Synthesis of enterolactone and enterodiol precursors as potential inhibitors of human estrogen synthetase (aromatase)

Article abstract of DOI:10.1016/S0039-128X(00)00104-5

A series of variably substituted derivatives of lignan lactones and diols were prepared using tandem conjugate addition reaction as a key step. These theoretical precursors of the mammalian lignans enterolactone 1 and enterodiol 3 are moderate or weak inhibitors of human aromatase activity. (C) 2000 Elsevier Science Inc.

Full text of DOI:10.1016/S0039-128X(00)00104-5

Steroids 65 (2000) 437–441
Synthesis of enterolactone and enterodiol precursors as potential
inhibitors of human estrogen synthetase (aromatase)
Taru H. Ma¨kela¨*, Kristiina T. Wa¨ha¨la¨, Tapio A. Hase
Organic Chemistry Laboratory, Department of Chemistry, P.O. Box 55 (A.I. Virtasen aukio 1), FIN-00014 University of Helsinki, Helsinki, Finland
Received 2 February 2000; received in revised form 7 March 2000; accepted 13 March 2000
Abstract
A series of variably substituted derivatives of lignan lactones and diols were prepared using tandem conjugate addition reaction as a key
step. These theoretical precursors of the mammalian lignans enterolactone 1 and enterodiol 3 are moderate or weak inhibitors of human
aromatase activity. © 2000 Elsevier Science Inc. All rights reserved.
Keywords: Lignan; Lactones; Michael reactions; Synthesis
1. Introduction
competitive inhibitors of aromatase, and that enterolactone
1 has the same effect on a human choriocarcinoma cell line
JEG-3. Later the activity was also observed in whole cells
derived from primary cultures of human tissue [18]. In
addition to the mammalian lignans, enterolactone 1 and
enterodiol 3, several of their theoretical precursors were
studied. Similar intermediates have been identified in pri-
mate urine, suggesting that they are true physiological in-
termediates [6].
In this paper we report the synthesis of these theoretical
precursors, four lignan lactones, 3,3Ј-didemethoxymatairesinol
(DDMM) 5, 3-demethoxymatairesinol 6, 3-demethoxy-3Ј-
O-demethylmatairesinol (DMDM) 7, and 4,4Ј-dihydroxy-
enterolactone 8, and three lignan diols, 3Ј-demethoxysecoiso-
lariciresinol (DMSI) 9, 3Ј-O-demethylsecoisolariciresinol
(ODSI) 10, and 3,3Ј-O,OЈ-didemethyl-secoisolariciresinol
(DDSI) 11. Lactones 5-7 and diols 9-11 are all novel com-
pounds.
Lignans have attracted much interest over the years on
account of their widespread occurrence in various plant
species [1], and their broad range of biologic activity [2].
Since the detection of the mammalian lignans enterolactone
1 and enterodiol 3 in human urine [3–6], there has been
much discussion about their biologic function. Especially
interesting is their suggested role as antiestrogens and an-
ticarcinogens among other possible biologic activities [7].
Enterolactone 1, alone or together with enterodiol 3, has
more recently been detected in human plasma and other
biologic fluids as well [8–10]. Human diet has been shown
to contain plant lignans, which act as precursors for the
mammalian lignans [8,11,12]. The enterolignans are pro-
duced by the action of intestinal microflora on the precur-
sors (i.e. matairesinol 2 and secoisolariciresinol 4) in dietary
fiber. The precursor lignans have also been detected in
human urine and plasma [13,14].
Earlier studies have shown that some isoflavonoid phy-
toestrogens inhibit human estrogen synthetase (aromatase)
[15,16], but no research data have, to our knowledge, ap-
peared concerning inhibition of human aromatase by mam-
malian lignans. Using human placental microsomes, Adler-
creutz et al. [17] first reported that these lignans were
2. Experimental
All experiments were monitored by thin layer chroma-
tography using aluminum based, precoated silica gel sheets
(Merck 60 F254, layer thickness 0.2 mm). Silica gel 60
(230–400 mesh, Merck) was used for flash column chro-
matography. Melting points were determined on an Elec-
trothermal melting point apparatus in an open capillary tube
and are uncorrected. UV spectra were recorded on Shi-
* Corresponding author. Tel.: ϩ358-9-19140392; fax: ϩ358-9-
19140366.
