close

Вход

Забыли?

вход по аккаунту

?

Synthesis and Evaluation of Sulfur-Containing Glutethimide Derivatives for Aromatase and Desmolase Inhibitory Activity.

код для вставкиСкачать
39 1
Sulfur-Containing Glutethimide Derivatives
Synthesis and Evaluation of Sulfur-Containing Glutethimide
Derivatives for Aromatase and Desrnolase InhibitoryActivity’)
Patrick J. Bednarskia)*and Rolf W. Hartmannb)
a) Lehrstuhl fur Pharmazeutische Chemie 11, Universitat Regensburg, W-8400 Regensburg, Germany,
b) Fachrichtung Pharmazeutische Chemie, Universitat des Saarlandes, W-6600 Saarbriicken, Germany
Received June 9, 1992
~
Synthese und Priifung schwefelhaltiger Glutethimid-Derivateauf Aromatase- bzw. Desmolase-hemmendeWirkung
Novel sulfur-containing glutethimide derivatives, substituted with either
thiol or methylsulfide groups in the ortho/paru positions of the aromatic
ring, were synthesized and tested for both human placental aromatase and
bovine adrenocortical desmolase inhibitory activities. The synthesis was
achieved by the chlorosulfonation of gluthethimide, which yielded a 3: 1
mixture of the para to orrho sulfonyl chlorides 2ab. The sulfonyl chlorides of gluthethimide were reduced with Zn/H2S04 to give the thioglutethimides 3ab, which in turn were methylated with MeI/EtOH to give the
corresponding methylsulfides 4ab. In comparison to aminoglutethimide
(AG), 3a/b and 4 a b were weak inhibitors of aromatase, with 3a/h being
more potent tban 4ab. Aromatase inhibition by the thiol compound was
pH-dependent; 3ab was most potent at higher pH (7.4) than at lower (6.6).
This suggested that the thiolate form of 4 coordinates with the femc heme
of aromatase. Likewise, both 3ab and 4 a b were less potent at inhibiting
bovine adrenal desmolase than AG. Possible reasons for the surprisingly
poor arornatase inhibitor activity of t k s e compounds are discussed.
~~~~
Neue schwefelhaltige Glutethimide - substituiert mit Thiol- oder
Methylthioether-Gruppen in ortholpara-Position des aromatischen Rings wurden synthetisiert und auf Hemmung der menschlichen placentaren
Aromatase und Rinder-Nebennieren-Desmolaseuntersucht. Chlorsulfonierung von Glutethimid fuhrte zu einem para:ortho = 3:l-Gemisch der entspr. Sulfonsaurechloride 2ab. Diese wurden mit Zn/H2S04 zu den Thiolsubstituierten Glutethimiden 3a/h reduziert und nachfolgend mit
MeI/EtOH zu den Methylthioethem 4 a b umgesetzt. Im Vergleich zu Aminoglutethimid (AG) zeigten 3 a b und 4 a b eine schwachere Hemmung der
Aromatase, wobei 3ab sich als st2rker erwies als 4ab. Die Aromatasehemmung des Thiols war pH-abhangig: 3a/b war bei hoherem pH-Wert
(7.4) starker wirksam als bei niedrigerem (6.6). Dies gibt AnlaB zu der
Vermutung, dab die Verbindung als Thiolat mit dem zentralen Eisen der
Aromatase in Wechselwirkung tritt. Ebenso zeigten 3 a b und 4 ab eine im
Vergleich zu AG schwachere Hemmung der Desmolase. Mogliche Griinde
fur die iiberraschend schwache Aromatasehemmung der Verbindungen
werden diskutiert.
~
Aromatase, a cytochrome P45D-dependent monooxygenase enzyme, catalyzes the conversion of 3-keto-4-ene androgens (ix. androstenedione) to
estrogens (i.e. estrone). Owing to the importance of this enzymatic reaction in both normal and diseased human physiology, there has been much
interest in understanding the mechanism of catalysis as well as in developing specific inhibitors to aromatase’I*). In particular, the treatment of postmenopausal, estrogen-dependent breast cancer with aromatase inhibitors
has attracted considerable attention.
