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Hydroxy Substituted 10-Ethyl-9-phenylphenanthrenesCompounds for the Investigation of the Influence of EZ-Isomerization on the Biological Properties of Mammary Tumor Inhibiting 1.1.2-Triphenylbutenes

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320187
1O-Ethyl-9-phenylphenanthrenes
159
Arch. Pharm. (Weinheim) 320,159-166 (1987)
Hydroxy Substituted 10-Ethyl-9-phenylphenanthrenes:
Compounds for the Investigation of the Influence of E,Z-Isomerization on the Biological Properties of Mammary Tumor Inhibiting
1.1.2-Triphenylbutenes"
Martin R. Schneider* and Claus-D. Schiller
Sonderforschungsbereich 234, Institut fur Pharmazie, Lehrstuhl Pharmazeutische Chemie 11, Universitat
Regensburg, Universitatsstraae 3 1, D-8400Regensburg
Eingegangen am 7. Februar 1986
10-Ethyl-9-phenylphenanthrenes
substituted with two hydroxy groups were synthesized and their biological properties were compared with the respective acetoxy substituted 1.1.2-triphenylbut-1-enes. Estrogen receptor binding affinities, estrogenic properties and mammary tumor inhibiting activities of the phenanthrene derivatives were strongly reduced compared to the corresponding triphenylbutenes. However,
with these phenylphenanthrenes, in which the geometric structure is fixed, it was possible to demonstrate
that E,Z-isomerization in vivo plays an important role for the biological properties of triphenylbutenes.
Hydroxy-substituierte 10-Ethyl-9-phenylphenanthrene:Substanzen zur Untersuchung des Einflusses der
EJ-lsomerisierung auf die biologische Wirkung mammatumorhemmender 1.1.2-Triphenylbutene.
Mit zwei Hydroxygruppen substituierte 10-Ethyl-9-phenylphenanthrenewurden synthetisiert und ihre
biologischen Eigenschaften mit denen der entspr. acetoxy-substituierten 1.1.2-Triphenylbut-1-eneverglichen. &trogenrezeptorafnitaten, ostrogene Eigenschaften und mammatumorhemmende Wirkung der
Phenanthrene waren gegenuber denen der entspr. Triphenylbutene stark reduziert. Mit diesen Phenylphenanthrenen, bei denen die geometrische Struktur festgelegt ist, war es jedoch moglich, die Bedeutung
der E,Z-Isomerisierung in vivo fur die biologische Wirkung von Triphenylbutenen zu zeigen.
Many compounds of the triarylethylene type have been developed as potential mammary tumor inhibiting antiestrogensl). Tamoxifen, e. g., is now routinely used for the treatment of hormone-dependent human breast cancer'). In this class of compounds, the geometric structure is of major importance for the
biological properties, as the isomers of tamoxifen and of similar compounds display very differing pharmacological activities with regard to estrogen receptor affinity, estrogenic, antiestrogenic and tumor inhiOn the other hand, especially in the case of hydroxylated substances, E,Z-isomerizabiting pr~pertiesl-~).
tion which can modulate those biological activities2s4)occurs in vivo as well as in vitro. In vitro, an E,Zisomerization of hydroxy-tamoxifen, the major metabolite of tamoxifen'), was proved using human MCF7 breast cancer cells4).The importance of this interconversion was further pointed out with other hydroxy
derivatives of tamoxifens). However, it is not clear to what degree isomerization may be a problem in characterizing isomers in in-vivo studies4).
As we have studied the structure-activity relationships of OAc-substituted 1.1.2-triphenylbut-lenes6-lo),which can also isomerize in vivo, we wanted to get some insight to what extent this phenomenom
+ ) H e mProf. Dr. H. Oelschlager zum 65.Geburtstag herzlich gewidmet.
0365-6233/87/0202-0159 $02.50/0
0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1987
160
Schneider und Schiller
Arch. Pharm.
contributes to their biological properties. In these studies, in which compounds with all possible combinations of 3-OAc, 4-OAc and 3.4-di-OAc substituents in the phenyl ring@) and with various moieties in position 29.lo)
were described, the pharmacological activities strongly depend on the mode of the aromatic
substitution and consequently on the geometric structure. In these studies, we also got several hints for
E,Z-isomerization.