E-mail address: taru.makela@helsinki.fi (T. Ma¨kela¨).
0039-128X/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved.
PII: S0039-128X(00)00104-5

438
T.H. Ma¨kela¨ et al. / Steroids 65 (2000) 437–441
madzu UV-200 spectrophotometer. 1H and 13C NMR spec-
tra were recorded 200 MHz Varian GEMINI spectrometer
in acetone-d6 and chemical shifts are relative to tetrameth-
ylsilane (TMS) as an internal standard. EIMS and HRMS
were obtained using JEOL JMS-SX102 spectrometer.
CH2Cl2 was distilled, and THF was freshly distilled from
sodium benzophenone ketyl. All commercially available
chemicals were used as supplied by the manufacturers.
(C-8Ј), 46.51 (C-8), 55.72 (CH3O), 71.17 (C-9Ј), 112.50
(C-2Ј), 115.32 (C-5Ј), 115.62 (C-3, C-5), 121.49 (C-6Ј),
129.44 (C-1Ј), 130.58 (C-1), 130.91 (C-2, C-6), 145.49
(C-4Ј), 147.82 (C-3Ј), 156.49 (C-4), 178.67 (C-9); HRMS
m/z calculated for C19H20O5 (Mϩ) 328.1311, found
328.1302; EIMS m/z 328 (Mϩ, 70), 164 (43), 138 (62), 137
(92), 122 (14), 108 (20), 107 (100), 95 (15), 94 (12), 85
(15), 77 (19).
2.1. General procedure for the preparation of lactones:
3,3Ј-Didemethoxymatairesinol 5
2.2. General demethylation procedure: 3-Demethoxy-3Ј-
O-demethylmatairesinol 7
To a stirred solution of 12a (5.0 g, 12 mmol) in dry THF
(30 ml) maintained under argon at Ϫ78°C was added a
solution of n-butyllithium in hexanes (1.6 M, 12 mmol).
The resulting solution was stirred for 2.5 h, and a solution of
2-butenolide (1.0 g, 12 mmol) dissolved in dry THF (4 ml)
was added. The reaction mixture was stirred for a further
2.5 h at Ϫ78°C and then treated dropwise with a solution of
13a (3.3 g, 12 mmol) and HMPA (2.1 ml, 12 mmol) in dry
THF (10 ml). The reaction mixture was allowed to reach
room temperature overnight, and then the reaction was
quenched with water. The mixture was extracted with
EtOAc, washed with water and dried over Na2SO4. Evap-
oration of the solvent left a gum, which was purified by flash
column chromatography eluting with CH2Cl2/pentane (2:1,
v/v) to give 14 as an amorphous solid.
To a stirred solution of 6 (0.3 g, 0.9 mmol) in dry CH2Cl2
(9 ml) maintained under argon at Ϫ78°C was added drop-
wise a solution of BBr3 in CH2Cl2 (1 M, 5.0 mmol). The
reaction mixture was allowed to warm to room temperature
during the same day, and then treated with water. The
mixture was stirred for fifteen minutes, and then extracted
with ether, dried over Na2SO4 and evaporated. The grude
product was purified by flash column chromatography elut-
ing with ethyl acetate/hexane (4:1, v/v) to afford 0.20 g
(69%) of 7.
7: Amorphous solid; UV (EtOH) ␭
nm (log ⑀) 283,
max
1
227 (3.48, 3.95); H NMR (200 MHz, d6-acetone) ␦ 2.41–
2.69 (4 H, m, H-7Ј, H-8, H-8Ј), 2.89 (2 H, dd, J ϭ 3.6, 5.8
Hz, H-7), 3.85 (1 H, m, H-9Ј), 4.03 (1 H, dd, J ϭ 7.2, 8.8
Hz, H-9Ј), 6.46 (dd, J ϭ 2.0, 8.0 Hz, ArH), 6.63 (d, J ϭ 2.0
Hz, ArH), 6.71–6.82 (m, 3 ArH), 7.08 (dd, J ϭ 1.7, 6.7 Hz,
2 ArH); 13C NMR (200 MHz, d6-acetone) ␦ 34.19 (C-7),
37.87 (C-7Ј), 41.95 (C-8Ј), 46.82 (C-8), 71.32 (C-9Ј),
115.84 (C-3, C-5, C-5Ј), 116.35 (C-2Ј), 120.56 (C-6Ј),
129.59 (C-1Ј), 131.12 (C-1, C-2, C-6), 144.21 (C-4Ј),
145.70 (C-3Ј), 156.74 (C-4), 178.78 (C-9); HRMS m/z calcd
for C18H18O5 (Mϩ) 314.1155, found 314.1150; EIMS m/z
314 (Mϩ, 58), 298 (25), 164 (14), 150 (20), 149 (24), 124
(15), 123 (28), 108 (17), 107 (100), 91 (9), 77 (13).