Over the last 20 years a wide variety of both steroidal and nonsteroidal
aromatase inhibitors have been reported. Not surprisingly, some of the first
nonsteroidal compounds that were found to inhibit human aromatase were
also the same classical “Type-11” inhibitors of hepatic cytochrome P450
activity (i.e. aminoglutethimide, AG)’), and to date the vast majority of
nonsteroidal inhibitors of aromatase can still be grouped in this classification’.’). In all cases to our knowledge the iron-coordinating heteroatom of
the piperidine-2,6-dione based aromatase inhibitors ( i . e . AG) has been
nitrogen. However, other heteroatoms are also known to coordinate with
the ferric heme of cytochrome P450 enzymes4). Most important amongst
these is sulfur, and indeed sulfur-containing compounds, such as thiols and
alkylsulfides, are known to inhibit rat hepatic P450 activity in a “Type-II”
fashions*6).More relevant to the case of human aromatase are the findings
that some sulfur-containing steroids are also potent inhibitors of that enzyme’-’”). These compounds can also, but need not bind in a “Type-11” fashion to the aromatase ferric
With this in mind, we were interested to know if sulfur-containing glutethimide analogues can inhibit
human aromatase.
+)Dedicatedto Prof. W . Wiegrebe on the occasion of his 60th birthday.
Arch. Pharm. (Weinheirn)326.391-394 (1993)
Like aromatase, desmolase (or cholesterol side-chain cleavage enzyme)
is also a P450-dependent monooxygenase enzyme, and catalyzes the conversion of cholesterol to pregnenolone12).Pregnenolone is the precursor to
all mammalian steroid hormones so that inhibition of desmolase would
adversely affect many vital physiological functions. AG inhibits bovine
adrenal desmolase and it is believed that the inhibition of the analogous
enzyme in the human is the cause for some of the side effects of the
drug”). Selective inhibition of aromatase would therefore be desirable and
it is for this reason that bovine adrenal desmolase and human placental
aromatase inhibitory activities are often compared for screening purposes.
For example, one of us has previously shown that the substitution of the 3ethyl group of AG for either isopentyl14)or cyclohexyl”) groups leads to
dramatic increases in the aromatase inhibitor potency while having little
effect on the desmolase inhibitory activity.
A thiol-containing cholesterol analogue, 22-thi0-23,24-bisnor-S-cholen3p-01, has also been reported to inhibit bovine adrenal demolase activity
by a mechanism that involves coordination of the sulfur atom with the ferric heme16). However, the inhibitory potency of this compound was 18
times less than that of its 22-amino-analogue, implying an unfavorable
coordination of sulfur to the cytochrome heme compared to nitrogen. In
light of this, it was of interest to determine whether or not sulfur-containing glutethimide analogues also possess weaker desmolase inhibitory properties compared to the amine analogue, AG.
This paper reports the syntheses of sulfur-containing derivatives of glutethimide; whereby the aromatic ring has been
ortholpuru substituted with either a thiol or a methylsulfide
functionality. The aromatase and desmolase inhibitory
activities of the novel compounds are described.
0VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1993 0365-6233/93/0707-0391 $5.00 + .25/0
392
Bednarski and Hartmann
RPsults
Chlorosulfonation of glutethimide with chlorosulfonic
acid gives two sulfonyl chloride regioisomers 2a/b. It is
apparent from the AA’BB’ pattern of the aromatic protons
in the 250 MHz NMR-spectra that the para isomer 2a is the
major product. In accordance with the rules of aromatic
electrophilic substitution, the second compound is assigned
the structure of the ortho-sulfonyl chloride 2b. Attempts to
separate the isomers by silica gel chromatography and
recrystallization were unsuccessful. The reduction of the
sulfonyl chlorides to the thiols 3a/b with Zn/H2S04 is a
standard procedure17). The NMR absorptions of the two
thiol protons are well resolved from one another, allowing
for the isomeric composition of the mixture to be determined the paralortho isomers are present in a 3:1 ratio. Methylation of the thiol group with CH31 in alcohol gives the
methylsulfides 4a/b.
