Androsterone 3α-ether-3β-substituted and androsterone 3β-substituted derivatives as inhibitors of type 3 17β-hydroxysteroid dehydrogenase: Chemical synthesis and structure - Activity relationship

Article abstract of DOI:10.1021/jm058179h

Type 3 17β-hydroxysteroid dehydrogenase (17β-HSD) is involved in the biosynthesis of androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we prepared a series of androsterone (ADT) derivatives by adding a variety of substi

Full text of DOI:10.1021/jm058179h

J. Med. Chem. 2005, 48, 5257-5268
5257
Androsterone 3r-Ether-3â-Substituted and Androsterone 3â-Substituted
Derivatives as Inhibitors of Type 3 17â-Hydroxysteroid Dehydrogenase:
Chemical Synthesis and Structure-Activity Relationship
Be´atrice Tche´dam Ngatcha, Van Luu-The, Fernand Labrie, and Donald Poirier*
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center,
CHUQ-Pavillon CHUL and Universite´ Laval, 2705 Boulevard Laurier, Que´bec G1V 4G2, Canada
Received January 26, 2005
Type 3 17â-hydroxysteroid dehydrogenase (17â-HSD) is involved in the biosynthesis of androgen
testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we prepared a
series of androsterone (ADT) derivatives by adding a variety of substituents at position 3. The
3â-substituted ADT derivatives proved to be good inhibitors (IC50 ) 57-147 nM) with better
inhibitory activities obtained for compounds bearing a propyl, s-butyl, cyclohexylalkyl, or
phenylalkyl group. With an IC50 value of 57 nM, the 3â-phenylmethyl-ADT was 6-fold more
potent than ADT, the lead compound, and 13-fold more potent than 4-androstene-3,17-dione,
the natural enzyme substrate used itself as inhibitor. The 3R-ether-3â-substituted ADT
derivatives had a lower inhibitory activity compared to the 3â-substituted ADT analogues except
for the 3â-phenylethyl-3R-methl-O-ADT (IC50 ) 73 nM), which proved to be a more potent
inhibitor than 3â-phenylethyl-ADT (IC50 ) 99 nM). The results of our study identified potent
type 3 17â-HSD inhibitors for potential use in the treatment of androgen-sensitive diseases.
Introduction
The last step in the formation of all androgens and
estrogens is controlled by the key steroidogenic enzymes
17â-hydroxysteroid dehydrogenases (17â-HSDs).1-6 Vari-
ous known isoforms are responsible for the intercon-
version of 17-ketosteroids (e.g., dehydroepiandrosterone
(DHEA), 4-androstenedione (∆4-dione), and estrone (E1))
and their corresponding more active 17â-hydroxys-
teroids (e.g., androst-5-ene-3â,17â-diol (∆5-diol), test-
osterone (T), and 17â-estradiol (E2)). The crucial role
played by the 17â-HSD family in steroid biology prob-
ably explains the existence of a large series of isoforms
having individual cell-specific expression, substrate
specificity, and regulatory mechanisms.7-10 Moreover,
it makes this group of enzymes a unique target for the
control of the intracellular concentration of all active
sex steroids.11-13
Among the 17â-HSDs, we are especially interested in
the third member of this ubiquitous enzyme family. In
fact, type 3 17â-HSD, also referred to as testicular 17â-
HSD, is principally found in the microsomal fraction of
Leydig cells of the testis, where it reduces ∆4-dione into
T using NADPH as a cofactor (Figure 1).14,15 For this
transformation, Km values of 0.28 and 0.77 µM were
determined for rat and human microsomal testis prepa-
rations, respectively.16,17 It was reported that type 3 17â-
HSD catalyzes the biosynthesis of approximately 50%
of the total amount of androgens in men from the
precursor ∆4-dione.1 The remaining 50% would result
from the same enzymatic reaction catalyzed by type 5
17â-HSD,18 in peripheral tissues.19 Deficiencies in tes-
ticular 17â-HSD (type 3) have been associated with
pseudohermaphroditism,14 thus showing the importance
Figure 1. Transformation of 4-androstene-3,17-dione (∆4-
dione) into testosterone (T) catalyzed by type 3 17â-HSD with
NADPH as cofactor.
of this enzyme in the production of T from ∆4-dione. It
follows that inhibition of this enzyme could block the
biosynthesis and, consequently, the action of androgens
originating from the testis. On this basis, selective
inhibitors of type 3 17â-HSD have the potential for being
used in preventing the development of androgen-sensi-
tive diseases such as benign hyperplasia and prostate
cancer. These inhibitors could also be used as adjuvants
to enhance the efficacy of androgen receptor antagonists.