A suspension of 14 (2.1 g, 3.0 mmol) in ethanol (150 ml)
and W-2 Raney nickel (36 g) was refluxed for 3 h. The
catalyst was removed by filtration and rinsed with acetone.
Evaporation of the solvents left a grude product, which was
purified by recrystallization from chloroform to give 0.12 g
(13%) of 5.
5: White solid from chloroform, m.p. 186–188°C; UV
1
(EtOH) ␭
nm (log ⑀) 280 (3.32); H NMR (200 MHz,
max
d6-acetone) ␦ 2.48–2.67 (4 H, m, H-7Ј, H-8, H-8Ј), 2.89 (2
H, dd, J ϭ 3.9, 5.6 Hz, H-7), 3.86 (1 H, m, H-9Ј), 4.03 (1
H, dd, J ϭ 6.9, 9.3 Hz, H-9Ј), 6.73–6.80 (m, 4 ArH), 6.97
(dd, J ϭ 2.0, 6.5 Hz, 2 ArH), 7.07 (dd, J ϭ 1.9, 6.7 Hz, 2
ArH), 8.27 (2 H, br s, OH); 13C NMR (200 MHz, d6-
acetone) ␦ 34.48 (C-7), 37.87 (C-7Ј), 42.26 (C-8Ј), 47.06
(C-8), 71.50 (C-9Ј), 116.09 (C-3Ј, C-5Ј), 116.17 (C-3, C-5),
129.86 (C-1Ј), 130.40 (C-1), 130.57 (C-2Ј, C-6Ј), 131.36
(C-2, C-6), 156.87 (C-4Ј), 157.02 (C-4), 178.91 (C-9);
HRMS m/z calcd for C18H18O4 (Mϩ) 298.1205, found
298.1197; EIMS m/z 298 (Mϩ, 4), 164 (41), 134 (32), 133
(20), 120 (0), 108 (59), 107 (100), 95 (18), 91 (18), 85 (20),
77 (31).
8: Amorphous solid; UV (EtOH) ␭
nm (log ⑀) 284
max
1
(3.56); H NMR (200 MHz, d6-acetone) ␦ 2.42–2.60 (4 H,
m, H-7Ј, H-8, H-8Ј), 2.84 (2 H, dd, J ϭ 3.4, 5.5 Hz, H-7),
3.83 (1 H, m, H-9Ј), 4.02 (1 H, m, H-9Ј), 6.45 (dd, J ϭ 2.1,
8.0 Hz, ArH), 6.60 (dt, J ϭ 2.0, 8.9 Hz, 2 ArH), 6.79–6.71
(m, 3 ArH), 7.65 (2 H, br s, OH); 13C NMR (200 MHz,
d6-acetone) ␦ 33.90 (C-7), 37.32 (C-7Ј), 41.40 (C-8Ј), 46.25
(C-8), 70.90 (C-9Ј), 115.31 (C-5Ј), 115.39 (C-5), 115.83
(C-2Ј), 116.49 (C-2), 120.11 (C-6Ј), 121.06 (C-6), 129.98
(C-1Ј), 130.64 (C-1), 143.59 (C-4Ј), 143.81 (C-4), 145.07
(C-3, C-3Ј), 178.51 (C-9); HRMS m/z calcd for C18H18O6
(Mϩ) 330.1103, found 330.1100; EIMS m/z 330 (Mϩ, 3),
207 (1), 150 (12), 149 (10), 124 (74), 123 (100), 110 (4),
105 (7), 91 (4), 85 (13), 77 (37).
