillaries on a Bu¨chi

melting point apparatus and are uncorrected. Column chro-

matography was carried out on flash silica gel (Merck

230-400 mesh). TLC analysis was conducted on silica gel

plates (Merck 60F₂₅₄). NMR spectra were recorded at 300 MHz

with a Bruker instrument. Chemical shifts (δ values) and

coupling constants (J values) are given in ppm and Hz,

respectively. Mass spectra were recorded at an ionizing voltage

of 70 eV on a Finnigan TQ70 spectrometer. The relative inten-

sities of mass spectrum peaks are listed in parentheses. HPLC

analysis of the mixture of diastereoisomers was performed on

an HP 1050 quaternary pump fitted with a Rheodyne injector

(20 µL loop) and a HP-1050 diode-array detector. Chromato-

grams were recorded at 360 and 400 nm. The column was a

Rainin C18, 25 cm × 0.4 cm, flow 1 mL/min, with a gradient

of CH₃CN/H₂O from 30:70 to 100:0 in 20 min.

compound 8b exhibited a potency toward RARγ com-

parable to compound 2, but it was substantially less

potent as an antiproliferative agent and less effective

as an apoptosis inducer. Thus, no precise correlation

could be found between these biological effects and

retinoid receptor binding. This is in agreement with

previous studies performed with other synthetic retin-

oids supporting the finding that the mechanism of action

is independent of retinoid receptors.²The molecular

mechanisms underlying the multiple effects of these

agents remain largely undefined. However, it is evident

that the antiproliferative activity of compounds tested

in this study could not be closely related to their

proapoptotic activity, thus supporting the involvement

of multiple targets in the biological activity of synthetic

Solvents were routinely distilled prior to use. Anhydrous

tetrahydrofuran (THF) and ether (Et₂O) were obtained by

distillation from sodium benzophenone ketyl. Dry methylene

chloride was obtained by distillation from phosphorus pen-

Retinoid-Related Acrylic Acids

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4939

) 8.60 Hz). MS (EI) m/z: 355 (56, M⁺), 97 (100). ¹H NMR

(CDCl₃), Z, δ: 1.78 (6H, s), 2.13 (3H, s), 2.17 (6H, s), 4.9 (1H,

bs, OH), 5.40 (1H, d, J ) 11.3 Hz), 6.72 (1H, d, J ) 8.50 Hz),

7.13 (1H, d, J ) 11.3 Hz), 7.33 (1H, dd, J ) 8.50 Hz, J ) 2.30

Hz), 7.48 (1H, d, J ) 2.30 Hz), 7.62 (2H, d, J ) 8.50 Hz), 7.85

(2H, d, 8.50 Hz). Anal. (C₂₅H₂₅NO) C, H, N.

E-3-(3′-Adamantan-1-yl-4′-hydroxybiphenyl-4-yl)acryl-

ic Acid (2). Compound 5 (3.28 g, 8.45 mmol) was added to a

solution of LiOH‚H₂O (1.77 g, 42.25 mmol) in 340 mL of THF/

H₂O, 1:1, and the mixture was kept under stirring at room

temperature overnight. The THF was evaporated and the

mixture was extracted with hexane, acidified with 2 N HCl,

1

and filtered to give 2.82 g (94%) of 2, mp >240 °C. H NMR

(DMSO-d₆) δ: 1.74 (6H, s, 6Ad), 2.04 (3H, s, 3Ad), 2.12 (6H, s,

6Ad.), 6.51 (1H, d, -CHd, J ) 16.18 Hz), 6.85 (1H, d, 1Ar, J

) 8.82 Hz), 7.30-7.40 (2H, m, 2Ar), 7.55-7.63 (3H, m, 2Ar +

CHd), 7.70 (2H, d, 2Ar, J ) 8.09 Hz), 9.54 (1H, s, -OH), 12.34

(1H, brs, -COOH). MS (m/z): 374 (M⁺, 100). Anal. (C₂₅H₂₆O₃)

C, H.

Figure 2. Modulation of MAPKs by compound 23 in ovarian

carcinoma IGROV-1 cells. MAPK activation and expression

were analyzed in whole-cell lysates by Western blotting.

Activated kinases were detected by the use of phosphospecific

antibodies recognizing phospho-p44/42 ERKs (p-ERK1/2),

phospho-JNK (p-JNKs), and phospho p38 (p-p38). Filters were

then stripped and reprobed with antibodies recognizing the

respective proteins (ERK1/2, JNKs, and p38).

4-Hydroxyphenylamide of E-3-(3′-Adamantan-1-yl-4′-

hydroxybiphenyl-4-yl)acrylic Acid. (7a). Compound 2 (348

mg, 0.93 mmol) was dissolved under N₂in 27 mL of a solution

of THF/CH₃CN, 5:4. After addition of 178 mg (0.93 mmol) of

WSC and 126 mg (0.93 mmol) of HOBT the solution was

warmed for 4 h at 60 °C. 4-Aminophenol (112 mg, 1.02 mmol)

in 5 mL of THF was then added, and the mixture was refluxed

for 3 h. The solvent was evaporated under reduced pressure,

and the residual slurry was washed twice with water, filtered,

and dried. Purification by flash chromatography (hexane ethyl

acetate, 1:1) afforded 200 mg of the pure product. Yield 46%,

mp 291-293 °C. ¹H NMR (DMSO-d₆) δ: 1.7 (6H, s, 6Ad), 2.03

(3H, s, 3Ad), 2.12 (6H, s, 6Ad), 6.70 (2H, d, 2Ar, J ) 8.56 Hz),

6.75 (1H, d, CHd, J ) 15.63 Hz), 7.35 (2H, m, 2Ar), 7.48 (2H,

d, 2Ar, J ) 8.56 Hz), 7.50 (1H, d, CHd, J ) 15.63 Hz), 7.55-

7.65 (4H, m, 4Ar), 7.85 (1H, d, 1Ar, J ) 8.56 Hz), 9.30 (1H, s,

NHCO), 9.51 (1H, s, OH). MS m/z: 465 (M⁺, 10), 357 (80), 135

(100), 109 (40), 79 (40). Anal. (C₃₁H₃₁NO₃) C, H, N.

toxide. All reactions requiring anhydrous conditions were

performed under a positive nitrogen flow, and all glassware

was oven-dried and/or flame-dried. Purity of the products to

be tested was checked by elemental analysis and HPLC.

MM2, AM1, and log P calculations were performed using

ChemOffice ChemBats3D, and molecular volume data were

obtained from the ChemSketch program.

2-(Adamantan-1-yl)-4-(4-bromophenyl)phenol (4). A

finely pulverized mixture of 4-(4-bromophenyl)phenol (3, 200

mg, 0.8 mmol) and adamantan-1-ol (122 mg, 0.8 mmol) was

added in portions and with stirring to 0.8 mL of a mixture of

9:1 AcOH/H₂SO₄. After 4 days at room temperature addition

of ice/water and filtration gave 100% of 4, mp 140-143 °C,

2-Aminophenylamide of E-3-(3′-Adamantan-1-yl)-4′-

hydroxybiphenyl-4-yl)acrylic Acid (7b). Compound 2 (200

mg, 0.53 mmol) was dissolved under N₂in 15.5 mL of a solution

of THF/CH₃CN, 5:4. After addition of 101 mg (0.53 mmol) of

WSC and 71 mg (0.53 mmol) of HOBT, the solution was heated

for 4 h at 60-70 °C. Then an amount of 65 mg (0.6 mmol) of

1,2-phenylenediamine was added, and the mixture was re-

fluxed for 4 h. The solvent was evaporated under reduced

pressure, and the residue was washed twice with water,

filtered, and dried. Purification by flash chromatography

(hexane/ethyl acetate, 55:45) afforded 60 mg of the title

1

lit.⁴148-149 °C. H NMR (CDCl₃) δ: 1.75 (6H, s, 6Ad), 2.03

(3H, s, 3Ad), 2.12 (6H, s, 6Ad), 6.70 (2H, d, 1Ar, J ) 8.56 Hz),

7.85 (1H, d, 1Ar, J ) 8.56 Hz), 7.25 (1H, m, 1Ar), 7.30-7.42

(3H, m, 3Ar), 7.45 (2H, m, 2Ar).

Methyl E-3-(3′-Adamantan-1-yl-4′-hydroxybiphenyl-4-

yl)acrylate (5). A flask containing a mixture of 3.34 g (8.71

mmol) of 4, 1.2 g (13.94 mmol) of methyl acrylate, 19.5 mg

(0.087 mmol) of palladium acetate, and 104 mg (0.34 mmol)

of tri-o-tolylphosphine in 4 mL of triethylamine was immersed

in an oil bath preheated at 50 °C and kept at 100-110 °C for

4 h. Ice was added, and the mixture was taken up with 1 N

HCl to pH 2-3 and extracted repeatedly with ethyl acetate.

The organic phases were washed with water and dried over

Na₂SO₄and the solvent was evaporated to give 3.3 g (98%) of

5, mp >240 °C. ¹H NMR (DMSO-d₆) δ: 1.75 (6H, s, 6Ad), 2.03

(3H, s, 3Ad), 2.12 (6H, s, 6Ad), 3.70 (3H, s, -OCH3), 6.60 (1H,

d, CHd, J ) 16.18 Hz), 6.85 (1H, d, 1Ar, J ) 8 Hz), 7.30-7.40

(2H, m, 2Ar), 7.55-7.80 (5H, m, 4Ar + CHd), 9.5 (1H, s, -OH).

Anal. (C₂₆H₂₈O₃) C, H.