Considering the crucial role of T in spermatogenesis,20
it would also be interesting to study the potential of such
inhibitors as contraceptive agents.
Although several inhibitors of type 1 and type 2 17â-
HSDs have been synthesized, few efforts have been
made to synthesize inhibitors of type 3 17â-HSD.11
Pittaway evaluated the ability of 20 steroidal com-
pounds to inhibit type 3 17â-HSD activity in a microso-
mal preparation of canine testis.21 This study led him
to suggest that a good inhibitor would require the
presence of a 17-keto group on a steroidal nucleus
having a nonaromatized A-ring. More recently, a screen-
ing study led us to consider the 17-ketosteroid andros-
* To whom correspondence should be addressed. Phone: (418) 654-
2296. Fax: (418) 654-2761. E-mail: donald.poirier@crchul.ulaval.ca.
10.1021/jm058179h CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/09/2005

5258 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Ngatcha et al.
Scheme 2. Chemical Synthesis of ADT 3R-Ether
Derivatives 6-9a
Figure 2. General structure of 3â-substituted ADT deriva-
tives designed to inhibit the steroidogenic enzyme type 3 17â-
HSD.
Scheme 1. Chemical Synthesis of ADT 3R-Ether
Derivatives 1-5a
a Reagents: (a) (i) BH3, THF, 0 °C; (ii) H2O2, NaOH (3 N); (b)
aqueous H2SO4 (5%) 1,4-dioxane, room temp; (c) Jones’ reagent
(2.7 M), acetone, 0 °C; (d) CBr4, PPh3, CH2Cl2, 0 °C.
chromatography. A sample of the secondary alcohol 50
was coupled to Mosher’s acid (R-(+)-R-methoxy-R-(tri-
fluoromethyl)phenylacetic acid) according to the proce-
1
dure described by Ward and Rhee.27 As expected, H
and 19F NMR spectral analysis of the resulting Mosher’s
ester revealed that 50 was an epimeric (50/50) mixture
of secondary alcohols. The ADT derivatives 6 and 7 were
obtained after hydrolysis of the ketal group of 50 and
51, respectively. Oxidation of alcohol 51 with Jones’
reagent in acetone afforded the acid 8, while submitting
this same compound to CBr4 and PPh3 in CH2Cl2 yielded
the bromide 9.
a Reagents: (a) HOCH2CH2OH, p-TSA, CH2Cl2, reflux; (b) NaH,
RI(Br), THF, reflux; (c) aqueous H2SO4 (5%), 1,4-dioxane, room
temp.
terone (ADT) as a potential nucleus for developing
selective inhibitors of this isoform.22 Following poor
results obtained with different kinds of chemical groups
at position 16 of ADT,23 we focused on the opposite
steroid nucleus side, obtaining better results by adding
a hydrophobic group at position 3.24-26 Following a
preliminary report,26 we herein present the full details
of the chemical synthesis of a series of ADT 3R-ether
and/or 3â-substituted derivatives, namely, compounds
1-43 (Figure 2), and an assessment of their ability to
inhibit type 3 17â-HSD.
Synthesis of epi-ADT/ADT Derivatives 10-37
Substituted at Position 3R or 3â (Schemes 3 and
4). Dihydrotestosterone (DHT) was used as starting
material for the synthesis of compounds 10-31 (Scheme
3). The 17â-hydroxy group of DHT was first protected
as a silylated ether, using TBDMS-Cl and imidazole in
DMF, and the carbonyl group at position 3 of 52 was
submitted to various alkylating reagents (Table 1). In
most cases, a commercially available Grignard reagent
was used and the reaction was done at 0 °C in dry THF.