6: Amorphous solid; UV (EtOH) ␭
nm (log ⑀) 281.5
max
1
(3.51); H NMR (200 MHz, d6-acetone) ␦ 2.51–2.64 (4 H,
m, H-7Ј, H-8, H-8Ј), 2.89 (2 H, t, J ϭ 5.5 Hz, H-7), 3.80 and
3.87 (4 H, s and m, MeO and H-9Ј), 4.07 (1 H, dd, J ϭ 6.5,
7.9 Hz, H-9Ј), 6.57 (dd, J ϭ 1.9, 7.9 Hz, ArH), 6.69 (d, J ϭ
1.9 Hz, ArH), 6.73–6.82 (m, 3 ArH), 7.07 (dd, J ϭ 1.9, 6.6
Hz, 2 ArH), 7.47 (1 H, s, OH), 8.29 (1 H, s, OH); 13C NMR
(200 MHz, d6-acetone) ␦ 34.06 (C-7), 37.83 (C-7Ј), 41.78
2.3. General procedure for the preparation of diols: 3Ј-
Demethoxysecoisolariciresinol 9
To a stirred solution of compound 19 (0.14 g, 0.4 mmol)
in dry THF (10 ml) maintained under argon at room tem-

T.H. Ma¨kela¨ et al. / Steroids 65 (2000) 437–441
439
Fig. 1. The structures of compounds 1–11.
perature was added LiAlH4 (0.030 g, 0.8 mmol). The reac-
tion mixture was stirred for 2 h, treated with 2 N H2SO4 and
extracted with ether. Ether was washed with water and dried
over MgSO4. Evaporation of the solvent left a grude prod-
uct, which was purified by recrystallization from CHCl3 to
give 0.07 g (50%) of 9.
(C-8, C-8Ј), 60.97 (C-9, C-9Ј), 115.81 (C-2, C-2Ј), 117.01
(C-5, C-5Ј), 121.19 (C-6, C-6Ј), 133.98 (C-1, C-1Ј), 143.84
(C-4, C-4Ј), 145.63 (C-3, C-3Ј); HRMS m/z calculated for
C18H22O6 (Mϩ) 334.1416, found 334.1423; EIMS m/z 334
(Mϩ, 15), 316 (36), 175 (15), 161 (9), 149 (10), 124 (66),
123 (100), 91 (4), 77 (9).
9: White solid from chloroform, m.p. 108–110°C; UV
Enterolactone 1 and enterodiol 3 were prepared as a
white powder from chloroform, m.p. 140–142°C (lit27,28
141–143°C, 142–143°C) and m.p. 175–179°C (lit.27 171–
173°C), respectively. Spectroscopic data were in agreement
with those reported in the literature [6,29].
1
(EtOH) ␭
nm (log ⑀) 282, 227 (3.52, 4.05); H NMR
max
(200 MHz, d6-acetone) ␦ 1.92 (2 H, m, H-8, H-8Ј), 2.64–
2.73 (4 H, m, H-7, H-7Ј), 3.14 (2 H, br s, OH), 3.55 (2 H,
m, H-9), 3.70 (2 H, dd, J ϭ 2.0, 11.2 Hz, H-9Ј), 3.77 (3 H,
s, OMe), 6.61 (dd, J ϭ 1.8, 8.0 Hz, ArH), 6.72 (dt, J ϭ 1.8,
8.1 Hz, 4 ArH), 6.99 (dd, J ϭ 1.8, 8.4 Hz, 2 ArH); 13C NMR
(200 MHz, d6-acetone) ␦ 35.50 (C-7Ј), 36.03 (C-7), 44.79
(C-8Ј), 44.93 (C-8), 56.16 (OCH3), 61.06 (C-9Ј), 61.11
(C-9), 113.29 (C-2), 115.48 (C-5), 115.83 (C-5Ј, C-3Ј),
122.40 (C-6), 130.87 (C-6Ј, C-2Ј), 132.93 (C-1Ј), 133.58
(C-1), 145.44 (C-4), 148.12 (C-3), 156.29 (C-4Ј); HRMS
m/z calcd for C19H24O5 (Mϩ) 332.1624, found 332.1622;
EIMS m/z 332 (Mϩ, 11), 314 (92), 138 (87), 137 (100), 123
(8), 108 (12), 107 (54), 77 (7).