(E/Z)-3-(3′-(Adamantan-1-yl-4′-hydroxy-biphenyl-4-yl)-

acrylonitrile (6). Compound 4 (300 mg, 0.782 mmol), 66.4

mg (1.25 mmol) of acrylonitrile, 8.78 mg (0.0391 mmol) of

Pd(OAc)₂, and 23.80 mg (0.00782 mmol) of tri-o-tolylphosphine

in 0.600 mL of Et₃N were mixed in a round flask and heated

at 100 °C for 8 h. Water and ice were added, 2 N HCl was

added, and the aqueous phase was extracted with ethyl

acetate. The organic phase was dried over Na₂SO₄, filtered,

and evaporated. The crude product was purified by flash

chromatography (hexane/ethyl acetate, 80:20) to give 124 mg

of the product.(E/Z isomers, 2:1). Yield 45%. ¹H NMR (CDCl₃),

E, δ: 1.78 (6H, s), 2.13 (3H, s), 2.17 (3H, s), 4.9 (1H, bs, OH),

5.87 (1H, d, J ) 16.5 Hz), 6.72 (1H, d, J ) 8.50 Hz), 7.30 (1H,

dd, J ) 8.50 Hz, J ) 2.30 Hz), 7.41 (1H, d, J ) 16.50 Hz), 7.45

(1H, d, J ) 2.30 Hz), 7.47 (2H, d, J ) 8.60 Hz), 7.58 (2H, d, J

1

compound. Yield 25%, mp 210-212 °C. H NMR (DMSO-d₆)

δ: 1.75 (6H, s, 6Ad), 2.05 (3H, s, 3Ad), 2.15 (6H, s, 6Ad), 4.95

(2H, s, NH₂), 6.55 (1H, dd, 1Ar, J ) 7.82, 7.82 Hz), 6.72 (1H,

dd, 1Ar, J ) 7.82, 1.86 Hz), 6.80-6.95 (3H, m, 2Ar + CHd),

7.30-7.45 (3H, m, 3Ar), 7.55 (1H, d, CHd, J ) 15.26 Hz),

7.58-7.70 (4H, m, 4Ar), 9.38 (1H, s, NHCO), 9.40 (1H, s, OH).

MS m/z: 464 (M⁺, 30), 445(90), 357 (100). Anal. (C₃₁H₃₂N₂O₂)

C, H, N.

E-3-(4′-Hydroxybiphenyl-4-yl)acrylic Acid (8a). Com-

pound 3 (500 mg, 2 mmol), 276 mg (3.2 mmol) of methyl

acrylate, 4.5 mg (0.02 mmol) of Pd(AcO)₂, and 24 mg (0.08

mmol) of TOTP in 0.95 mL of TEA were mixed in a round flask,

which was then put in an oil bath preheated at 60 °C. The

mixture was refluxed for 8 h, ice/water was added, and the

solution was acidified with 2 N HCl. The aqueous phase was

extracted with ethyl acetate (4 × 10 mL), dried, filtered, and

evaporated. The product was crystallized from diethyl ether

to obtain 352 mg (70%) of methyl E-3-(4′-hydroxybiphenyl-4-

yl)acrylate, mp 227 °C. The above ester (350 mg, 1.38 mmol)

was suspended in a solution of 289 mg (6.88 mmol) of LiOH‚

H₂O in 44 mL of THF/H₂O, 1:1, and stirred for 23 h at room

temperature in the dark. THF was evaporated, and the

remaining aqueous phase was washed with hexane and

acidified with 0.5 mL of 2 N HCl. The light-yellow precipitate

was filtered, dried, and crystallized from diisopropyl ether to

afford 213 mg (65%) of the title compound, mp 265 °C. ¹H NMR

4940 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

(DMSO-d₆) δ 6.50 (1H, d, CHd, J ) 16.1 Hz), 6.82 (2H, d, 2

Ar, J ) 8.3 Hz), 7.55 (2H, d, 2 Ar, J ) 8.8 Hz), 7.60 (2H, d, 2

Ar, J ) 8.1 Hz), 7.65 (1H, d, CHd, J ) 16.1 Hz), 7.71 (2H, d,

2 Ar, J ) 8.1 Hz). MS (EI) m/z: 240 (M⁺, 100), 165 (50). Anal.

(C₁₅H₁₂O₃) C, H.

137 µL of H₂SO₄, 98%, the mixture was stirred at room

temperature for 24 h, then washed with water and neutralized

with NaHCO₃. The aqueous phase was extracted with ethyl

acetate, and the collected organic layers were dried, filtered,

and evaporated. Chromatography (hexane/ethyl acetate, 80:

20) afforded 2-(1-methylcyclododecyl)phenol as an oil. Yield

10%.

The above compound (86 mg, 0.244 mmol), 75 mg (0.29

mmol) of bis(pinacolato)diboron, 72 mg (0.73 mmol) of KOAc,

and 5.36 mg (0.0073 mmol) of PdCl₂(dppf) were dissolved in

1.5 mL of dioxane and heated at 80 °C for 2 h under nitrogen.

After the solution was cooled to room temperature, methyl

4-bromocinnamate (118 mg, 0.49 mmol), PdCl₂(dppf) (5.36 mg,

0.0073 mmol), and 2 N Na₂CO₃(0.3 mL, 0.61 mmol) were

added, and the mixture was heated at 80 °C for 3 h. The

solution was cooled to room temperature, diluted with water,

and acidified with 2 N HCl (2.6 mL), and the product was

extracted with ethyl acetate. The organic phase was washed

with brine, dried over Na₂SO₄, and filtered, and the solvent

was evaporated. The crude product was purified by flash

chromatography (hexane/ethyl acetate, 75:25) to give 15 mg

of methyl E-3-[3′-(1-methylcyclododecyl)-4′-hydroxybiphenyl-

4-yl]acrylate. Yield 28%, mp 198 °C.

The above ester (15 mg, 0.0345 mmol) was dissolved in a

solution of 7.3 mg (0.173 mmol) of LiOH‚H₂O in 1.4 mL of THF/

H₂O, 1:1, and the solution was stirred overnight at room

temperature in the dark. THF was evaporated, and the

aqueous phase was washed with hexane and Et₂O and

acidified with 2 N HCl (0.19 mL). The solid formed was filtered

and dried to give 10 mg of a crude product that was purified

by reverse-phase chromatography (MeOH/H₂O, 90:10) to ob-

tain 5 mg of the title compound as a white solid. Yield 34%,

mp 173 °C. ¹H NMR (acetone-d₆) δ 1.1-2.2 (25H, m, cyclodod),

6.50 (1H, d, CHd, J ) 16.0 Hz), 6.90 (1H, d, 1Ar, J ) 8.12

Hz), 7.35 (1H, dd, 1Ar, J ) 2.20 Hz, J ) 8.12 Hz), 7.55 (1H, d,

1Ar, J ) 2.20 Hz), 7.60-7.75 (5H, m, 4Ar + CHd), 8.60 (1H,

s, OH), 12.0 (1H, bs, COOH).

E-3-[3′-(Adamantan-1-yl)-4′-hydroxybiphenyl-4-yl]cro-

tonic Acid (9). Compound 4 (200 mg, 0.52 mmol), 75 mg (0.87

mmol) of crotonic acid, 1.4 mg (0.006 mmol) of Pd(OAc)₂, and

7.3 mg (0.024 mmol) of tri-o-tolylphosphine in 0.6 mL of Et₃N

were mixed in a round flask and heated at 100-110 °C for 12

h. A 1 M HCl sample was added. The product was extracted

with ethyl acetate, the organic phase was dried over Na₂SO₄

and filtered, and the solvent was evaporated. The crude

product was purified by reverse-phase flash chromatography

(methanol) and crystallized from Et₂O to give 58 mg of pure

product. Yield 29%, mp 215-220 °C. ¹H NMR (DMSO-d₆) δ

1.75 (6H, s, 6Ad), 2.05 (3H, s, 3Ad), 2.15 (6H, s, 6Ad), 2.50

(3H, s, CH₃), 6.15 (1H, s, CHd), 6.85 (1H, d, 1Ar, J ) 8.25

Hz), 7.33 (1H, dd, 1Ar, J ) 8.25 Hz, J ) 1.50 Hz), 7.35 (1H, d,

1Ar, J ) 1.50 Hz), 7.55-7-65 (4H, m, 4Ar). MS (EI) m/z: 388

(M⁺, 100). Anal. (C₂₆H₂₈O₃) C, H.

E-3-(4′-Hydroxy-3′-(1-methylcyclohexyl)biphenyl-4-yl)-

acrylic Acid (8b). 4-(4-Bromophenyl)phenol (3, 300 mg, 1.2

mmol) and 211 mg (1.85 mmol) of 1-methylcyclohexan-1-ol

were dissolved in 20 mL of dichloromethane. After addition of

92 µL of H₂SO₄, 98%, the mixture was refluxed for 90 h, then

washed with water and neutralized with NaHCO₃. The organic

layer was dried and evaporated. Chromatography (hexane/

ethyl acetate, 95:5) afforded 86 mg (21%) of 2-(1-methylcyclo-

hexyl)-4-(4-bromophenyl)phenol as an oil. The above compound

(77 mg, 0.23 mmol), 32 mg (0.37 mmol) of methyl acrylate,

0.5 mg (0.0023 mmol) of Pd(AcO)₂, and 4 mg (0.011 mmol) of

TOTP in 0.1 mL of TEA were mixed in a round flask, which

was then put in an oil bath preheated at 60 °C. The mixture

was refluxed for 8 h. After addition of ice/water, the solution

was acidified with 2 N HCl. The aqueous phase was extracted

with ethyl acetate (4 × 10 mL), dried, filtered, and evaporated.

The product was crystallized from diethyl ether to obtain 71

mg (88%) of the methyl ester of 8b, mp 253 °C. The above ester

(71 mg, 0.203 mmol) was suspended in a solution of 43 mg

(1.01 mmol) of LiOH‚H₂O in 8 mL of THF/H₂O, 1:1, and stirred

overnight at room temperature in the dark. THF was evapo-

rated, and the remaining aqueous phase was washed with

hexane and then acidified with 0.5 mL of 2 N HCl. The light-

yellow solid precipitate was filtered and dried to afford

33 mg (48%) of the title compound, mp 215-220 °C. ¹H NMR

(DMSO-d₆) δ: 1.30 (3H, s, CH3), 1.32-1.5 (8H, m, cyclohex),

2.1-2.3 (2H, m, cyclohex), 6.50 (1H, d, CHd, J ) 15.81 Hz),

6.87 (1H, d, 1Ar, J ) 8.5 Hz), 7.32 (1H, dd, 1Ar, J ) 8.5 Hz,

2.6 Hz), 7.53-7.7 (5H, m, 4 Ar + CHd). MS (EI) m/z: 336

(M⁺, 100), 253 (35). Anal. (C₂₂H₂₄O₃) C, H.