The potential for the thiol glutethimides 3a/b and methylsulfide glutethimides 4a/b to inhibit human placental aromatase was investigated and compared with the inhibitory
potency of AG (Table 1). (Since a mixture of isomers was
tested, only qualitative comparisons with AG can be made.)
Replacement of the amino group of AG for a thiol group
drastically reduces aromatase inhibition at pH 7.4. The
methylsulfide 4 is even less active than the thiol 3. The
inhibitory potency of 3 is pH-dependent (Table 1); decreasing the pH from 7.4 to 6.6 increases the ICs0 by 40%.
The inhibitory activity of the new compounds towards
bovine adrenal desmolase is compared with AG in Table 2.
As in the case of aromatase, replacement of the amino
Table 1. Inhibition of human placental aromatase”
Cmpd.
PH
ICm’ (pM)
AG
7.4
18.5 f 1.7
RP
1
3a/bd
6.6
238
19
0.078
3aP
7.0
220 f 23
0.084
3a/b
7.4
174
0.106
4a/b
7.4
.
~
.~
~~~
+_
+_
11
0.07
> 250
~
~~~~~~~
~~~~
a) testosterone concentration: 2.5 pM.
b) mean ? SD of at least 4 independent determination!;.
c) calculated from the ICsn-values and relative to that of AG.
d) as a 3: 1 niixture of para and ortho isomers.
Table 2. Inhibition of bovine adrenocortical desmolase
% Inhibition a at 25 pM
Cmpd.
AG
50.4
* 2.3
3a/bb
20.6
f
0.7
4a/b
10.4
?
0.8
a ) mean
2
SD of three determinations.
b) as a 3:l mixture of para and ortbo isomers.
group of AG for a thiol group leads to a decreased enzyme
inhibition. Methylation of the thiol group gives an even
weaker desmolase inhibitor [4a/b].
Discussion
The sulfur-containing glutethimide derivatives 3a and 4a
are only weak inhibitors of aromatase and desmolase. Although 3: l mixtures of the pura and ortho isomers of 3 and
4 were used, it is assumed that what little enzyme inhibition
is observed is due to the para isomers 3a and 4a. This
assumption is based on studies with AG analogues, which
have shown that the best aromatase inhibition is obtained
when the iron-coordinating amine nitrogen is para located”). The same is true for 3-ethyl-3-pyridylpiperidine-2,6dione; while the 4-pyridyl analogue showed comparable
aromatase inhibitory activity to AG, the 2- and 3-pyridyl
compound were inactive”). If it is assumed that 25% of the
mixture of 3a/b consisted of an inactive or nearly inactive
isomer (3b), a corrected IC5” of 131 pM for 3a at pH 7.4
can be estimated. This still leaves 3a ca. 7 times less potent
than AG.
The mechanism of aromatase inhibition by 3a appears to
involve a thiolate anion. The first line of evidence for this is
the pH-dependent inhibition. The pKa of the thiol group of
3a would be expected to be around 6.5 (6.52 for 4-thiotolulene2*)).This would mean that at physiological pH (i.e. 7.4)
most of 3a would be in form of the thiolate anion. At pH
7.4 the lowest ICs0 value for 3a is found. Decreasing the pH
to 6.6 would give an approximate 1: 1 ratio of thiol to thiolate species, leading to lower concentrations of the Fe(lI1)binding thiolate species and hence weaker inhibition. Similar effects of pH on the binding affinities of thiols to P-450CAM have been reported2’). The second piece of evidence
for the involvement of a thiolate species in the binding of
3a to aromatase comes from the observation that upon
methylating the thiol group to give a methylsulfide 4a, the
aromatase inhibition decreases dramatically. A decrease in
desmolase inhibitory activity is also observed on going
from the thiol 3 to the methylsulfide 4. Interestingly, the
opposite effect was reported with phenobarbital (PB)induced rat hepatic cytochrome P450; octylmethylsulfide
bound tighter than o ~ t a n e t h i o l ~ ? ~ ) .