3. Results
The trans-␣,␤-dibenzyl-␥-butyrolactone framework is
generally obtained by the Michael addition of an anion
derived from dithioacetal to butenolide followed by benzy-
lation in situ [19–21]. In our synthetic study, the method
was chosen for general use due to the flexibility in regard to
the aromatic ring substituents. The resultant intermediate
lactones can subsequently be transformed into target lac-
tones and diols in 1 to 3 steps.
10: Light yellow solid from chloroform, m.p.
1
145–147°C; UV (EtOH) ␭
nm (log ⑀) 284 (3.69); H
max
NMR (200 MHz, d6-acetone) ␦ 1.93 (2 H, m, H-8, H-8Ј),
2.60–2.70 (4 H, m, H-7, H-7Ј), 3.51 (2 H, dd, J ϭ 3.0, 11.2
Hz, H-9), 3.69 (2 H, dd, J ϭ 3.3, 11.0 Hz, H-9Ј), 3.78 (3 H,
s, OMe), 6.50 (dd, J ϭ 2.1, 8.0 Hz, ArH), 6.62 (dd, J ϭ 1.8,
7.9 Hz, ArH), 6.68–6.79 (m, 4 ArH); 13C NMR (200 MHz,
d6-acetone) ␦ 35.71 (C-7Ј), 35.95 (C-7), 44.73 (C-8Ј), 44.88
(C-8), 56.10 (OCH3), 61.04 (C-9Ј, C-9), 113.19 (C-2),
115.38 (C-2Ј), 115.76 (C-5Ј), 116.98 (C-5), 121.15 (C-6Ј),
122.32 (C-6), 133.54 (C-1Ј), 133.89 (C-1), 143.82 (C-4Ј),
145.37 (C-3Ј), 145.62 (C-4), 148.05 (C-3); HRMS m/z cal-
culated for C19H24O6 (Mϩ) 348.1573, found 348.1570;
EIMS m/z 348 (Mϩ, 20), 330 (57), 175 (9), 138 (53), 137
(100), 124 (25), 123 (33), 77 (7).
Thioacetal derivatives of dibenzylbutyrolactone 14
through 18 were prepared from the corresponding dithioac-
etals [22] 12a-c by reaction with n-butyllithium and
2-butenolide in THF followed by in situ alkylation with the
properly substituted benzyl bromides [23] 13a-b in the
presence of HMPA (Scheme 1) [21]. Simultaneous desul-
furization and debenzylation were achieved by treatment
with Raney nickel in refluxing ethanol to afford directly two
of the desired lactones 5 and 6 [21]. To avoid polymeriza-
tion caused by abundant phenolic hydroxy groups, lactones
7 and 8 were prepared by demethylation with BBr3 in
CH2Cl2 at Ϫ78°C from 3-demethoxymatairesinol 6 and
matairesinol 2, respectively [24]. The desired diols 9–11
were prepared by reduction with LiAlH4 in dry THF from
the corresponding lactones 19, 20, and 8, respectively [21].
In the biologic studies enterolactone 1 and its theoretical
precursors 5-8 were found moderate inhibitors whereas en-
terodiol 3 and its precursors 9 through 11 were weak inhib-
itors [17,18]. Lactones 7 and 8 were the most potent inhib-
itors in whole cell and placental microsome system,
11: Light brown solid from chloroform, m.p. 208°C; UV
1
(EtOH) ␭
nm (log ⑀) 285.5 (3.76); H NMR (200 MHz,
max
d6-acetone) ␦ 1.90 (2 H, m, H-8, H-8Ј), 2.59–2.63 (4 H, m,
H-7, H-7Ј), 3.50 (2 H, m, H-9), 3.67 (2 H, dd, J ϭ 3.2, 11.0
Hz, H-9Ј), 4.19 (2 H, br s, OH), 6.51 (dd, J ϭ 2.0, 8.1 Hz,
2 ArH), 6.68–6.72 (m, 4 ArH), 7.72 (4 H, br s, OH); 13C
NMR (200 MHz, d6-acetone) ␦ 35.67 (C-7, C-7Ј), 45.09

440
T.H. Ma¨kela¨ et al. / Steroids 65 (2000) 437–441
Scheme 1. The synthesis of lignan lactones 5–8 and diols 9–11.