Compounds with a rigid structure may thus be suitable for determining the contribution of isomerism to the biological potencies of E- and Z-isomers"). There are studies
about triphenylethylenes with two linked phenyl rings'*- 13). However, no direct comparison with their parent compounds was made in in vivo tests. In this paper, we therefore
report on the syntheses and biological properties of 10-ethylWphenylphenanthrenes in
relation to their corresponding 1.1.2-triphenylbut- 1-enes.
Chemistry
The methoxy-substituted 1.1.2-triphenylbut-1-enes 1, E-2 and Z-2, and their acetoxy-substituted derivatives 3, E-4 and 2-4 were synthesized as described6).
R'
-
5
6
7
i
R'
R2
R3
OCHB H
OCH,
OCH3 OCH3 H
H
OCH, OCH,
I
1. BBra
2. A c p
lBBr3
pyridine
R'
R 2 R3
~
OH
8 OH H
9 OH OH H
10 H
OH OH
The methoxy-substituted 10-ethyl-9-phenylphenanthrenes5-7 were synthesized
from 1, E-2 and 2-2 by photocyclization under 12 cataly~is'~).
Even if pure E-2 or 2-2
was used mixtures of the phenylphenanthrenes 6 and 7 were obtained on account of
E,Z-isomerization during the reaction. Therefore, a mixture of E-2 and 2-2 was cyclized, 6 and 7 were separated by column chromatography on silica gel with toluene/
ligroin. Compounds 5-7 were converted to the hydroxy derivatives 8-10 by ether cleavage with BBr,6).
1 O-Ethy Wphenylphenanthrenes
32018 7
161
The purity of the compounds was proved by HPLC, the identity was established by 'H NMR and mass
spectrometry. The structures of compounds 6 and 7 were assigned by 'H-NMR spectroscopy. In the case
of our triphenylbutenes the E- and Z-isomers can be established by the signals of the aromatic rings and
the methoxy groups6-8).For the phenylphenanthrenes, the resonances of the arom.H's of the phenyl ring
at C-9 and of the methoxy groups were used. Regioisomerization of 5 is excluded. The 4-methoxy- or hydroxy-substituted phenyl ring of 5 and 8 shows an AB system at 6.97,7.18 ppm. An AB pattern with the
same chemical shift is found for the methoxy-substituted compound 6 and its phenolic analog 9. Thus, in
6 and 9, the phenyl ring is also substituted. The NMR spectra of 7 with an unsubstituted aromatic ring at
C-9 and of its OH-substituted analog 10, show no AB system. The structure of 6 and 7 was further confirmed by the resonances of the methoxy groups: the OCH, signals of 5 appear at 3.87 and 3.93 ppm. The
resonance at 3.87 is that of the H,CO-C6H,-group, as its position is nearly identical with that of the respective triphenylbutene. 6 and 7 have OCH, signals at 3.87 and 4.00, and at 3.93 and at 4.00, respectively. Thus, the signal resonance at 4.00 belongs to the 3-OCH3group and that at 3.93 to the 6-OCH3moiety of the phenanthrene system.
Biological Properties and Discussion
In this study and in our former one@), we have used acetoxy- instead of hydroxy-substituted triphenylbutenes because of better crystallization, simple handling and especially of their reduced tendency to
E,Z-isomerization. Hydroxytamoxifen, e. g., is converted to a mixture of isomers in solution*).The relative binding affinities (RBA-values) for the estrogen receptor were determined with calf uterine cytosol as
the receptor source and the dextran coated charcoal method in a competitive binding assay using 13H]
17p-estradiol as competitor6-I0).As the RBA-values of the OAc-substituted 3 and its phenolic analog are
nearly identicallo. 151, a comparison between OAc- and OH-substituted compounds is possible.
Tab. 1:Estrogen Receptor Binding Affinities
~~
compd.