In the cases of entries 10 and 13, the Grignard reagent
was generated in situ by a well-known procedure
described by Smith,28 using magnesium amalgams and
the corresponding halide. Commercially available (en-
tries 4 and 5) and generated (entries 11 and 12) lithium
reagents were also used in some cases. When necessary,
the lithium reagent was generated in situ in a mixture
of diethyl ether and pentane (2:3), t-BuLi, and the
corresponding bromide according to the procedure de-
scribed by Bailey and Punzalan.29 In all cases, a mixture
of two stereoisomers at position 3 (Table 1) was ob-
tained, the proportions varying according to the nature
of the alkyl group.30 The â-alkylated isomer was the
major compound for entries 1-13, whereas it was the
other one when the less nucleophilic Grignard reagents
were used (entries 14-17). Both pure stereoisomers
Results and Discussion
Chemistry. Synthesis of ADT 3R-Ether Deriva-
tives 1-9 (Schemes 1 and 2). The synthesis of ADT
3R-ether derivatives 1-5 is depicted in Scheme 1. To
avoid alkylation at position 16 of the keto steroid, the
carbonyl of ADT was first protected as ketal with
ethylene glycol in the presence of p-TSA. The protected
form of ADT (compound 44) was then alkylated in THF
at refluxing temperature, using NaH as base and the
corresponding alkyl halide (iodide or bromide). The
ketals 45-49 were thereafter hydrolyzed with a 5%
aqueous H2SO4 solution in dioxane to afford the desired
ADT 3R-ether derivatives 1-5. Other ADT 3R-ether
derivatives 6-9 were derived from 49, as depicted in
Scheme 2. Reduction of 49 with borane in THF followed
by oxidation with H2O2 (30%) and NaOH led to a
mixture of secondary alcohol 50 and primary alcohol 51
in a ratio of 1:3, which was easily separated by flash

Inhibitors of 17â-Hydroxysteroid Dehydrogenase
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5259
Scheme 3. Chemical Synthesis of epi-ADT and ADT
Derivatives Substituted at Positions 3R and 3â
(Compounds 10-31 (See Table 1))a
tertiary alcohol at C3, the signal of which was always
lower in ppm for the 3â isomer (axial 3R-OH) than for
the 3R isomer (equatorial 3â-OH). This result agrees
with literature data on ADT (3R-OH) and epi-ADT (3â-
OH) derivatives.30 As a typical example, chemical shifts
(δ) of 71.22 and 72.42 ppm were observed for 81 (3â-
alkylated and 3R-OH) and 64 (3R-alkylated and 3â-OH),
respectively.
The TBDMS groups of 3R-alkylated compounds 53,
55, 56, 62, and 64 and of all 3â-alkylated compounds
70-86 were removed by hydrolysis (2% HCl in MeOH
or TBAF) and the corresponding alcohols were oxidized
(Jones’ reagent or PCC) to afford in very good yields the
final ketones 10-31, which were characterized by IR,
1H NMR, 13C NMR, and elemental analyses. A repre-
sentative 3R derivative of ADT, compound 14, was also
analyzed using X-ray crystallography (Figure 3) in order
to confirm unambiguously the C3 stereochemistry pre-
viously determined on the basis of TLC characteristics
and 13C NMR signal at C3.
Compounds 32-37 were obtained from 12 and 18
following the sequences of reactions depicted in Scheme
4. After protection of the C17-ketone as a 1,3-dioxolane
derivative, oxidative hydroboration (BH3 in THF fol-
lowed by H2O2 and NaOH) of the double bond of 87 and
88 yielded 89 and 90, respectively. Hydrolysis of the
ketal afforded the desired epi-ADT and ADT derivatives
32 and 33. On the other hand, submitting 89 and 90 to
bromination conditions (CBr4 and PPh3) led in both
cases to a cyclization with epimerization around C3. In
addition, the hydrolysis of the ketal group occurred
during this reaction. Separation by flash chromatogra-
phy allowed us to obtain an epimeric (50/50) mixture of
34 and the ADT derivative 35 alone, and the identifica-
tion was made on the basis of 13C NMR data. Com-
pounds 12 and 18 were also submitted to oxidative
hydroboration conditions (BH3 in THF followed by H2O2
and NaOH) to yield the corresponding triols 91 and 92,
which were directly oxidized with Jones’ reagent in
acetone to afford the lactones 36 and 37, respectively.
a Reagents: (a) TBDMS-Cl, imidazole, DMF, room temp; (b) (i)
RMgBr(Cl) or RLi, THF, 0 °C; (ii) flash chromatography; (c) (i)
MeOH/HCl (2%), room temp or TBAF, THF, reflux; (ii) Jones’
reagent (2.7 M), acetone, 0 °C or PCC, CH2Cl2, room temp.