E-3-(3′-tert-Butyl-4′-hydroxybiphenyl-4-yl)acrylic Acid

(8c). To a solution of CH₃COOH/concentrated H₂SO₄, 9:1 (2

mL), an amount of 500 mg (2.01 mmol) of 4-(4′-bromophenyl)-

phenol was added. Then an amount of 0.192 mL (2.01 mmol)

of tert-butyl alcohol was added dropwise. The mixture was

stirred at room temperature for 2 weeks. CH₃COOH was

evaporated, and water and ice were added. The white solid

was filtered and washed with water. The crude product was

purified by flash chromatography (hexane/ethyl acetate, 85:

15) to give 163 mg of 2-tert-butyl-4-(4′-bromophenyl)phenol.

Yield 27%, mp 114-116 °C.

The above compound (160 mg, 0.524 mmol), 72 mg (0.838

mmol) of methyl acrylate, 5 mg (0.0223 mmol) of Pd(OAc)₂,

and 27 mg (0.0887 mmol) of tri-o-tolylphosphine in 0.243

mL of Et₃N were mixed in a round flask and heated at 100 °C

for 4 h. Water and ice were added, 2 N HCl was added, and

the aqueous phase was extracted with ethyl acetate. The

organic phase was dried over Na₂SO₄, filtered, and evaporated.

The crude product was purified by flash chromatography

(dichloromethane/hexane, 95:5), to give 121 mg of methyl E-3-

(3′-tert-butyl-4′-hydroxybiphenyl-4-yl)acrylate. Yield 74%, mp

182 °C.

3-Adamantan-1-yl-4′-(3-hydroxypropenyl)biphenyl-4-

ol (10). A solution of 1 M LiAlH₄in THF (386 µL) was diluted

in 1 mL of THF and cooled to -5 °C with an ice/salt bath under

N₂. To this solution an amount of 150 mg (0.386 mmol) of 4 in

4 mL of anhydrous THF was dropped, and stirring was

continued for 2 h at 0 °C. A solution of 10% NH₄Cl was slowly

added, cooling with an ice bath. THF was evaporated, and the

aqueous phase was extracted with ethyl acetate. The organic

layer was dried, filtered, and evaporated. The product was

purified by flash chromatography (eluent AcOEt/hexane, 1:2)

The above compound (70 mg, 0.226 mmol) was dissolved in

a solution of 47.4 mg (1.13 mmol) of LiOH‚H₂O in 9.30 mL of

THF/H₂O, 1:1, and the solution was stirred overnight at room

temperature in the dark. THF was evaporated. The aqueous

phase was washed with hexane and Et₂O and then acidified

with 2 N HCl (0.6 mL). The white solid was filtered and dried

to give 54 mg of pure product. Yield 81%, mp 218 °C. ¹H NMR

(DMSO-d₆) δ 1.34 (9H, s, 3CH₃), 6.47 (1H, d, CHd, J ) 16.38

Hz), 6.83 (1H, d, 1Ar, J ) 8.19 Hz), 7.34 (1H, dd, 1Ar, J )

8.19 Hz, J ) 2.23 Hz), 7.40 (1H, d, 1Ar, J ) 2.23 Hz), 7.55

(1H, d, CHd, J ) 16.38 Hz), 7.58 (2H, d, 2Ar, J ) 8.25 Hz),

7.68 (2H, d, 2Ar, J ) 8.25 Hz), 9.63 (1H, s, OH). MS (EI) m/z:

296 (97, M⁺), 281 (100), 253 (64). Anal. (C₁₉H₂₀O₃) C, H.

1

and crystallized from Et₂O. Yield 10%, mp 196 °C. H NMR

(acetone-d₆) δ: 1.75 (6H, s, 6Ad), 2.06 (3H, s, 3Ad), 2.25 (6H,

s, 6Ad), 4.25 (2H, d, -CH₂OH, J ) 5.15 Hz), 6.45 (1H, dt,

-CHd, J ) 15.81 Hz, 5.15 Hz), 6.65 (1H, d, CHd, J ) 15.81

Hz), 6.90 (1H, d, 1Ar, J ) 8.46 Hz), 7.31 (1H, dd, 1Ar, J )

8.46 Hz, 2.57 Hz), 7.45-7.55 (4H, m, 4Ar), 8.45 (1H, brs, OH).

MS (EI) m/z: 360 (M⁺, 100), 317 (50). Anal. (C₂₅H₂₈O₂) C, H.

E-3-[3′-(1-Methylcyclododecyl)-4′-hydroxybiphenyl-4-

yl]acrylic Acid (8d). 4-Bromophenol (446 mg, 2.58 mmol) and

510 mg (2.58 mmol) of 1-methylcyclododecan-1-ol were dis-

solved in 1.3 mL of dichloromethane. After slow addition of

3-(3′-Adamantan-1-yl-4′-hydroxybiphenyl-4-yl)propi-

onic Acid (11). Compound 5 (80 mg) was dissolved in 40 mL

of AcOEt, an amount of 30 mg of PtO₂was added, and the

mixture was hydrogenated for 40 min. After filtration of the

Retinoid-Related Acrylic Acids

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4941

catalyst, the solvent was evaporated to obtain 80 mg (100%)

of methyl 3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)pro-

pionate, mp 150 °C. A solution of 43 mg (1.03 mmol) of LiOH‚

H₂O and 80 mg (0.205 mmol) of the above ester in 8.4 mL of

THF/H₂O, 1:1, was stirred at room temperature for 1.5 h. THF

was evaporated, and the remaining aqueous layer was washed

with hexane and then acidified with 1 M HCl to pH 2 to obtain,

after filtration, 57 mg of a white solid. Yield 74%, mp 197-

200 °C. ¹H NMR (acetone-d₆) δ: 1.80 (6H, s, 6Ad), 2.10 (3H, s,

3Ad), 2.25 (6H, s, 6Ad), 2.65 (2H, t, -CH₂-, J ) 7.72 Hz), 2.95

(2H, t, -CH₂-, J ) 7.72 Hz), 6.90 (1H, d, 1Ar, J ) 8.09 Hz),

7.25-7.35 (3H, m, 3Ar), 7.42 (1H, d, 1 Ar, J ) 2.21 Hz), 7.50

(2H, d, 2Ar, J ) 8.34 Hz), 8.45 (1H, brs, OH). MS (EI) m/z:

376 (M⁺, 100). Anal. (C₂₅H₂₈O₃) C, H.

2-(Adamantan-1-yl)-5-methyl-4-bromophenol (12c). A

finely pulverized mixture of 3-methyl-4-bromophenol (500 mg,

2.7 mmol) and 1-adamantanol (409 mg, 2.7 mmol) was added

portionwise with stirring to 2.7 mL of CH₃COOH/concentrated

H₂SO₄, 9:1. The mixture was stirred at room temperature for

4 days, water and ice were added, and the solid was filtered

and washed with water to give 722 mg of the desired product.

Yield 84%, mp 155-156 °C.

3′-(Adamantan-1-yl)-4′-hydroxybiphenyl-4-aldehyde

(13a). 2-(1-Adamantan-1-yl)-4-bromophenol (12a, 2 g, 6.51

mmol) in 13 mL of toluene was added, under a stream of

nitrogen, with 6.51 mL of 2 M aqueous Na₂CO₃, 226 mg (0.195

mmol) of Pd(Ph₃P)₄, and 1.074 g (7.16 mmol) of 4-formylben-

zeneboronic acid (previously suspended in 3.03 mL of EtOH).

The resulting solution was refluxed 3 h, then extracted with

ethyl acetate. The organic layer was washed with brine and

water, dried, and evaporated to give, after chromatography

with hexane/ethyl acetate, 7:3, 630 mg of 13a, yield 30%, mp

252 °C.

3′-(Adamantan-1-yl)-4′-tert-butyldimethylsilyloxybi-

phenyl-4-aldehyde (13b). 3-(Adamantan-1-yl)-4-(tert-bu-

tyldimethylsilyloxy)bromobenzene 12b⁴(1.56 g, 3.70 mmol)

was dissolved in 7.5 mL of toluene. Then 3.7 mL of a 2 M

aqueous solution of Na₂CO₃, 0.128 g (0.11 mmol) of tetrakis-

triphenylphosphine-palladium, and a solution of 610 mg (4.07

mmol) of 4-formylbenzeneboronic acid in 1.73 mL of ethanol

were added. The mixture was refluxed for 2 h in a stream of

nitrogen. It was then cooled, taken up with ethyl acetate, and

washed with a NaCl saturated solution. The phases were

separated, the organic layer was filtered, dried over Na₂SO₄,

and filtered, the solvent was evaporated, and the residue was

subjected to flash chromatography (hexane/ethyl acetate, 3:1)

to give 1.09 g of the title compound, mp 158 °C.

and 7.5 (ABX, J_AB) 17.3 Hz, J_P-HA) 17.3 Hz, J_P-HB) 22 Hz,

PO-CH_AdCH_B), 6.80 (1H, d, J ) 8.5 Hz), 7.43 (1H, dd, J )

8.5 and 2.2 Hz), 7.48 (1H, d, J ) 2.2 Hz), 7.5-7.6 (4H, m, Ar).

MS (EI) m/z: 466 (M⁺, 100), 317 (40), 275 (75). Anal.

(C₂₈H₃₅O₄P) C, H.

E-[3-(3′-Adamantan-1-yl)-4′-hydroxybiphenyl-4-yl)vinyl]-

phosphonic Acid (14b). The ester 14a (90 mg, 0.193 mmol)

was dissolved under a stream of nitrogen in 7.5 mL of

anhydrous dichloromethane. Trimethylsilyl bromide (259 mg,

1.93 mmol) was then dropped, and the solution was stirred

overnight at room temperature protected from light. The

solvent and the excess of trimethylsilyl bromide were evapo-

rated, and an amount of 5.4 mL of water was added. After

stirring 30 min at room temperature, the solid was evaporated.