3
E -4
z -4
8
9
10
R'
R2
R3
RBAa)%
OAc
OAc
H
OH
OH
H
H
OAc
OAc
H
OH
OH
OAc
H
OAc
OH
H
6.8
5.9
1.o
0.04
0.03
0.01
OH
a) Relative binding affinities for the calf uterine estrogen receptor
in vitro = ratio of molar conc. of 17p-estradiol (E2) and inhibitor required to decrease the amount of bound [3H]E2 by
50 %, RBA of E 2 = 100.
The RBA-values of the triphenylbutenes 3, E-4 and 2-4 strongly depend on the
substitution of the aromatic rings, i. e. A, C 'v A, B >> B, C6),(for A, B and C see
Scheme). Conversion of the triphenylbutenes to the phenylphenanthrenes leads to a
tremendous decrease in receptor affinity. The rank of the RBA-values, however, is the
same as with the triphenylbutenes. As the difference in receptor affinity between 9 and
10 is even smaller than that of E-4 and 2-4, an isomerization of 2-4 to its more potent
isomer E-4 in the receptor assay is very unlikely.
162
Schneider und Schiller
Arch. Pharm.
Tab. 2: Estrogenic and Antiestrogenic Properties in the Immature Mouse Uterine Weight Test
compd.
3
E -4
z -4
dose, pga)
1.o
5 .o
25
100
0.25
1.o
5 .o
25
0.25
1.o
5 .O
25
100
estrogenic
effectb)
31
72
98
107
91
166
156
123
dose, &pa)
1.o
5 .O
antiestrogenic
effectc)
% inhibition
0
0
ND
ND
46
92
150
158
134
8
50
250
45
50
10
50
9
50
250
54
92
10
50
250
0
4
10
50
50
250
a) Dose per animal and day.
b) Estrogenic effect = (ET-Ev)/(Es-Ev)
X 100. Effect = uterus dry weight (milligrams)/body
weight (grams) X 100. ET = effect of test compound; EV = effect of vehicle; ES = effect of
estrone standard (0.4 pg). Estrone produces a maximum stimulation of the uterine growth at
a dose of 0.4 pg/mouse and day16 (100 %).
c) Antiestrogenic effect = 7% inhibition = (Es-Es,T)/(Es-Ev)
X 100. ES = effect of estrone
standard (0.1 p g ) ; ES,T = effect of standard under simultaneous application of test compound.
ND = not determined.
Estrogenic activity was determined in the immature mouse uterine weight test7-'!
The triphenylbutenes E-4 and 2-4 exerted a very strong uterotrophic potency that
even surpassed the maximum activity of estrone. 2-4, which has a lower receptor affnity than E-4, was only slightly less potent than its respective E-isomer. In clear contrast to this, there was an extreme difference in estrogenic activity between 9 and 10,
the phenylphenanthrene analogs of E-4 and 2-4. Whereas 9 nearly reached the 100 %
level, 10 did not exert any significant uterotrophic effect. These results demonstrate a
cis/trans-isomerization of 2-4 to the more estrogenic E-4 and possibly vice versa in
vivo. The A, C-disubstituted triphenylbutene 3 had a lower estrogenic activity than
E-4 with OAc groups in A and B though its receptor affinity is higher than that of E-4.
A similar result was obtained for the phenylphenanthrenes 8 and 9. The A, C-disubstitution pattern is a suitable structural element to create low estrogenic and very often
antiestrogenic properties, as we have already shown7.').
320187
1 O-Ethvl-9-~henvl~henanthrenes
163
The antiestrogenic activity was determined in the immature mouse uterine weight test by the ability of
the compounds to antagonize the action of estrone7.8). In our former studies, triphenylbutenes with low
estrogenic properties mostly had estrogen antagonistic activity6-*).As 3 with the lowest agonistic potency
of all triphenylbutenes had no antiestrogenic effect, we have not tested the strong estrogens E-4 and 2-4.
A change of certain structural elements, e. g. shifting the hydroxy groups in diethylstilbestrol from the parat0 the meta-position"), can lead to antiestrogenic activity. Therefore, it was possible that the conversion
of the triphenylbutene to the phenylphenanthrene structure creates compounds with antagonistic activity.