Scheme 4. Chemical Synthesis of epi-ADT and ADT
Derivatives Substituted at Positions 3R and 3â
(Compounds 32-37)a
Synthesis of ADT 3R-Ether-3â-Substituted De-
rivatives 38-43 (Scheme 5). The ethers were formed
from intermediate compounds 81, 83, and 84 using NaH
and the corresponding iodide or bromide in refluxing
THF. Then the TBDMS protective group of compounds
93-98 was hydrolyzed with a 2% methanolic HCl
solution. The resulting 17â-alcohol was directly submit-
ted to Jones’ oxidation to afford the desired ADT 3R-
ether-3â-substituted derivatives 38-43.
Inhibition of Type 3 17â-HSD (SAR Results). The
inhibitory activity of ADT derivatives 1-43 was deter-
mined for the transformation of labeled ∆4-dione (0.1
µM) into T catalyzed by a homogenate of HEK-293_17â-
HSD3 cells that overexpress type 3 17â-HSD. As
reported in the literature,31 the cells were obtained by
transfecting a pCMV-neo_17â-HSD3 vector containing
the coding region of human type 3 17â-HSD gene into
wild-type HEK-293 cells, which only express low levels
of steroidogenic enzymes. A screening study was first
performed at two concentrations of inhibitor (0.3 and 3
µM) in order to rapidly identify active compounds
(Tables 2-5). ADT, which was previously identified as
a lead compound,22,23 was used as a reference. For
compounds showing the best inhibitory activity, further
a Reagents: (a) HOCH2CH2OH, p-TSA, CH2Cl2; (b) (i) BH3,
THF, 0 °C; (ii) H2O2, NaOH (3 N); (c) H2SO2 (5%), 1,4-dioxane,
room temp; (d) CBr4, PPh3, CH2Cl2, 0 °C; (e) Jones’ reagent (2.7
M), acetone, 0 °C.
were obtained after a separation by flash chromatog-
raphy and were differentiated by TLC (silica gel normal
phase), the 3â-substituted derivative being the less polar
one (higher Rf value) (Table 1). In addition to their
characteristic chromatographic properties, the stereoi-
somers were identified by the 13C NMR signal of their

5260 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Ngatcha et al.
Table 1. Yields, Ratios, and Characteristic Data of 3R (C) and 3â (D) Alkylated Products and Identification of Compounds C-F
Reported in Scheme 3
identification of compounds and characteristic datab
starting material
yield of
ratio
C/D (%)
entry
R
(52) (%)a
C + D (%)a
C (Rf, δ of C3)
D (Rf, δ of C3)
E
F
1c,d
2c,d
3c,d
4c,f
CH3
18
13
5
60
65
71
60
72
76
61
51
76
37
89
58
52
56
66
88
61
35/65
31/69
30/70
44/56
34/66
26/74
31/69
25/75
18/82
13/87
36/64
33/66
31/69
58/42
58/42
57/43
60/40
53 (0.26, 71.45)
55 (0.38, 72.87)
57 (0.50, 72.80)
58 (0.54, 74.51)
59 (0.47, 71.33)
60 (0.54, 72.80)
65 (0.31, 72.80)
69 (0.56, 72.82)
61 (0.54, 74.01)
63 (0.54, 73.63)
66 (0.52, 72.74)
67 (0.27, 72.77)
68 (0.41, 72.73)
54 (0.36, 72.54)
56 (0.45, 72.22)
62 (0.41, 74.14)
64 (0.58, 72.42)
70 (0.75, 69.78)
72 (0.60, 71.61)
74 (0.72, 71.60)
75 (0.73, 74.03)
76 (0.82, 75.45)
77 (0.67, 71.56)
82 (0.84, 71.62)
86 (0.83, 71.56)
78 (0.76, 73.39)
80 (0.73, 72.28)