The mixture was dissolved in 1 N NaOH and stirred 30 min

at room temperature, then acidified and stirred for a fur-

ther 30 min. The solid was filtered to obtain 60 mg of pure

product. Yield 76%, mp 200 °C. ¹H NMR (DMSO-d₆) δ 1.73

(6H, s, 6 Ad), 2.0 (3H, s, 3 Ad), 2.1 (6H, s, 6 Ad), 6.18 and 6.44

(ABX, J_AB) 17.5 Hz, J_P-HA) 17.5 Hz, J_P-HB) 22 Hz,

PO-CH_AdCH_B), 6.83 (1H, d, J ) 8.6 Hz), 7.30 (1H, dd, J )

8.6 Hz, J ) 2.2 Hz), 7.32 (1H, d, J ) 2.2 Hz), 7.52-7.65 (4H,

m, Ar), 9.5 (1H, s, OH). MS (EI) m/z: 411 (M⁺, 50), 301 (35),

205 (35), 149 (70), 93 (65), 91 (100). Anal. (C₂₄H₂₇O₄P) C, H.

3-[3′-(Adamantan-1-yl)-4′-hydroxybiphenyl-4-yl]-pro-

pynoic acid (15). To a vigorously stirred suspension of

367 mg (2.66 mmol) of K₂CO₃and 800 mg (1.33 mmol) of

Ph₃P⁺-CH(I)-COOEt I^-(in 2 mL of MeOH), an amount of

5.92 mg (1.33 mmol) of the aldehyde 13b (previously dissolved

in 3 mL of CHCl₃) was dropped. The resulting suspension was

stirred for 11 h. After filtration the solvent was evaporated.

Purification by flash chromatography (eluent hexane/dichlo-

rometane, 2:1) led to methyl Z-2-iodo-3-(3′-adamantan-1-yl)-

4′-tert-butyldimethylsilanoxybiphenyl-4-yl)acrylate (where the

ester group had exchanged with methanol) as an oil. The above

ester (50 mg, 0.080 mmol) was added to a solution of 25% KOH

in 4.5 mL of MeOH, and the resulting suspension was refluxed

for 1 h. The solvent was evaporated, and water was added.

The solid formed after acidification with 2 M HCl was filtered

and dried. Purification by reverse-phase chromatography

(Merck Lichroprep RP-18, MeOH/H₂O, 7:3) afforded 20 mg of

1

pure 15. Yield 70%, mp 201 °C. H NMR (MeOD) δ 1.80 (6H,

s, 6Ad.), 2.10 (3H, s, 3Ad.), 2.25 (6H, s, 6Ad.), 6.85 (1H, d, 1Ar,

J ) 8.0 Hz), 7.35 (1H, dd, 1Ar, J ) 8.0 Hz, 1.84 Hz), 7.45 (1H,

d, 1Ar, J ) 1.84 Hz), 7.5-7.65 (4H, m, 4Ar). MS (FAB glycerol)

m/z: 373 (M + 1, 100), 301 (50), 207 (40), 115 (40). Anal.

(C₂₅H₂₄O₃) C, H.

3-[3′-(Adamantan-1-yl)-4′-hydroxybiphenyl-4-yl]-4-car-

boxylic Acid (16). To a solution of the aldehyde 13b (50 mg,

0.112 mmol) in 1.6 mL of acetone, an amount of 26 mg (0.168

mmol) of KMnO₄dissolved in 0.5 mL of H₂O was dropped. The

solution was heated at 50 °C for 1 h. After filtration of MnO₂,

water was added and the aqueous phase was extracted with

AcOEt (2 × 5 mL) and CH₂Cl₂(2 × 5 mL). The organic layers

were collected, dried, and evaporated to obtain 40 mg of the

tert-butyldimethylsilyl derivative of 16 as a white solid. Yield

77%, mp 263 °C. The above compound (32 mg, 0.069 mmol)

was dissolved in 0.3 mL of DMF. After addition of 11.6 mg

(0.277 mmol) of LiOH‚H₂O, the solution was stirred at room

temperature overnight and then acidified with 2 N HCl. The

white solid precipitate was filtered, washed with water, and

dried to obtain 11 mg of pure product. Yield 46%, mp 272 °C.

¹H NMR (CDCl₃) δ 1.73 (6H, s, 6 Ad), 2.05 (3H, s, 3 Ad), 2.1

(6H, s, 6 Ad), 6.85 (1H, d, J ) 8.6 Hz), 7.35 (1H, dd, J ) 8.6

and 2.2 Hz), 7.37 (1H, s), 7.56 (2H, d, J ) 8.6), 7.91 (2H, d, J

) 8.6). MS (EI) m/z: 348 (M⁺, 100), 291 (25), 227(25). Anal.

(C₂₃H₂₄O₃) C, H.

2′-Methyl-4′-hydroxy-5′-adamantan-1-ylbiphenyl-4-al-

dehyde (13c). 2-(1-Adamantan-1-yl)-5-methyl-4-bromophenol

(12c, 393 mg, 1.23 mmol) was dissolved in 2.5 mL of toluene.

Then 1.25 mL (2.5 mmol) of 2 N Na₂CO₃, 44 mg (0.038 mmol)

of Pd(PPh₃)₄, and a suspension of 207 mg (1.38 mmol) of

4-formylbenzeneboronic acid in 0.6 mL of ethanol were added.

The mixture was refluxed for 3 h in a current of nitrogen and

then diluted with water, and the product was extracted with

ethyl acetate. The organic phase was washed with brine, dried

over Na₂SO₄, and filtered. The crude product was purified by

flash chromatography (hexane/ethyl acetate, 85:15) to give 231

mg of the pure aldehyde. Yield 55%, mp 84 °C.

Diethyl E-[2-(3′-Adamantan-1-yl-4′-hydroxybiphenyl-

4-yl)vinyl]phosphonate (14a). The aldehyde 13a (200 mg,

0.602 mmol) was dissolved in the minimum amount of THF.

Then 350 mg (6.02 mmol) of finely crushed KF/Al₂O₃and

174 mg (0.602 mmol) of tetraethylmethylenediphosponate

were added, and the solvent was evaporated. The mixture was

left for 3 h at room temperature. THF was then added, and

KF/Al₂O₃was filtered on a Celite pad. The solvent was

evaporated, and water was added and acidified with 2 M HCl.

The white solid formed was filtered and washed with diiso-

propyl ether. Flash chromatography (eluent ethyl acetate/

hexane, 8:2) afforded the product as a white solid. Yield 38%,

E-2-Methyl-3-[3′-(adamantan-1-yl)-4′-hydroxybiphenyl-

4-yl]acrylic Acid (17a). Under a stream of nitrogen 200 mg

(0.448 mmol) of the aldehyde 13b and 167 mg (0.448 mmol) of

Ph₃PdC(CH₃)-COOEt were dissolved in 2.3 mL of CHCl₃, and

the resulting solution was refluxed for 21 h. The solvent was

evaporated, and the crude ester obtained was used without

further purification. This compound (390 mg, 0.714 mmol) was

1

mp 229-230 °C. H NMR (CDCl₃) δ: 1.40 (6H, t, J ) 7.3 Hz,

CH₃CH₂O-), 1.82 (6H, s, 6 Ad), 2.1 (3H, s, 3 Ad), 2.2 (6H, s, 6

Ad), 4.18 (q, J ) 7.3 Hz, CH₃CH₂O-), 5.7 (1H, br s, OH), 6.28

4942 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

added to 90 mg (2.14 mmol) of LiOH‚H₂O dissolved in 30 mL

of THF/H₂O, 1:1. The solution was stirred at room temperature

for 2 days. After evaporation of THF, the aqueous phase was

acidified with 3 mL of 1 M HCl and extracted with AcOEt.

Drying, filtration and evaporation of the solvent afforded 312

mg of crude product, which was purified by flash chromatog-

raphy (hexane/ethyl acetate, 2:1 and then 3:2) to obtain 69

mg of the title compound as a white solid, mp 200 °C. ¹H NMR

(600 MHz) (DMSO-d₆) δ 1.73-1.76 (6H, s, 6Ad), 2.04-2.06 (3H,

m, 3Ad), 2.08 (Me, d, J ) 1.59 Hz), 2.12-2.94 (6H, m, Ad),

6.86 (1H, d, H-5′, J ) 8.27 Hz), 7.36 (1H, dd, H-6′, J ) 2.38

Hz, J ) 8.27 Hz), 7.38 (1H, d, H-2′, J ) 2.38 Hz), 7.51 (2H, d,

H-3 and H-5, J ) 8.42 Hz), 7.60 (1H, br s, CHd), 7.63 (2H, d,

H-2 and H-6, d, J ) 8.42 Hz) 9.50 (1H, s, OH), 12.4 (1H, s,

COOH). MS (m/z): 388 (M⁺, 100), 267 (40), 178 (40), 79 (60).

Anal. (C₂₆H₂₈O₃) C, H.

methyl E-3-[5′-(1-adamantan-1-yl)-2′-methyl-4′-hydroxybiphe-

nyl-4-yl]acrylate. Yield 80%, mp 236-237 °C.

The above ester (150 mg, 0.37 mmol) was dissolved in a

solution of 78 mg (1.86 mmol) of LiOH‚H₂O in 12 mL of THF/

H₂O, 1:1, and the resulting solution was stirred for 18 h at

room temperature in the dark. THF was evaporated, the

aqueous phase was washed with hexane and Et₂O and

acidified with 2 N HCl. The solid formed was filtered and dried

to give 137 mg of pure product. Yield 95%, mp 203 °C. ¹H NMR

(DMSO-d₆) δ 1.70 (6H, s, 6Ad), 2.00 (3H, s, 3Ad), 2.03 (6H, s,

6Ad), 2.13 (3H, s, CH₃), 6.50 (1H, d, CHd, J ) 16.5 Hz), 6.63

(1H, s, 1Ar), 6.85 (1H, s, 1Ar), 7.30 (2H, d, 2Ar, J ) 8.25 Hz),

7.58 (1H, d, CHd, J ) 16.5 Hz), 7.66 (2H, d, 2Ar, J ) 8.25

Hz), 9.28 (1H, s, OH), 12.34 (1H, bs, COOH). MS (EI) m/z: 388

(M⁺). Anal. (C₂₆H₂₈O₃) C, H.

(2-(3-(Adamantan-1-yl)-4-hydroxybiphenyl-4-yl)cyclo-

propanecarboxylic Acid (Cis and Trans Mixture) (18).