However, none of the phenanthrenes 8-10 exerted any antiestrogenic potency.
The tumor inhibiting activity was tested on the hormone-dependent MXT mammary carcinoma of the
BDF,-mouse. In this tumor model, ovariectomy as well as estrogens like diethylstilbestrol or antiestrogens like tamoxifen cause a strong reduction in tumor size7-9).However, whereas the antitumor effect of
diethylstilbestrol is accompanied by estrogenic side effects determined by the uterine weight at the end of
therapy, tamoxifen inhibits the tumor growth without affecting the uterus7-9).
Tab. 3: Tumor Inhibiting Activity on the MXT Mouse Mammary
Tumor and Estrogenic Effects on the Uterus
compd.
3
E -4
2-4
8
dose
(mg/kg)
% TIC
tumora)
8.0
8.0
8.0
8 .O
16
32
7c)
1
2c)
91
126
49')
'
uterusb)
110
235')
186')
112
108
123
a) % TIC: tumor weight of the treated animalsftumor weight of
the solvent control X 100 after 6 weeks of therapy (mean of
10 animals).
b) % TIC = uterotrophic effect of the treated animals/uterotrophic effect of the solvent control X 100 after 6 weeks of
therapy.
c) Significant (p C 0.01). The U-test according to Wilcoxon, Mann
and Whitney was used.
The triphenylbutenes E-4 and 2-4 strongly inhibited the tumor growth together
with an about twofold increase in uterine weight. Their inhibiting properties are similar
to those of strong estrogens. The A, C-disubstituted compound 3, however, exerted a
good antitumor effect, too, without any significant influence on the uterus. Therefore,
we have also tested the phenylphenanthrene 8 in this tumor model. At a dose of 8 and
16 mg/kg, no tumor inhibiting effect occured. 32 mg, however, led to a significant antitumor activity without estrogenic side effect. This was rather surprising, as the receptor
affinity of 8 was more than 100 times lower than that of 3.
The low receptor affinities of our phenylphenanthrenes were not very appropriate
for these studies, as much higher doses than for the triphenylbutenes must be used in
the in vivo tests. These low binding affinities may be due to the flatness of the phenylphenanthrene molecule. In a series of tamoxifen analogs, in which the phenylrings B
and C are connected with bridging groups like 0, S, CH,CH, and SCH2, the flatest
compounds, i. e. the oxygen bridged analogs, had the lowest RBA-~alues'~).
164
Schneider und Schiller
Arch. Pharm.
However, whereas the triphenylbutene E-4 and 2-4 have very similar estrogenic activities, the uterotrophic potencies of their phenylphenanthrene analogs 9 and 10 strongly differ: it can be concluded that in vivo E,Z-isomerization is important for the biological properties of triphenylbutenes. In vitro, an E,Z-isomerization does not seem to
take place in the case of these OAc-substituted triphenylbutenes during the receptor assay. A further aspect, which can influence the pharmacological activities of such compounds is an in vivo hydroxylation in the phenylring A, as was described for the metabolism of tamoxifen". In our studies, we have noted several hints at this phenomen0n798! To clarify these problems, metabolic studies about the concentration of individual isomers within the target organs are necessary.
Thanks are due to the Deutsche Forschungsgemeinschaft (SFB 234) and to the Verband der Chemischen Industrie, Fonds der Chemischen Industrie, who supported this work by grants.
Experimental Part
Mp: Biichi 5 10 apparatus (uncorr.). - ' H NMR Spectra: Varian E 390 spectrometer. - Mass Spectra:
Varian MAT CH 5- HPLC: Altex 110 A pump; Kontron Uvikon 720 LC spectrophotometer; Column:
Lichrosorb RP 18, 10 Fm. - Elemental Analyses: Mikroanalyt. Laboratorium, Univ. Regensburg.
Methoxy Substituted IO-Ethvl-9-phenylphenarithrenes5-7.