The reason(s) for the poor aromatase inhibitory activity of
3a remain(s) unclear. It is surprising that 3a is not at least
as good as AG at inhibiting aromatase since benzenethiol
binds better to PB-induced rat hepatic P450 than aniline,
with spectral dissociation constants (K,) of 0.16, and 0.4822)
mM for benzenethiol and aniline, respectively. Although
Fe(II1) hemes are prone to reduction to Fe(I1) by thiolates, a
low-spin ferric protoporphyrin(1X) compound with benzenethiols coordinated in the axial positions has been synthesized and characterized at low temp. by x-ray diffraction2”.
Even if heme reduction were the reason for the poor inhibitory activity of the thiol 3a, this does not explain the poor
Arch. Pharm. (Weinheim) 326,391-394 (1993)
393
Sulfur-Containing Glutethimide Derivatives
activity of the methylsulfide 4a. In light of the fact that the
sulfur of the aromatase inhibitor 19-thioandrostenedione is
known to coordinate tightly with the ferric heme of aromatase' '), it seems unlikely that poor coordinating properties
of sulfur are the reason for the poor inhibitory activity of
3a.
Several explanations for the poor aromatase inhibitory
activity of the sulfur-containing glutethimide compounds
are conceivable. One could be that there are differences in
the geometric constraints of coordinating the sulfur of 3a
versus the amine-N of AG within the active site of aromatase. The active site of human aromatase is considered to be
relatively inflexible in accommodating xenobiotics, as indicated by the high binding ~ e l e c t i v i t y ~ ~and
~ ~ "the
) , strict
and substrate requirement^^^) of the enzyme.
The geometry of a sulfur ligand coordinated to iron would
be expected to be more directional than with an analogous
aniline ligandZ6).For the Fe(II1)-thiolate bond, the 3d electrons of iron (low-spin t2g electrons) might be able to participate in n backbonding with the unoccupied 3d orbitals of
sulfur. This would result in a stable bond to iron but at the
cost of restricted rotation around that bond. On the other
hand, an aniline nitrogen is a weaker n-acceptor and the
predominate (3 character of the coordination bond should
allow for more rotational freedom around the Fe(II1)-N
axis. This might allow AG to position the glutethimide
moiety in the most favorable direction so as to either avoid
steric conflicts with the enzyme active site or to take advantage of attractive interactions with the active site. The coordinated sulfur of 3a might, however, "lock" the glutethimide functionality into either a sterically unfavorable conformation or a conformation that can not take full advantage of other attractive interactions of the active site. It
should be mentioned, nonetheless, that the aromatase inhibitor 3-ethyl-3-(4-pyridyI)piperidine-2,6-dione,
a compound
that would be expected to have an entirely different hemecoordination geometry compared to AG, is only 50% less
potent than AGI9).
The poor inhibition of bovine adrenocortical desmolase
by 3 and 4 relative to AG is consistent with a report that a
thiol containing cholesterol analogue was a weaker inhibitor of desmolase activity than the corresponding amine analogueI6). However, due to the very poor aromatase inhibition by 3 and 4, there is no reason to believe that these sulfur-containing glutethimide analogues would be very selective inhibitors of that enzyme.
In conclusion, the first sulfur-containing glutethimide
analogues to be investigated for aromatase and desmolase
inhibitory properties have been reported. A definitive
explanation for the unexpectedly poor aromatase inhibitory
activities of these compounds will have to wait until more
thorough structure-activity-relationships with other sulfurcontaining nonsteroidal compounds can be done.