To a solution of 12b (400 mg, 0.949 mmol) in 1 mL of toluene,

0.95 mL of a 2 M solution of Na₂CO₃, 33 mg (0.285 mmol) of

Pd tetrakis, and 154 mg (1.04 mmol) of p-vinylbenzeneboronic

acid (previously dissolved in 0.9 mL of toluene and 0.44 mL of

EtOH) were added. The solution was refluxed for 2 h. After

addition of AcOEt the organic phase was washed with brine,

dried, filtered, and evaporated to obtain 427 mg of crude (3-

adamantan-1-yl-4′-vinylbiphenyl-4-oxy)-tert-butyldimethylsi-

lane. Purification by flash chromatography using as eluent

hexane afforded 277 mg of this compound, mp 137-139 °C.

¹H NMR (CDCl₃) δ 0.35 (6H, s, -Si(CH₃)₂), 1.05 (9H, s, -t-

Bu), 1.75 (6H, s, 6Ad), 2.05 (3H, s, 3Ad), 2.12 (6H, s, 6Ad),

5.25 (1H, d, CHd, J ) 7.5 Hz), 5.75 (1H, d, CHd, J ) 14 Hz),

6.75 (1H, dd, CHd, J ) 7.5 Hz, 14 Hz), 6.90 (1H, d, 1Ar, J )

7.0 Hz), 7.40-7.65 (6H, m, 6Ar).

E-2-Fluoro-3-[3′-(adamantan-1-yl)-4′-hydroxybiphenyl-

4-yl]-acrylic Acid (17b). EtOOC-CH(F)-PO(OEt)₂(124 mg,

0.493 mmol) was dissolved in 1 mL of anhydrous THF, cooled

to -78 °C, and treated with a solution of 1.6 M BuLi in hexane

(0.364 mL). After stirring for 30 min at -78 °C, an amount of

200 mg (0.448 mmol) of the aldehyde 13b dissolved in 0.5 mL

of THF was dropped, and the solution was slowly brought to

room temperature (3 h). After acidification with 6 mL of 2 N

HCl the aqueous phase was extracted with AcOEt. The organic

layers were washed with brine, dried, filtered, and evaporated

to afford 280 mg of a crude product. Purification by flash

chromatography (hexane/ethyl acetate, 95:5) gave 180 mg

(75%) of the ethyl ester of the tertbutyldimethylsilyl derivative

of 17b as an oil. This compound (97 mg, 0.181 mmol) was

suspended in a solution of 38 mg (0.905 mmol) of LiOH‚H₂O

in 7.4 mL of THF/H₂O, 1:1, and stirred overnight at room

temperature in the dark. THF was evaporated and the

remaining aqueous phase was washed with hexane, then

acidified with 0.5 mL of 2 N HCl. The light-yellow precipitate

was filtered and dried to afford 55 mg of the title compound.

Rhodium tetraacetate bihydrate (0.5 mg) and 36 µL of ethyl

diazoacetate were added to a solution of 150 mg of the above

compound in 2 mL of dichloromethane. The reaction mixture

was left for 5 days at room temperature, with the addition of

a total of 5 mg of catalyst and 10 µL of ethyl diazoacetate.

The catalyst was filtered through Celite, dried over sodium

sulfate, evaporated, and chromatographed on silica gel with

hexane/ethyl acetate (65:35). A mixture (43 mg) of the two cis

and trans diastereoisomers of methyl 2-[(3-(1-adamantan-1-

yl)-4-hydroxybiphenyl-4-yl)cyclopropanecarboxylate was ob-

tained.

1

Yield 77%, mp 202 °C. H NMR (acetone-d₆): δ 1.8 (8H, s, 8

Ad), 2.2 (6H, s, 6 Ad), 6.90 (1H, d, J ) 8.5 Hz), 7.00 (1H, d,

J_H,F) 23.9 Hz), 7.36 (1H, dd, J ) 8.5 and 2.6 Hz), 7.50 (1H, d,

J ) 2.6 Hz), 7.60 (2H, d, J ) 8.8 Hz), 7.71 (2H, d, J ) 8.8 Hz).

MS (EI) m/z: 392 (M⁺, 100). Anal. (C₂₅H₂₅FO₃) C, H.

Z-2-Fluoro-3-[3′-(adamantan-1-yl)-4′-hydroxybiphenyl-

4-yl]acrylic Acid (17c). EtOOC-CH(F)-PO(OEt)₂(124 mg

(0.493 mmol) was dissolved in 1 mL of anhydrous THF, cooled

to 0 °C, and treated with 0.364 mL of a solution of 1.6 M BuLi

in hexane. After the mixture was stirred for 1 h at 0 °C, the

solution was heated to reflux and an amount of 200 mg (0.448

mmol) of the aldehyde 13b dissolved in 0.5 mL of THF was

dropped. Heating was continued for 8 h, then an amount of 6

mL of 2 N HCl was added and the aqueous phase was

extracted with AcOEt. The organic layers were washed with

brine, dried, filtered, and evaporated to give a crude mixture

of the E and Z isomers. Purification by flash chromatography

(hexane/ethyl acetate, 95:5) afforded 38 mg (16%) of the ethyl

ester of the tert-butyldimethylsilyl derivative of 17c, mp 125

°C. This ester (30 mg, 0.056 mmol) was suspended in a solution

of 12 mg (0.281 mmol) of LiOH‚H₂O in 2.3 mL of THF/H₂O,

1:1, and stirred overnight at room temperature in the dark.

THF was evaporated, and the remaining aqueous phase was

washed with hexane and diethyl ether, then acidified with 0.15

mL of 2 N HCl. The light-yellow solid was filtered and dried

KF on finely crushed Al₂O₃(40%) (113 mg) was added to a

solution of the above ester (110 mg) in 4.4 mL of dimethoxy-

ethane, and the mixture was stirred at room temperature for

2 days. After filtration, the solvent was evaporated and the

crude product was added to a solution of 63 mg of LiOH‚H₂O

in 12.4 mL of 50% aqueous THF. This was stirred at room

temperature for 3 days, and the solvent was evaporated,

extracted with ethyl ether, acidified with 2 M HCl, and

extracted with ethyl acetate. After evaporation, the product

(58 mg) was chromatographed on silica gel (hexane/ethyl

acetate, 40:60) to give 6 mg of trans-2-(3-(1-adamantan-1-yl)-

4-hydroxybiphenyl-4-yl)cyclopropanecarboxylic acid, mp 190

°C, 10 mg of a mixture of diastereoisomers, and 20 mg of cis-

2-(3-(1-adamantan-1-yl)-4-hydroxybiphenyl-4-yl)cyclopropan-

ecarboxylic acid, mp 204 °C. R_fis 0.23 for cis and 0.44 trans

in hexane/ethyl acetate, 4:6. ¹H NMR (MeOD), trans, δ: 1.45-

1.50 (1H, m, 1-CH₂), 1.60-1-65 (1H, m, 1-CH₂), 1.95-2.0 (7H,

m, -CHCOOH + 6Ad), 2.2 (3H, s, 3Ad), 2.35 (6H,s, 6Ad),

2.50-2.58 (1H, m, -CHAr), 6.84 (1H, d, 1Ar, J ) 8.46 Hz),

7.24 (2H, dd, 2Ar, J ) 7.35 Hz, J ) 1.84 Hz), 7.31 (1H, dd,

1Ar, J ) 8.46 Hz, 2.57 Hz), 7.42 (1H, d, 1Ar, J ) 2.57 Hz),

7.52 (2H, dd, 2Ar, J ) 7.35 Hz, J ) 1.84 Hz). ¹H NMR (MeOD),

cis, δ: 1.40-1.50 (1H, m, 1-CH₂), 1.70-1.75 (1H, m, 1-CH₂),

1.95-2.0 (6H, s, 6Ad), 2.10-2.15 (4H, m, 3Ad + -CHCOOH),

2.30 (6H, s, 6Ad), 2.70-2.78 (1H, m, -CHAr), 6.83 (1H, d, 1Ar,

J ) 8.46 Hz), 7.30 (1H, dd, 1Ar, J ) 8.46 Hz, J ) 2.57 Hz),

7.38 (2H, dd, 2Ar, J ) 7.30 Hz, J ) 1.84 Hz), 7.42 (1H, d, 1Ar,

J ) 2.57 Hz), 7.49 (2H, dd, 2Ar, J ) 7.30 Hz, J ) 1.84 Hz).

MS (m/z): 388 (M⁺, 100), 135 (50). Anal. (C₂₆H₂₈O₃) C, H.

1

to afford 16 mg (73%) of 17c, mp 282 °C. H NMR (acetone-

d₆): δ 1.8 (8H, s, 8 Ad), 2.2 (6H, s, 6 Ad), 6.94 (1H, d, J ) 8.5

Hz), 7.06 (1H, d, J_H,F36 Hz), 7.40 (1H, dd, J ) 8.5 and 2.5

Hz), 7.53 (1H, d, J ) 2.5 Hz), 7.70 (2H, d, J ) 8.5 Hz), 7.77

(2H, d, J ) 8.5 Hz). Anal. (C₂₅H₂₅FO₃) C, H.

E-3-[5′-(Adamantan-1-yl)-2′-methyl-4′-hydroxy-bi-

phenyl-4-yl]acrylic Acid (17d). Aldehyde 13c (210 mg, 0.61

mmol) and 204 mg (0.61 mmol) of methoxycarbonylmethylene-

triphenylphosphorane were dissolved in 3.2 mL of chloroform

and refluxed for 5 h in a current of nitrogen. The solvent was

evaporated, and the residue was purified by flash chromatog-

raphy (hexane/dichloromethane, 20:80) to give 194 mg of

E-3-[3′-Adamantan-1-yl)-3-fluoro-4′-hydroxybiphenyl-

4-yl]acrylic Acid (19). 2-(1-Adamantan-1-yl)-4-bromophenol

Retinoid-Related Acrylic Acids

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4943

12a (200 mg, 0.651 mmol), 182 mg (0.716 mmol) of bis-

(pinacolate)diboron, 191 mg (1.95 mmol) of KOAc, and 14.3

mg (0.0195 mmol) of PdCl₂(dppf) were dissolved in 3.9 mL of

dioxane and heated at 100 °C for 2 h under nitrogen. After

the solution was cooled to room temperature, methyl 4-bromo-

2-fluorocinnamate (337 mg, 1.30 mmol), PdCl₂(dppf) (14.3 mg,

0.0195 mmol), and 2 N Na₂CO₃(0.815 mL, 1.63 mmol) were

added, and the mixture was heated at 100 °C for 1 h. The

solution was cooled to room temperature, diluted with water,

and acidified with 2 N HCl (2.6 mL), and the product was

extracted with ethyl acetate. The organic phase was washed

with brine, dried over Na₂SO₄, and filtered, and the solvent

was evaporated. The crude product was purified by flash

chromatography (dichloromethane/hexane, 80:20) to give 133

mg of methyl E-3-[3′-(1-adamantan-1-yl)-3-fluoro-4′-hydroxy-

biphenyl-4-yl]acrylate. Yield 50%, mp 245 °C.