5.0 mmol (1.7 g) of 1.1-bis(4-methoxyphenyl)-2-phenylbut-I-ene(3) or of a mixture of E- and Z-1,2bis(4-methoxyphenyl)-l-phenylbut-l-ene(E, 2-2) and 0.25 mmol(63 mg) I2 in cylohexane was irradiated
with an unfiltered mercury lamp for 3 h under stirring. At the end of the reaction, the mixture was washed
with saturated Na,S,O,-solution and water, and dried over CaCI,; in the case of 6 and 7 the regioisomers
were separated by cc, the crude products were crystallized from EtOH.
IO-Ethyl-6-methoxy-9-(4-methoxypheny~-phenanthrene
(5)
Yield 55 %. mp 150-152", C,,H,,O, (342.5); 'H-NMR (CDCI,): 6(ppm) = 1.15 (t. J = 7 Hz, 3H,
-CH,); 2.86 (q, J = 7 Hz, 2H, -CH,); 3.87, 3.93 (2s, 6H, -OCH,); 6.83-8.72(m, 1lH, aromat. H), 6.97,
7.18 (AB, J = 9 Hz).
I O-Ethyl-3-methoxy-9-(4-methoxyphenyl)-phenanthrene
(6)
Yield 60 %, mp 130-132", C,,H,,O, (342.5); 'H-NMR (CDCI,): 6 (ppm) = 1.15 (t, J = 7 Hz, 3H,
-CH,); 2.84 (9. J = 7 Hz, 2H, -CH,); 3.87,4.00 (2s, 6H, -OCH,); 6.81-8.67 (m, 1IH, aromat. H), 6.97,
7.18 (AB, J = 9 Hz).
IO-Ethy1-3.6-dimethoxy-9-phenylphenanthne (7)
Yield 20 %, mp 121-123", C,,H,,O, (342.5); 'H-NMR (CDCI,): 6 (ppm) = 1.13 (t, J = 7 Hz, 3H,
-CH,); 2.78 (q, J = 7 Hz, 3H, -CH,); 3.93,4.00(2s, 6H, -OCH,); 6.83-8.12 (m, I IH, aromat. H).
Hydroxy-Substituted 10-Ethyl-9-phenylphenanthrenes 8- 10
2.9 mmol(1,O g) of the methoxy substituted 10-ethyl-9-phenylphenanthrenes
5-7 in 30 ml of dry CH,CI,
was cooled to -60" under N,, then 7.25 mmol(l.82 g) BBr, was added. After 15 min the cooling bath was
removed and the mixture was stirred for 3 h. With cooling, 10 mi of MeOH was added, and the solvents
were removed. The residue was dissolved in 2N-NaOH and filtered. After precipitation with 3N-HCI, the
product was collected and recrystallized from toluene.
320/87
1O-Ethyl-9-~henvf~henanthrenes
165
1O-Ethyl-6-hydroxy-9-(4-hydroxyphenyl)-phenanthrene
(8)
Yield 90 %, mp 113-15', C,,H,,O, (314.4) Calcd C 84.0 H 5.77 Found C 83.7 H 5.68. - MS: m/e =
314 (Mt). - 'H-NMR (d6-acetone): 6(ppm) = 1.15 (t, J = 7 Hz, 3H, -CH,); 2.87 (q, J = 7 Hz, 2H,
-CH,); 6.83-8.73 (m, l I H , aromat. H), 6.97, 7.18 (AB, J = 9 Hz); 8.50, 8.65 (2s, 2H, -OH).
1O-Ethyl-3-hydroxy-9-(4-hydroxyphenyl)-phenanthrene
(9)
Yield 85 %, rnp 215-216', C,,H,,O, . H,O (332.4) Calcd C 79.5 H 6.07 Found C 79.2 H 6.16. - MS:
m/e = 314 (Mt).- 'H-NMR (d6-acetone): 6 (pprn) = 1.15 (t, J = 7 Hz, 3H, -CH,); 2.87 (q, J = 7 Hz,
2H, -CH,); 6.85-8.71 (m, lIH, aromat. H), 6.98, 7.19 (AB, J = 9 Hz); 8.53, 8.67 (2s, 2H, -OH).