respectively. Compound 8 has also been found the most
active inhibitor in the study of HIV-1 integrase [25]. The
semisynthetic compound 8 was obtained from natural ma-
tairesinol by demethylation procedure with AlCl3 and pyri-
dine in CH2Cl2. The receptor binding activity of compound
5 among some other possible non-steroidal antiprogestins
has been evaluated with no noticeable activity [26].
between enterolactone 1 and enterodiol 2 to be greater in
whole cell than in placental microsome system, with entero-
diol 3 being a far weaker inhibitor in whole cells. Another
characteristic feature is the catecholic structure in aromatic
rings that seems to increase the ability to inhibit aromatase
activity. This would in part explain why lactones 7 and 8 are
the most potent inhibitors.
4. Discussion
Acknowledgments
In conclusion, a series of lignan lactones and diols with
variably substituted aromatic rings were prepared using
tandem conjugate addition reaction and subsequent modifi-
cation procedures. A number of these compounds are mod-
erate or weak inhibitors of human aromatase activity and
thereby may contribute to the prevention of hormone de-
pendent cancers [17,18]. Enterodiol 3 is a weaker aromatase
inhibitor than enterolactone 1. The observed difference in
potency may result in the structural differences. Although
both are diphenolic compounds, enterolactone 1 and its
theoretical precursors have a lactone ring as distinct from
the diols. The presence of the ring moiety may either di-
rectly increase the affinity of enterolactone 1 to aromatase
enzyme, or increase lipid solubility, allowing enterolactone
1 and other lactones to enter the cell more easily and gain
access to the binding site of aromatase. The ring effect on
lipid solubility may also explain the difference in potency
We thank Jorma Matikainen for running the mass spec-
tra.
References
[1] Cole JR, Wiedhopf RM. Distribution. In: Rao CBS, editor. Chemistry
of lignans. Waltair: Andhra University Press, 1978. p. 39–64.
[2] MacRae WD, Towers GHN. Biological activities of lignans. Phyto-
chemistry 1984;23:1207–20.
[3] Setchell KDR, Adlercreutz H. The excretion of two new phenolic
compounds (180/442 and 180/410) during the human menstrual cycle
and in pregnancy. J Steroid Biochem 1979;11:15–6.
[4] Setchell KDR, Lawson AM, Mitchell FL, Adlercreutz H, Kirk DN,
Axelson M. Lignans in man and in animal species. Nature 1980;287:
740–2.
[5] Stitch SR, Toumba JK, Groen MB, et al. Excretion, isolation and
structure of a new phenolic constituent of female urine. Nature 1980;
287:738–40.

T.H. Ma¨kela¨ et al. / Steroids 65 (2000) 437–441
441
[6] Setchell KDR, Lawson AM, Conway E, et al. The definitive identi-
fication of the lignans trans-2,3-bis(3-hydroxybenzyl)-␥-butyrolac-
tone and 2,3-bis(3-hydroxybenzyl)butane-1,4-diol in human and an-
imal urine. Biochem J 1981;197:447–58.
[7] Setchell KDR, Adlercreutz H. Mammalian lignans and phytoestro-
gens: recent studies on their formation, metabolism and biological
role in health and disease: In: Rowland IR, editor. Role of the gut
flora in toxicity and cancer. London: Academic Press, 1988. p. 315–
45.
[17] Adlercreutz H, Bannwart C, Wa¨ha¨la¨ K, et al. Inhibition of human
aromatase by mammalian lignans and isoflavonoid phytoestrogens. J
Steroid Biochem Molec Biol 1993;44:147–53.
[18] Wang C, Ma¨kela¨ T, Hase T, Adlercreutz H, Kurzer M. Lignans and
flavonoids inhibit aromatase enzyme in human preadipocytes. J Ste-
roid Biochem Molec Biol 1994;50:205–12.
[19] Ziegler FE, Schwartz JA. Synthetic studies on lignan lactones: aryldi-
thiane route to ( Ϯ )-podorhizol and ( Ϯ )-isopodophyllotoxone and
approaches to the stegane skeleton. J Org Chem 1978;43:985–91.
[20] Pelter A, Ward RS, Satyanarayana P, Collins P. Synthesis of lignan
lactones by conjugate addition of thioacetal carbanions to butenolide.