83 (0.73, 71.59)
84 (0.65, 71.48)
85 (0.61, 71.51)
71 (0.57, 72.07)
73 (0.66, 71.05)
79 (0.65, 73.55)
81 (0.75, 71.22)
10
11
15
17
19
20
21
22
27
31
23
25
28
29
30
16
18
24
26
CH3(CH2)2
CH3(CH2)3
CH3CH2(CH3)CH
(CH3)3C
CH3(CH2)5
CH3(CH2)7
CH3(CH2)11
cyclohexyl
cyclohexyl-CH2
cyclohexyl-(CH2)2
phenyl-(CH2)2
phenyl-(CH2)3
CH2dCH
CH2dCHCH2
phenyl
phenyl-CH2
20
20
10
5
5f
6c,d
7c,d
8c,d
9c,d
10c,e
11g
12g
13c,e
14d
15d
16d
17d
5
0
8
0
0
25
22
10
0
12
13
14
18
a Isolated yield after chromatography. b Rf values obtained on TLC and chemical shift (δ in ppm) of C3. c 10-20% of reduction products
were also isolated. d Commercially available Grignard reagent. e Grignard reagent generated in situ. f Commercially available lithium
reagent. g Lithium reagent generated in situ.
Table 2. Inhibition of Type 3 17â-HSD by ADT 3R-Ether
Derivatives 1-9
assays were carried out in order to determine their IC50
values (Tables 4 and 5).
ADT 3R-ether derivatives 1-9 showed only weak
inhibitory activities (Table 2), those substituted with a
methyl, an ethyl, or an allyl group being the best. In
the linear alkyl series tested at 0.3 µM, the smaller was
inhibition of type 3 17â-HSD (%)a
compd
R
0.3 µM
3 µM
ADT
H
50
83
69
49
45
73
40
38
7
88
94
95
93
92
95
89
86
48
93
78
1
CH3
2
CH3CH2
3
CH3(CH2)2
CH3(CH2)5
CH2dCHCH2
CH3CH(OH)CH2
HO(CH2)3
4
5
6
7
8
HOOC(CH2)2
Br(CH2)3
Figure 3. Crystal 3D structure (A) and corresponding 2D
structure (B) of 14. A few carbons are numbered in the
structure in (B).
9
56
24
∆4-dioneb
a Compounds were tested at two concentrations (0.3 and 3 µM),
and the error was (10%. b Unlabeled 4-androstene-3,17-dione.
Scheme 5. Chemical Synthesis of ADT
3R-Ether-3â-Substituted Derivatives 38-43a
the substituent, the higher was the percentage of
inhibition (83-45% for the 3R-methyl ether 1 to the 3R-
n-hexyl ether 4). For the same length of alkyl side chain,
the inhibitory activity decreased when a polar group,
such as alcohol (compounds 6 and 7) or carboxylic acid
(compound 8), was present. The 3R-methyl ether 1 was
the most potent inhibitor in this series of ADT deriva-
tives 1-9.
None of the epi-ADT derivatives, namely, 3R-alky-
lated derivatives 10-14, 32, and 36 and epi-ADT itself,
showed inhibitory activities at 0.3 µM (Table 3). At 3
µM, they were less potent inhibitors than ADT or
unlabeled ∆4-dione used as inhibitor. The ADT 3â-
alkylated derivatives 15-31, 33, 35, and 37 were
generally good inhibitors of type 3 17â-HSD; almost all
showed an inhibitory activity higher than that of ADT
(Table 4). As for the 3R-ether derivatives, a hydrophobic
substituent has better inhibitory potency than a hydro-
philic one, but a loss of inhibitory activity was observed
when this 3â substituent became too large (only 50%
inhibition at 0.3 µM for 3â-n-dodecyl-ADT (31)). In the
a Reagents: (a) NaH, R′I(Br), THF, reflux; (b) (i) MeOH/HCl
(2%), room temp; (ii) Jones’ reagent (2.7 M), acetone, 0 °C.