The above ester (70 mg, 0.172 mmol) was dissolved in a

solution of 36.1 mg (0.85 mmol) of LiOH‚H₂O in 7 mL of THF/

H₂O, 1:1, and the solution was stirred overnight at room

temperature in the dark. THF was evaporated, and the

aqueous phase was washed with hexane and Et₂O and

acidified with 2 N HCl (0.440 mL). The solid formed was

filtered and dried to give 60 mg of the pure product. Yield 89%,

mp 314 °C. ¹H NMR (DMSO-d₆) δ: 1.74 (6H, s, 6Ad), 2.05 (3H,

s, 3Ad), 2.13 (6H, s, 6Ad), 6.56 (1H, d, CHd, J ) 16.0 Hz),

6.85 (1H, d, 1Ar, J ) 8.56 Hz), 7.35 (1H, d, 1Ar, J ) 1.49 Hz),

7.38 (1H, dd, 1Ar, J ) 8.56 Hz, J ) 1.49 Hz), 7.43-7.53 (2H,

m, 2Ar), 7.63 (1H, d, CHd, J ) 16.0 Hz), 7.80 (1H, dd, 1Ar, J

) 8.70 Hz, J ) 8.10 Hz), 9.63 (1H, s, OH), 12.5 (1H, bs, COOH).

Anal. (C₂₅H₂₅FO₃) C, H.

E-3-(4′-Hydroxy-[1,1′,3′,1”]terphenyl-4-yl)acrylic Acid

(23). To a solution of 1 g (5.88 mmol) of 2-phenylphenol 20

and 1.058 g (7.06 mmol) of NaI in 39 mL of DMF, an amount

of 1.989 g (7.06 mmol) of chloramine T were added in one

portion at 22 °C. The solution was stirred 3.5 h at 25 °C, an

amount of 40 mL of water was added, and the solution was

acidified with 2 N HCl to pH 1 and extracted with AcOEt (2

× 70 mL). After being washed with Na₂S₂O₃(30 mL) and brine

(30 mL), the collected organic layers were dried, filtered, and

evaporated. Purification by flash chromatography (eluent

hexane/dichloromethane, 7:3) gave 1.348 g (77%) of 2-phenyl-

4-iodophenol (21), mp 35 °C.

Compound 21 (70 mg, 0.172 mmol) was dissolved in 2.5 mL

of toluene under a stream of nitrogen. To this solution 1.35

mL of 2 M Na₂CO₃, 94 mg (0.06 mmol) of Pd(Ph₃P)₄, and 223

mg (1.49 mmol) of 4-formylbenzeneboronic acid (previously

suspended in 0.7 mL of EtOH) were added. The resulting

solution was refluxed for 17 h, then extracted with ethyl

acetate. The organic layer was washed with water and brine,

then dried, filtered, and evaporated. An amount of 15 mg (42%)

of pure 4′-hydroxy[1,1′,3′,1′′]terphenyl-4-yl)aldehyde (22) was

obtained as an oil after flash chromatography (hexane/ethyl

acetate, 8:2).

11 mg (0.05 mmol) of Pd(OAc)₂, and 60 mg (0.2 mmol) of tri-

o-tolylphosphine in 1 mL of Et₃N were mixed in a round flask

and heated at 100-110 °C for 5 h. Water and ice were added,

2 N HCl was added, and the aqueous phase was extracted with

ethyl acetate. The organic phase was dried over Na₂SO₄,

filtered, and evaporated to give 500 mg (97%) of methyl 3-(4-

hydroxy-3-formylphenyl)acrylate, mp 100-101 °C.

The above product (1.030 g, 5 mmol) was dissolved under

nitrogen in 29 mL of dry dichloromethane, Et₃N (2.1 mL, 15

mmol) was added, and the solution was cooled at 0-5 °C.

N-Phenylbis(trifluoromethanesulfonimide) (2.32 g, 6.5 mmol)

was added, and the reaction mixture was allowed to stir at

0-5 °C for 2.5 h. The solvent was evaporated, water was

added, and the product was extracted with ethyl acetate. The

organic phase was dried over Na₂SO₄, filtered, and evaporated,

and the crude product was purified by flash chromatography

(hexane/ethyl acetate, 70:30) to give 1.40 g (83%) of methyl

3-(3-formyl-4-trifluoromethanesulfonyloxyphenyl)acrylate, mp

43 °C.

Compound 12b (810 mg, 1.92 mmol), 533 mg (2.1 mmol) of

bis(pinacolate)diboron, 564 mg (5.76 mmol) of KOAc, and 42

mg (0.058 mmol) of PdCl₂(dppf) were dissolved in dioxane and

heated at 100 °C for 1.5 h under nitrogen. After the solution

was cooled to room temperature, methyl 3-(3-formyl-4-trifluo-

romethanesulfonyloxyphenyl)acrylate (1.30 g, 3.8 mmol), PdCl₂-

(dppf) (42 mg, 0.058 mmol), and 2 N Na₂CO₃(2.4 mL, 4.8

mmol) were added, and the mixture was heated at 100 °C for

3.5 h. The solution was cooled to room temperature and diluted

with water, and the product was extracted with ethyl acetate.

The organic phase was washed with brine, dried over Na₂SO₄,

filtered, and evaporated. After flash chromatography (hexane/

ethyl acetate, 85:15), an amount of 447 mg of methyl E-3-[3′-

(1-adamantan-1-yl)-4′-(tert-butyldimethylsilyloxy)-2-formylbi-

phenyl-4-yl]acrylate 26a was obtained. Yield 47%, mp 147 °C.

The above ester (100 mg, 0.19 mmol) was dissolved in a

solution of 40 mg (0.94 mmol) of LiOH‚H₂O in 6.2 mL of THF/

H₂O, 1:1, and the solution was stirred overnight at room

temperature in the dark. THF was evaporated, and the

aqueous phase was washed with hexane and Et₂O and then

acidified with 2 N HCl. The solid formed after acidification

was filtered and dried to give 65 mg of 27a. Yield 85%, mp

284 °C. ¹H NMR (DMSO-d₆) δ: 1.72 (6H, s, 6Ad), 2.00 (3H, s,

3Ad), 2.05 (6H, s, 6Ad), 6.60 (1H, d, CHd, J ) 16.51 Hz),

6.88 (1H, d, 1Ar, J ) 8.62 Hz), 7.07 (1H, d, 1Ar, J ) 2.23 Hz),

7.11 (1H, dd, 1Ar, J ) 8.62 Hz, J ) 2.23 Hz), 7.53 (1H, d, 1Ar,

J ) 8.25 Hz), 7.66 (1H, d, CHd, J ) 16.51 Hz), 8.02 (2H, m,

2Ar), 9.73 (1H, s, OH), 9.85 (1H, s, CHO), 12.45 (1H, bs,

COOH). MS (EI) m/z: 402 (M⁺), 327 (30), 135 (29). Anal.

(C₂₆H₂₆O₄) C, H.

E-3-[3′-(1-Adamantyl)-2-chloro-4′-hydroxybiphenyl-4-

yl]acrylic Acid (27b). 4-Bromo-2-chlorophenol (24b, 600 mg,

2.89 mmol), 397 mg (4.62 mmol) of methyl acrylate, 6.49 mg

(0.0289 mmol) of Pd(OAc)₂, and 34.4 mg (0.113 mmol) of tri-

o-tolylphosphine in 1.14 mL of Et₃N were mixed in a round

flask and heated at 100 °C for 4 h. Water and ice were added,

2 N HCl was added, and the aqueous phase was extracted with

ethyl acetate. The organic phase was dried over Na₂SO₄,

filtered, and evaporated. The crude product was purified by

flash chromatography (hexane/ethyl acetate, 70:30) to give 477

mg of (3-chloro-4-hydroxyphenyl)methyl acrylate (25b). Yield

78%, mp 73 °C.

The above ester (440 mg, 2.07 mmol) was dissolved under

nitrogen in 12 mL of dry dichloromethane. Et₃N (0.864 mL,

6.21 mmol) was added, and the solution was cooled at 0-5

°C. N-Phenylbis(trifluoromethanesulfonimide) (961 mg, 2.69

mmol) was added, and the reaction mixture was allowed to

stir at 0-5 °C for 2 h. Dichloromethane was removed, the

residue was suspended in water and filtered. After flash

chromatography (hexane/ethyl acetate, 90:10) an amount of

656 mg of methyl 3-(3-chloro-4-trifluoromethanesulfonyloxy-

phenyl)acrylate was obtained. Yield 92%, mp 69-70 °C.

The aldehyde 22 (132 mg, 0.48 mmol) was dissolved in 2

mL of CHCl₃under N₂, an amount of 161 mg (0.48 mmol) of

Ph₃PdCH-COOCH₃was added, and the resulting solution

was refluxed for 5 h. The solvent was evaporated and the crude

product was purified by chromatography (hexane/ethyl acetate

8:2) to give 130 mg (82%) of the methyl ester of 23, mp 145

°C. To a solution of 82 mg (1.95 mmol) of LiOH‚H₂O in 6.3

mL of H₂O, a solution of 129 mg (0.39 mmol) of the above ester

in 6.3 mL of THF was added. After the mixture was stirred at

room temperature for 18 h, THF was evaporated. The aqueous

phase was washed with hexane and diethyl ether, then

acidified with 2 N HCl. The precipitate was filtered and dried.