We thank Drs. T. Burgemeister and K.K. Mayer for the 250 MHz NMRspectra and EI-MS, respectively. P.J.B. acknowledges the generous financial stipend from the Alexander V O I Z Humboldr-Sriftung. This work was
made possible with funds from the Deursche Forschungsgemeinschqfi
(Sonderforschungsbereich 234).
Arch. Pharnr. (Weinheim)326,391-394 (1993)
Experimental Part
Materials
Unless otherwise mentioned, all chemicals were of standard reagent quality. Glutethimide: Pfannenschmidt (Hamburg, FRG); aminoglutethimide:
Buchem Feinchemikalien, AG (Bubendorf, Switzerland). Melting points:
Buchi 530 melting point apparatus, uncorrected.- UV- and IR-spectra:
Kontron Uvikon 8 10 spectrophotometer and Beckman Acculab7, respectively.- 'H-NMR spectra: 250 MHz Bruker WM 250, TMS as intern. standard.- Electron impact mass spectra (EI-MS): Varian 112S, 70 eV.- Elemental analysis: Microanalytical Laboratory, University of Regensburg
(within 0.4% of the theoretical values).
Syntheses
.~-Eth~~l-3-(4l2-henzenesulfonyl~hloro~piperidine-2,6-dione
(Za und 2b)
To 30 mL (0.45 mol) chlorosulfonic acid stirred at lO"C, 10.85 g (0.05
mol) glutethimide (1) was added slowly over 1 h. Then the flask was fitted
with a drying tube and the reaction was stirred an additional hour, after
which time the reaction was poured onto crushed ice and extracted twice
with 250 mL chloroform. The org. phases were washed once with water,
once with Na*CO, solution and again with water. The org. phase was dried
with MgSO,, filtered, and the solvent was removed by a rotary evaporator
to give a yellowish oil. The crude product was chromatographed on 300 g
silica gel (70-300 mesh) with 50% ethyl acetate/petrolether. Fractions containing the product were combined (no separation of the isomers was
achieved) and the solvent removed to give 8.3 g (53%) of a white solid,
mp. 97-110°C.- IR (Nujol): 'ii = 3200, m (NH); 3150, m (NH), 1700, vs
(C=O); 1600, m (C=C); 1380, s (S02CI); 1190 cm-', s (S02CI).- 'H-NMR
(CDCI,): 6 (ppm) = 0.86-0.94 (3H); 0.90 [t; J = 7.4 Hz, CH, (2b)l; 0.91 [t;
J = 7.4 Hz, CH, (2a)l; 1.92-2.80 [m; 6H, CH2 (2aib)l: 7.4-8.0 (5H); 7.58
Id; J = 9.0 Hz (AA'BB'), ortho H (2a)l; 8.06 [d; J = 9.0 Hz (AA'BB'),
meta H (2a)l; 7.96 [bs, NH (2a/b)]; 7.4-8.0 [m (ABCD); aromatic H
(2b)l.- EIMS: m/z (%) = 315 (6.5, "CI; M"); 287 (100); 280 (10; M+'CI); 230 (70).- C,,HI4NCIO,S: calcd. C 49.44, H 4.47, N 4.44, CI 11.23;
found C 49.48, H 4.71, N 4.31, CI 11.28.