1O-Ethyl-3,6-dihydroxy-9-phenylphenanthrene
( 10)
Yield 90 %, mp 189-191", C,,H,,O, . H,O (332.4) Calcd C 79.5 H 6.07 Found C 79.6 H 6.19. - MS:
m/e = 3 14 (Mf). - 'H-NMR (d6-acetone).6 (ppm) = 1.13 (t, J = 7 Hz, 3H, -CH,); 2.78 (t, J = 7 Hz, 2H,
-CH,), 6.90-8.10 (m, 11 H, aromat. H); 8.57, 8.70 (2s, 2H, -OH).
Estradiol Receptor Binding Assay
Test compounds were incubated with cytosol from calf uteri and l3H1-estradiolat 4'for 16 h6-'0, 16). Incubation was stopped by adding dextran coated charcoal. After centrifugation, the radioactivity of a 100 p1
supernatant aliquot was counted. The percentage bound radioligand was plotted vs. the concentration of
unlabeled test compounds. Five or six concentrations of the competitors were tested. They were chosen to
provide a linear portion on a semilog plot crossing the point of 50 % competition. From this plot, the molar concentrations of unlabeled estradiol and of test compounds reducing radioligand binding by 50 %
were determined.
Estrogen and Antiestrogen Assays
Estrogenic and antiestrogenic properties were determined by stimulation of the uterine growth or by inhibition of the uterine growth stimulated by estrone, respectively, using immature NMRI mice as described7-9316). Female mice (body weight 10-12 g; age 20 d at test beginning, ten mice per group) were injected
sc daily for 3 consecutive days with solutions of the test compounds in olive oil (0,l ml/mouse). The uteri
were removed 24 h after the last injection, fixed with Bouin's solution, dried and. weighed.
Hormone-Dependent, TransplantableMXT Mammary Tumor of the BDF,-Mouse
The method was identical to that described by us7-93. The MXT tumor used was the MXT line 3.2 kindly
provided by Dr. Bogden, Laboratory of Experimental Oncology, EG & G Bogden Laboratories, Worcester, Mass., USA. The tumor was transplanted in pieces of about 2 mm3 (1 tumor piece/animal) subcutaneously in female, 8 weeks old BDF,-mice(body weight 20 k 1,6 g, Charles River Wiga, West Germany).
After transplantation, the animals were randomly distributed into groups of ten. Starting with the first day
after transplantation, the test compounds were injected sc 3 times a week (Monday, Wednesday, Friday)
in olive oil (0,l ml/rnouse) for 6 weeks. After treatment, the animals were killed by cervical dislocation
and weighed. The tumors were removed and weighed, and the average tumor weight was calculated. The
uteri were also removed and prepared as described'$)to serve as an indicator of the estrogenic side effects
of the compounds.
166
Liu and Hu
Arch. Pharm.
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IPh 1911
Arch. Pharm. (Weinheim) 320, 166-171 (1987)
Synthesis and Antihypertensive Activity of 2-Imino-2,3-dihydro5H-1,3,4-thiadiazolo[2,3-b]quinazolin-5-ones’’
Kang-Chien Liu’) +) and Ming-Kuan Hu
School of Pharmcy, National Defense Medical Center, P.O. Box 8244, Taiwan,
Republic of China
Received February, 12th, 1986
Hydrolysis of isatoic anhydride (1) with hydrazine derivatives gave the o-aminobenzohydrazides 2a-c.
Treatment of these compounds with carbon disulfide provided the 3-substituted amino-2-mercapto-quinazolin-4(3H)-ones 3a-c. Compounds 3a-c underwent cyclo-condensation with cyanogen bromide to
+)
Dedicated to my teacher Prof. E. Graffor his 651hbirthday.
0365-6233/87/0202-0166 $02.50/0
<cC V C H Verlagsgesellschaft mbH, D-6940 Weinheim, 1987
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properties, triphenylbutenes, phenylphenanthrenescompounds, inhibition, biological, ethyl, influence, investigation, mammary, isomerization, substituted, tumors, hydroxy
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