Purification by flash chromatography on reverse-phase (MeOH/

H₂O, 3:1) afforded the title compound as a white solid. Yield

60%, mp 173-174 °C. ¹H NMR (CDCl₃) δ: 6.50 (1H, d, CHd,

J ) 16.0 Hz), 7.02 (1H, d, 1Ar, J ) 8.10 Hz), 7.23-8.00 (12H,

m, 11Ar + CHd), 9.78 (1H, s, OH), 12.33 (1H, brs, COOH).

MS (EI) m/z: 316 (M⁺). Anal. (C₂₁H₁₆O₃) C, H.

E-3-[3′-(Adamantan-1-yl)-4′-hydroxy-2-formylbiphenyl-

4-yl]acrylic Acid (27a). 2-Hydroxy-5-bromobenzaldehyde

(24a, 500 mg, 2.5 mmol), 344 mg (4 mmol) of methyl acrylate,

2-(Adamantan-1-yl)-4-bromophenol (12a, 200 mg, 0.651

mmol), 184 mg (0.176 mmol) of bis(pinacolate)diboron, 191 mg

(1.95 mmol) of KOAc, and 14.3 mg (0.0195 mmol) of PdCl₂-

4944 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15

Cincinelli et al.

(dppf) were dissolved in 3.98 mL of dioxane and heated at 100

°C for 2 h. After the solution was cooled to room temperature,

an amount of 448 mg (1.30 mmol) of methyl 3-(3-chloro-4-

trifluoromethanesulfonyloxyphenyl)acrylate, 2 M Na₂CO₃(0.814

mL, 1.63 mmol), and 14.3 mg (0.0195 mmol) of PdCl₂(dppf)

were added, and the mixture was heated at 100 °C for 11 h.

The solution was cooled to room temperature, diluted with

water, and acidified with 2N HCl (2.61 mL), and the product

was extracted with ethyl acetate. The organic phase was

washed with brine, dried over Na₂SO₄, filtered, and evapo-

rated. The crude product was purified by flash chromatography

(hexane/ethyl acetate, 80:20) to give 64 mg of methyl E-3-[3′-

(adamantan-1-yl)-2-chloro-4′-hydroxybiphenyl-4-yl]acrylate

(26b). Yield 23%, mp 218 °C.

The above ester (60 mg, 0.142 mmol) was dissolved in a

solution of 29.8 mg (0.71 mmol) of LiOH‚H₂O in 5.8 mL of THF/

H₂O, 1:1, and the mixture was stirred overnight at room

temperature in the dark. THF was evaporated, the remaining

aqueous phase was washed with hexane and Et₂O and then

acidified with 2 N HCl (0.360 mL). The solid obtained was

purified by reverse-phase flash chromatography (methanol/

water, 85:15) to give 52 mg (90%) of 27b, mp 259 °C. ¹H NMR

(DMSO-d₆) δ: 1.68 (6H, s, 6Ad), 1.98 (3H, s, 3Ad), 2.06 (6H, s,

6Ad), 6.57 (1H, d, CHd, J ) 16.0 Hz), 6.95 (1H, d, 1Ar, J )

8.20 Hz), 7.10 (1H, dd, 1Ar, J ) 8.20 Hz, J ) 2.20 Hz), 7.14

(1H, d, 1Ar, J ) 2.20 Hz), 7.37 (1H, d, 1Ar, J ) 8.60 Hz), 7.54

(1H, d, CHd, J ) 16.0 Hz), 7.65 (1H, dd, 1Ar, J ) 8.60 Hz, J

) 2.20 Hz), 7.82 (1H, d, 1Ar, J ) 2.20 Hz), 9.60 (1H, s, OH).

MS (EI) m/z: 408 (M⁺). Anal. (C₂₅H₂₅ClO₃) C, H.

E-3-(6-Adamantan-1-yl-7-hydroxyphenanthren-2-yl)-

acrylic Acid (29). A suspension of 599 mg (1.75 mmol) of

(methoxymethyl)triphenylphosphonium chloride in 4 mL of

anhydrous THF was cooled to 0 °C under nitrogen atmosphere

and treated dropwise with 1.1 mL (1.75 mmol) of 1.6 N n-BuLi

in hexane. The resulting red solution was stirred for 20 min

at 0 °C and then treated with 370 mg (0.7 mmol) of 26a

previously dissolved in 3 mL of dry THF. The solution was

stirred at room temperature for 3 h. After concentration of the

solvent in vacuo, the residue was taken up in ethyl acetate,

washed sequentially with water and saturated brine, dried

over Na₂SO₄, filtered, and evaporated. The crude mixture of

E/Z vinyl ethers 28 was purified by flash chromatography

(hexane/ethyl acetate, 95:5) to give 75 mg of the desired

product and 58 mg of a product where the ester group had

exchanged with butanol from n-BuLi.

To a stirred solution of the isomeric mixture of methyl 3-[3′-

(1-adamantan-1-yl)-4′-(tert-butyldimethylsilyloxy)-2-(2-meth-

oxyvinyl)biphenyl-4-yl]acrylate (70 mg, 0.125 mmol) in 2.4 mL

of dry dichloromethane at 0 °C under nitrogen was added

methanesulfonic acid (0.5 mL, 6.8 mmol) in 5 min. The reaction

mixture was stirred for 2 h at 0 °C, diluted with ice-cold water,

and extracted with dichloromethane. The aqueous phase was

washed with Et₂O, and the organic phase was dried over

Na₂SO₄. Purification of the crude product by flash chroma-

tography (hexane/ethyl acetate, 80.20) afforded 15 mg of a

mixture of methyl 3-(8-adamantan-1-yl-7-hydroxyphenanthren-

2-yl)acrylate (a) and methyl 3-(6-adamantan-1-yl-7-hydroxy-

phenanthren-2-yl)acrylate (b). Yield 29%.

mg (1.06 mmol) of bis(pinacolato)diboron, 282 mg (3 mmol) of

KOAc, and 21 mg (0.03 mmol) of PdCl₂(dppf) was dissolved in

dioxane and heated at reflux for 8 h under nitrogen. Then 20

mg of PdCl₂(dppf) and 50 mg of bis(pinacolato)diboron were

added and the mixture was heated for another 4 h. After the

solution was cooled to room temperature, methyl 4-bromocin-

namate (463 mg, 1.9 mmol), PdCl₂(dppf) (21 mg (0.03 mmol),

and 2 N Na₂CO₃(1.4 mL, 2.78 mmol) were added, and the

mixture was heated at reflux for 4 h. The solution was cooled

to room temperature and diluted with 6 mL of 2 N HCl, and

the product was extracted with ethyl acetate. The organic

phase was washed with brine, dried over Na₂SO₄, filtered, and

evaporated. Flash chromatography with hexane/AcOEt, 8:2,

gave 110 mg (40%) of methyl E-3-(3′-chloro-4′-hydroxybi-

phenyl-4-yl)acrylate, mp 153-154 °C. The above ester (110 mg,

0.38 mmol) was dissolved in 8 mL of THF/H₂O, 1:1, containing

80 mg (1.9 mmol) of LiOH‚H₂O, and the solution was stirred

overnight at room temperature in the dark. THF was evapo-

rated, the aqueous phase was washed with hexane and Et₂O

and acidified with 2 N HCl (1 mL). The solid formed was

filtered and dried to give 98 mg (94%) of the pure product, mp

233-234 °C. ¹H NMR (DMSO-d₆) δ: 6.55 (1H, d, -CHd, J )

16.00 Hz), 7.05 (1H, d, 1Ar, J ) 8.56 Hz), 7.53 (1H, dd, 1Ar, J

) 8.56 Hz, J ) 1.86 Hz), 7.60 (1H, d, -CHd, J ) 16.00 Hz),

7.60-7.80 (5H, m, 5Ar), 10.5 (1H, s, -OH), 12.50 (1H, brs,

-COOH). Anal. (C₁₅H₁₁ClO₃) C, H.

2-(Adamantan-1-yl)-5-bromophenol (31). An amount of

0.44 mL of concentrated H₂SO₄was added to a mixture of

3-bromophenol (1.42 g, 8.2 mmol) and 1-adamantanol (1.25 g,

8.2 mmol) in 4.1 mL of CH₂Cl₂. The mixture was stirred at

room temperature for 24 h. Water and ice were added and then

aqueous NaHCO₃. The aqueous phase was extracted with

Et₂O, and the solvent was dried and evaporated. Chromatog-

raphy with hexane/CH₂Cl₂, 1:1, gave 400 mg of the desired

product. Yield 16%, mp 118 °C.

E-3-(4′-Adamantan-1-yl-3′-hydroxybiphenyl-4-yl)acryl-

ic Acid (33). Compound 31 (340 mg, 1.11 mmol), 313 mg (1.22

mmol) of bis(pinacolato)diboron, 326 mg (3.33 mmol) of KOAc,

and 25 mg (0.033 mmol) of PdCl₂(dppf) were dissolved in

dioxane and heated at 100 °C for 1.5 h under nitrogen. After

the solution was cooled to room temperature, methyl 4-bro-

mocinnamate (535 mg, 2.2 mmol), PdCl₂(dppf) (25 mg (0.033

mmol), and 2 N Na₂CO₃(1.4 mL, 2.78 mmol) were added, and

the mixture was heated at 100 °C for 2 h. The solution was

cooled to room temperature and diluted with 4.4 mL of 2 N

HCl, and the product was extracted with ethyl acetate. The

organic phase was washed with brine, dried over Na₂SO₄,

filtered, and evaporated. Crystallization from CH₂Cl₂gave 180

mg of methyl E-3-(4′-adamantan-1-yl-3′-hydroxybiphenyl-4-yl)-

acrylate 32. Yield 42%, mp 273 °C.

The above ester (155 mg, 0.4 mmol) was dissolved in 23 mL

of 0.7 N NaOH in MeOH and refluxed for 2 h. Evaporation,

taking up with water, acidification with 37% HCl (1.4 mL),

and filtration gave 137 mg of 32, which was purified by

chromatography with Lichroprep RP-18 (MeOH/H₂O, 8:2 to

100% MeOH) (93 mg), mp >300 °C. ¹H NMR (DMSO-d₆) δ:

1.73 (6H, s, 6Ad), 2.03 (3H, s, 3Ad), 2.09 (6H, s, 6Ad), 6.55

(1H, d, CHd, J ) 16.38 Hz), 7.06 (1H, d, 1Ar, J ) 2.23 Hz),

7.08 (1H, dd, 1Ar, J ) 8.56 Hz, J ) 2.23 Hz), 7.16 (1H, d, 1Ar,

J ) 8.56 Hz), 7.60 (2H, d, 2Ar, J ) 7.82 Hz), 7.60 (1H, d, CHd,

J ) 16.38 Hz), 7.75 (2H, d, 2Ar, J ) 7.82 Hz), 9.49 (1H, s,

OH), 12.40 (1H, brs, COOH). Anal. (C₂₅H₂₆O₃) C, H.