3-Ethyl-3-(412-thiophenyl)piperidine-2,6-dione
(3a and 3b)
As 15 mL conc. H2S04 and 80 g of crushed ice stirred at 0"C, 9.6 (0.03
mol) of 2a/b were added as a solid over 30 min. After pulverizing any
large chunks of material that had formed during the addition, 12 g (0.165
mol) zinc dust was carefully added with constant stirring over 1 h. The
reaction was loosely stoppered and allowed to stir overnight while warming to room temp. The mixture was poured into water and extracted several times with CHCI,. The org. extracts were combined, washed several
times with water, dried (MgSO,), filtered and the solvent was evaporated
i.isac. to give 5.1 g (66%) of a clear oil which slowly solidified upon standing; mp. 72-85°C.- UV (methanol): hmax = 245 nm (& = 8.723). IR (neat):
'ii = 3220, ni (NH); 3100, w (NH); 2560, m (SH); 1700, vs (C=O); 1600
cin-', w (C=C).- 'H-NMR (CDCI,): 6 = 0.84-0.90 (3H); 0.86 [t; J = 7.5 Hz,
CH, (3a)l; 0.87 [t; J = 7.4 Hz, CH, (3b)l; 1.81-2.65 [m; 6H, CH2 (Sam)];
3.47 [s; 0.73 H, (SH 3a)l; 3.52 [s; 0.27 H, SH (3b)l; 7.04-7.31 (4H); 7.14
[d (AA'BB'); J = 8.7 Hz, Ar-H (3a)l; 7.26 [d (AA'BB'); J = 8.7 Hz, Ar-H,
(3a)l; 7.04-7.31 [m (ABCD); Ar-H (3b)j; 8.38 [bs: l H , NH (3aib)l.EIMS: m/z (%): 249 (100, M+'); 221 (41); 220 (41); 192 (40); 164 (SO)..
(C,,H1sN02S: calcd. C 62.63, H 6.06, N 5.62; found C 62.36, H 6.13, N
5.34.
3-Ethyl-3-(412-methyithiophenyl)piperid~ne-2,6-dione
(4a and 4b)
As 0.5 g (2 mmol) 3a/b and 10 g Na2C03 stirred under N2 in 10 mL
absol. ethanol, 0.3 mL (4.8 mmol) CH,I in 10 mL absol. ethanol were
394
added dropwise over 15 min. The reaction was further stirred for 1 h and
poured into 2N HCI. After extracting the aqueous phase three times with
diethyl ether, the org. phases were combined, washed three times with
water, dried (MgSO,), filtered, and the solvent was removed i.vac. The
crude product was chromatographed on 60 g silica gel (70-230 mesh)/diethyl ether. Fractions containing the product were combined and the solvent was removed to give 0.25 g (48%) of a colorless oil.- UV (methanol):
hmax = 257 nm (E = 9.757).- IR (neat): V = 3220, m (NH); 3100, w (NH),
1705, s (C=O): 1600, w (C=C).- ‘H-NMR (CDCL,): 6 = 0.84-0.91 (3H);
0.87 [t; J = 7.4 Hz, CH, (4a)l; 0.88 [t; J = 7.4 Hz, CH3 (4b)l; 1.82-2.64
(9H); 1.82-2.64 ([m; CH2 (4a/b)]; 2.48 [s; SCH, (4a/b)]; 7.16-7.34 (4H);
7.19 [d (AA’BB’); J = 9.0 Hz, Ar-H (4a)l; 7.24 [d (AA’BB’); J = 8.9 Hz,
Ar-H (4a)l; 7.16-7.34 [m; Ar-H (4b)l; 8.06 [IH. bs; NH (4a/b)].- EIMS:
mlz (%) = 263 (100, M+’); 234 (52); 206 (34); 205 (38); 189 (50):
(C14Hl,N02S):calcd. C 63.85, H 6.51, N 5.32; found C 63.60, H 6.79, N
5.03.
Enzyme inhibifory assays: The aromatase and desmolase inhibition
assays were done with either human placental microsomes or bovine
adrenocortical mitochondria, respectively, as de~cribed’~).
Bednarski and Hartmann
8
9
10
11
12
13
14
15
16
17
18
19
20
References
21
I
2
22
3
4
5
6
7
P.A. Cole, C.H. Robinson, .1. Med. Chem., 1990,33, 2933-2944.
D.F. Covey, Sterol Biosynthesis Inhibitors (Eds.: D. Berg, M. Plempel), VCH Publishers, Weinheim, 1988, p. 534-571.