J Chem Soc, Perkin Trans 1 1983:643–7.
[8] Setchell KDR, Borriello SP, Gordon H, et al. Lignan formation in
man. Microbial involvement and possible roles in relation to cancer.
Lancet 1981;2:4–7.
[9] Dehennin L, Reiffsteck A, Jondet M, Thibier M. Identification and
quantitative estimation of a lignan in human and bovine semen. J
Reprod Fert 1982;66:305–9.
[21] Adlercreutz H, Musey PI, Fotsis T, et al. Identification of lignans and
phytoestrogens in urine of chimpanzees. Clin Chim Acta 1986;158:
147–54.
[10] Finlay EMH, Wilson DW, Adlercreutz H, Griffits K. The identifica-
tion and measurement of ‘phyto-oestrogens’ in human saliva, plasma,
breast aspirate or cyst fluid, and prostatic fluid using gas chromatog-
raphy-mass spectrometry. J Endocrinol 1991;129(suppl.):Abstract No
49.
[11] Axelson M, Sjo¨vall J, Gustafsson B, Setchell KDR. Origin of lignans
in mammals and identification of a precursor from plants. Nature
1982;298:659–60.
[22] Ong BS, Chan TH. A simple method of dithioacetal and ketalization.
Synth Commun 1977;7:283–6.
[23] Baxter I, Allan LT, Swan GA. Synthesis and oxidation of some
1-benzylisoquinoline derivatives. J Chem Soc 1965:3645.
[24] Buckleton JS, Cambie RC, Clark GR, et al. Oxidative coupling of
lignans. II Non-phenolic coupling of diarylbutane lignans related to
matairesinol dimethyl ether. Aust J Chem 1988;41:305–24.
[25] Eich E, Pertz H, Kaloga M, et al. (Ϫ)-Arctigenin as a lead structure
for inhibitors of human immunodeficiency virus type-1 integrase.
J Med Chem 1996;39:86–95.
[26] Agnihotri A, Neelima Seth M, Bhaduri AP, Srivastava AK, Kamboj
VP. Molecular interaction of non-steroidal compounds with uterine
progesterone receptor (part II). Exp Clin Endocrinol 1988;91:327–33.
[27] Groen MB, Leemhuis J. Synthesis of compound X, a non-steroidal
constituent of female urine, and congeners. Tetrahedron Lett 1980;
21:5043–6.
[12] Borriello SP, Setchell KDR, Axelson M, Lawson AM. Production
and metabolism of lignans by the human fecal flora. J Appl Bacteriol
1985;58:37–43.
[13] Bannwart C, Adlercreutz H, Fotsis T, Wa¨ha¨la¨ K, Hase T, Brunow G.
Identification of O-desmethylangolensin, a metabolite of daidzein,
and of matairesinol, one likely plant precursor of the animal lignan
enterolactone, in human urine. Finn Chem Lett 1984:120–5.
[14] Adlercreutz H, Fotsis T, Lampe J, et al. Quantitative determination of
lignans and isoflavonoids in plasma of omnivorous and vegetarian
women by isotope dilution gas chromatography-mass spectrometry.
Scand J Clin Lab Invest 1993;53(suppl. 215):5–18.
[28] Kirk DN, McLaughlin LM, Lawson AM, Setchell KDR, Patel SK.
Synthesis of the [2H]-labeled urinary lignans enterolactone and en-
terodiol. J Chem Soc, Perkin Trans 1 1985:35–7.
[15] Ibrahim A-R, Abul–Hajj YL. Aromatase inhibition by flavonoids. J
Steroid Biochem Molec Biol 1990;37:257–60.
[16] Kellis JT, Nesnow S, Vickery LE. Inhibition of aromatase cyto-
chrome P-450 (estrogen synthetase) by derivatives of ␣-naphthofla-
vone. Biochem Pharmac 1986;35:2887–91.
[29] Cooley G, Farrant RD, Kirk DN, et al. Structural analysis of the
urinary lignan 2,3-bis-(3-hydroxybenzyl)butan-4-olide (‘Enterolac-
tone’). A 400 MHz nuclear magnetic resonance study for the solution
state and X-ray study for the crystal state. J Chem Soc, Perkin Trans
2 1984:489–97.