1-(Adamantan-1-yl)-3-(4-bromophenyl)propenone (34).

To a solution of 0.09 mL of 21% (w/v) EtONa in 3 mL of EtOH

were added 1-adamantylmethyl ketone (0.5 g, 2.8 mmol) and

4-bromobenzaldehyde (0.5 g, 2.8 mmol), and the mixture was

stirred for 3 days at room temperature. Cooling at -10 °C,

filtration, and washing with cold EtOH gave 320 mg (85%) of

the title compound, mp 135 °C.

The above mixture (15 mg, 0.03 mmol) was suspended in a

solution of 7.5 mg (0.18 mmol) of LiOH‚H₂O in 1.4 mL of THF/

H₂O, 3:2, and the suspension was stirred for 5 days at room

temperature in the dark. THF was evaporated, the aqueous

phase was washed with hexane and Et₂O and then acidified

with 2 N HCl. The solid formed was filtered and dried to give

8 mg of the desired product 29. Yield 60%, mp 290 °C. ¹H NMR

(acetone-d₆) δ: 1.85 (6H, s, 6Ad), 2.13 (3H, s, 3Ad), 2.35 (6H,

s, 6Ad), 6.68 (1H, d, CHd, J ) 16.00 Hz), 7.32 (1H, s, 1Ar),

7.70 (1H, d, 1Ar, J ) 8.60 Hz), 7.71 (1H, d, 1Ar, J ) 8.60 Hz),

7.85 (1H, d, CHd, J ) 16.00 Hz), 7.95 (1H, dd, 1Ar, J ) 8.25

Hz, J ) 2.23 Hz), 8.15 (1H, d, 1Ar, J ) 2.23 Hz), 8.55 (1H, s,

1Ar), 8.75 (1H, d, 1Ar, J ) 8.25 Hz), 9.01 (1H, brs, OH). MS

(EI) m/z: 398 (M⁺), 277 (40). Anal. (C₂₇H₂₆O₃) C, H.

5-(Adamantan-1-yl)-4′-bromobiphenyl-3-ol (35). To a

suspension of 1-acetylmethylpyridinium chloride³⁸(224 mg,

1.3 mmol) and 34 (300 mg, 0.9 mmol) in 9 mL of absolute

EtOH was added DBU (194 µL). The red solution was

stirred under nitrogen for 6 h. Dilution with 10% HCl,

E-3-(3′-Chloro-4′-hydroxybiphenyl-4-yl)acrylic Acid (30).

A mixture of 2-chloro-4-bromophenol (200 mg, 0.96 mmol), 268

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A. Retinoid induced apoptosis in leukemia cells through a

retinoic acid nuclear receptor-independent pathway. Blood 1997,

89, 4470-4479.

(8) Keedwell, R. G.; Zhao, Y.; Hammond, L. A.; Qin, S.; Tsang, K.-

Y.; Reitmair, A.; Molina, Y.; Okawa, Y.; Atangan, L. I.; Shurland,

D.-L.; Wen, K.; Wallace, D. M. A.; Bird, R.; Chandraratna, R. A.

S.; Brown, G. A Retinoid-related molecule that does not bind to

classical retinoid receptor potently induces apoptosis in human

prostate cancer cells through rapid caspase activation. Cancer

Res. 2004, 64, 3002-3012 and references therein.

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Hook, K.; Carter, B.; Piedrafita, J.; Tang, S.; Fabbrizio, E. Novel

retinoid-related molecules as apoptosis inducers and effective

inhibitors of human lung cancer cells in vivo. Nat. Med. 1997,

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activated protein kinase phosphatase 1 by retinoids. Selective

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effect. J. Biol Chem. 2002, 277, 41693-41700.

(11) Marchetti, P.; Zamzami, N.; Joseph, B.; Schraen-Maschke, S.;

Mereau-Richard, C.; Costantini, P.; Metivier, D.; Susin, S. A.;

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trigger apoptosis through a mitochondrial pathway independent

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as inducers of apoptosis in ovarian carcinoma cell lines. J. Cell.

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C.; Zanier, R.; Giordano, V.; Garattini, E.; Zunino, F. Induction

of apoptosis and stress response in ovarian carcinoma cell lines

treated with ST1926, an atypical retinoid. Cell Death Differ.

2004, 11, 280-289.

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Magalhaes, P. J.; Di Virgilio, F.; Pozzan, T. Calcium and

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In The Retinoids, Biology, Chemistry and Medicine; Sporn, M.

B., Roberts, A. B., Goodman, D. S., Eds.; Raven Press: New

York, 1994.

(17) Cincinelli, R.; Dallavalle, S.; Merlini, L.; Penco, S.; Pisano, C.;

Carminati, P.; Giannini, G.; Vesci, L.; Gaetano, C.; Illy, B.; Zuco,

extraction with AcOEt, drying, evaporation, and chromatog-

raphy with CH₂Cl₂/AcOEt, 9:1 gave 140 mg (42%) of the title

compound, mp 156-158 °C.

E-3-(5′-Adamantan-1-yl-3′-hydroxybiphenyl-4-yl)acryl-

ic Acid (37). The above compound (70 mg, 0.18 mmol), 32 µL

(0.36 mmol) of methyl acrylate, 1 mg (0.0045 mmol) of

Pd(OAc)₂, 5.5 mg (0.007 mmol) of tri-o-tolylphosphine in 0.163

mL of Et₃N were mixed in a round flask and heated at reflux

for 2 days. Water and brine were added, and the aqueous phase

was extracted with AcOEt. The organic phase was dried over

Na₂SO₄, filtered, and evaporated. The crude product was

purified by flash chromatography (hexane/AcOEt, 9:1) to give

35 mg (50%) of methyl 3-(5′-adamantan-1-yl-3′-hydroxybi-

phenyl-4-yl)acrylate 36, mp 184-186 °C.

The above ester (40 mg, 0.1 mmol) was dissolved in a

solution of 21 mg (0.5 mmol) of LiOH‚H₂O in 4 mL of THF/

H₂O, 1:1, and the solution was stirred overnight at room

temperature in the dark. THF was evaporated, and the

aqueous phase was acidified with 2 N HCl (0.2 mL). The white

solid was filtered and dried to give 30 mg of pure product. Yield

1

80%, mp >240 °C. H NMR (DMSO-d₆) δ: 1.71 (6H, s, 6Ad),

1.85 (6H, s, 3Ad), 2.02 (3H, s, 6Ad), 6.52 (1H, d, CHd, J )

16.0 Hz), 6.75 (1H, dd, 1Ar, J ) 1.86 Hz, J ) 1.86 Hz), 6.83

(1H, dd, 1Ar, J ) 1.86 Hz, J ) 1.86 Hz), 7.04 (1H, dd, 1Ar, J

) 1.86 Hz, J ) 1.86 Hz), 7.58 (1H, d, CHd, J ) 16.0 Hz), 7.60

(2H, d, 2Ar, J ) 8.56 Hz), 7.72 (2H, d, 2Ar, J ) 8.56 Hz). MS

(EI) m/z:355 (56, M⁺), 97 (100). Anal. (C₂₅H₂₆O₃) C, H.

Cellular Sensitivity to Drugs. In ovarian carcinoma cells,

cellular sensitivity to drugs was evaluated by growth-inhibition

assay after 72 h of drug exposure. Cells in the logarithmic

phase of growth were seeded in duplicates into six-well plates.

Twenty-four hours after seeding, the drug was added to the

medium. Cells were harvested 72 h after drug exposure and

counted with a cell counter. In leukemia cells, drug exposure

was 24 h and the growth inhibition was assessed after 72 h.

IC₅₀is defined as the drug concentration causing a 50%

reduction of cell number compared with that of untreated

control. When standard deviation is reported, the mean value

is from three independent experiments.

Determination of Apoptosis. Apoptosis was determined

in ovarian carcinoma IGROV-1 cells by TUNEL assay follow-

ing 72 h of exposure to the drug.¹³Treated cells were fixed in

4% paraformaldehyde for 60 min at room temperature, washed,

and resuspended in ice-cold PBS. The in situ cell death

detection kit fluorescein (Roche, Mannheim, Germany) was

used according to the manufacturers’ instructions, and the

samples were analyzed by flow cytometry (Becton Dickinson).

Alkaline Elution Assay. DNA single strand breaks were

detected by the alkaline elution method. Cells were incubated

in the presence of 0.08 µCi/mL [¹⁴C]thymidine (Amersham

Biosciences, Amersham, U.K.) for 30 h and then for 18 h in

the absence of labeled thymidine to chase the DNA-incorpo-

rated radioactivity. After treatment with different concentra-

tions of 1 for 6 h, cells were immediately processed for alkaline

elution as previously described.¹³A positive control consisting

of cells irradiated with 0.4 Gy was used as a reference.

Cell Cycle Analysis. The cell cycle distribution was

analyzed in propidium iodide stained cells by FACScan flow

cytometry, as previously described.¹³

Western Blot Analysis. Cells were treated for the indi-

cated times with compound 23 at a cytotoxic concentration (20

µM) corresponding to IC₈₀. Analysis of each MAP protein and

their activated (i.e., phosphorylated) form was performed as

previously reported.¹³

V.; Supino, R.; Zunino, F.

A novel atypical retinoid with

proapoptotic and antitumor activity. J. Med. Chem. 2003, 46,

909-912.

Supporting Information Available: NMR data of inter-

mediates and compounds that were not tested for cytotoxic

activity; results from elemental analysis. This material is

available free of charge via the Internet at http://pubs.acs.org.

(18) Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling

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JM049440H

Article Doi

Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity

DOI: 10.1021/jm049440h

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Article abstract of DOI:10.1021/jm049440h

Full text of DOI:10.1021/jm049440h

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