P.K. Zachariah, Q.P. Lee, K.G. Symms, M.R. Juchau, Biochem. Pharmacol., 1976,25, 793-800.
V. Ullrich, Microsomes and Drug Oxidations (Ed.: V. Ullrich), Pergamon Press, Oxford, 1977, p. 192-20I .
W. Nastainzcyk, H.H. Ruf, V. Ullrich, Eur. .I. Biochem., 1975, 60,
6 15-620.
W. Nastainczyk, H.H. Ruf, V. Ullrich, Chem.-Bid. Interactions, 1976,
14,251-263.
P.J. Bednarski, D.J. Porubek, S.D. Nelson, J . Med. Chem., 1985, 28,
775-779.
23
24
25
26
J.N. Wright, M.R. Calder, M. Akhtar, J . Chem. SOC.,Chem. Commun.,
1985, 1733-1735.
J.T. Kellis, W.E. Childers, C.H. Robinson, L.E. Vickery, .I. B i d .
Chem., 1987,262,4421-4426.
G.H. Deckers, A.H.W.M. Schuurs, J . Steroid Biochem., 1989, 32,
625-63 I ,
P.J. Bednarski, S.D. Nelson, J . Med. Chem., 1989,32, 203-213.
F.J. Zeelen, Medicinal Chemistry of Steroids, Elsevier, Amsterdam
1990, p. 83-86.
P.F. Bruning, J.B.M. Bonfrer, E. Engelsman, E.H. Linden, M. JongBakker, W. Nooyen, Breast Cancer Res. Treat., 1984,4,289-295.
R.W. Hartmann, C. Batz1,J. Med. Chem., 1986,29, 1362-1369.
R.W. Hartmann, C. Batzl, T. Pongratz, A. Mannschreck, J . Med.
Chem., 1992,35,2210-2214.
L.E. Vickery, J. Singh, J . Steroid Biochem., 1988,29,539-543.
R. Adams, C.S. Marvel, Organic Reactions, Col. Vol. I (Ed.: H. Gilman), John Wiley & Sons, N.Y., 1932, p. 504-505.
A.B. Foster, M. Jarman, C.S. Leung, M.G. Rowlands, G.N. Taylor, J .
Med. Chem., 1983,26,50-54.
A.B. Foster, M. Jarman, C.S. Leung, M.G. Rowlands, G.N. Taylor,
R.G. Plevey, P. Sampson, J . Med. Chern., 1985,28,200-204.
J.P. Ddnehy, K.N. Paramswarn, J . Chem. Engineer. Data, 1968, 13,
386-389.
M. Sono, L.A. Anderson, J.H. Dawson, J . Biol. Chem., 1982, 257,
8308-8320.
J.R. Hayes, M.U.K. Mgbodile, T.C. Cambell, Biochem. Pharmcol.,
1973,22, 1005-1014.
J.P. Collman, T.N. Sorrell, K.O. Hodgson, A.K. Kulshrestha, C.E.
Strouse,J.Am. Chem. Soc., 1977,99, 5180-5181.
L. Banting, H.J. Smith, M. James, G. Jones, W. Nazareth, P.J.
Nicholls, M.J.E. Hewlins, M.G. Rowlands, J . Enzyme Inhibition,
1988, 2, 215-229.
M.R. Juchau, P.K. Zachariah, Biochem. Pharmacol., 1975, 24, 227233.
G.H. Loew, In: Iron Porphyrins, Part 1, (Eds.: A.B.P. Lever, H.G.
Gray), Addison-Wesley Publishing Co., Reading, 1983, p. 1-87.
[Ph64]
Arch. Pharm. (Weinheim)326,391-394 (1993)
Документ
Категория
Без категории
Просмотров
0
Размер файла
444 Кб
Теги
synthesis, containing, inhibitors, evaluation, sulfur, aromatase, glutethimide, activity, derivatives, desmolase
1/--страниц
Пожаловаться на содержимое документа