Inhibitors of 17â-Hydroxysteroid Dehydrogenase
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5261
Table 3. Inhibition of Type 3 17â-HSD by epi-ADT
3R-Alkylated Derivatives 10-14, 32, and 36
Table 5. Inhibition of Type 3 17â-HSD by ADT
3R-Ether-3â-Alkylated Derivatives 38-43
inhibition of
type 3
inhibition of type 3
17â-HSD (%)a
17â-HSD (%)a
compd
R
0.3 µM 3 µM
compd
R
R′
0.3 µM 3 µM IC50 (nM)
ADT
50
1
88
18
16
33
36
39
39
17
53
78
ADT
H
H
50
91
80
60
24
61
80
24
88
93
92
87
28
95
88
78
330 ( 60
154 ( 16
352 ( 71
ndb
epi-ADT
H
38
phenyl-CH2
phenyl-CH2
phenyl-CH2
phenyl-CH2
phenyl-(CH2)2
CH3
10
CH3
9
39
CH3CH2
CH3(CH2)2
CH3(CH2)5
CH3
11
CH3(CH2)2
9
40
12
CH2dCHCH2
phenyl-CH2
14
10
7
41
ndb
13
42
73 ( 11
354 ( 116
758 ( 139
14
phenyl
HO(CH2)3
43
cyclohexyl-(CH2)2 CH3
32
2
9
24
∆4-dionec
36
(CH2)2CO (lactone, 3â-O)
a Compounds were tested at two concentrations (0.3 and 3 µM),
and the error was (10%. b Not determined. c Unlabeled 4-andros-
tene-3,17-dione.
∆4-dioneb
a Compounds were tested at two concentrations (0.3 and 3 µM),
and the error was (10%. b Unlabeled 4-androstene-3,17-dione.
activity (IC50 ) 100 and 97 nM, respectively), but 3â-
cyclohexylmethyl-ADT (25) and 3â-cyclohexylethyl-ADT
(28) derivatives gave better results with IC50 values of
87 and 60 nM, respectively. On the other hand, 3â-
cyclohexyl-ADT (23) and 3â-phenyl-ADT (24) gave
almost the same inhibitory activity (IC50 ) 97 and 81
nM, respectively). Replacing the phenyl group by a
phenylmethyl resulted in a significant increase of
inhibitory activity; an IC50 value of 57 nM being
obtained for 26 compared to 81 nM for 24. This activity,
however, dropped when other methylene groups were
added. Thus, for 3â-phenylethyl-ADT (29), an IC50 value
of 99 nM was obtained. For two of our best 3â-alkylated
ADT derivatives, the 3â-phenylmethyl-ADT (26), 3â-
phenylethyl-ADT (29), the 17â-OH analogues were also
Table 4. Inhibition of Type 3 17â-HSD by ADT 3â-Alkylated
Derivatives 15-31, 33, 35, and 37
inhibition of type 3
17â-HSD (%)a
compd
R
0.3 µM
3 µM
IC50 (nM)
ADT
H
50
72
77
89
31
88
85
89
93
88
88
93
90
88
92
93
93
50
17
3
88
93
94
94
76
92
90
93
95
95
95
95
94
92
93
93
97
77
74
94
93
78
330 ( 60
ndb
15
CH3
16
CH2dCH
CH3(CH2)2
CH2dCHCH2
CH3(CH2)3
ndb
tested, and as expected from previous studies,19-21
a
17
67 ( 6
18
ndb
drastic drop of inhibitory activity was noted in both
cases (results not shown).
19
116 ( 10
73 ( 5
142 ( 4
100 ( 10
97 ( 3
81 ( 6
87 ( 19
57 ( 5
147 ( 29
60 ( 16
99 ( 1
ndb
20
CH3CH2(CH3)CH
(CH3)3C
In the last series of synthesized compounds, we
explored the effect of a combination of 3R-ether and 3â-
alkyl on an ADT nucleus. The results obtained are
presented in Table 5. Generally, a loss of inhibitory
activity was observed when compared to the corre-
sponding 3â-alkylated derivatives. Indeed, the 3â-phen-
ylmethyl-ADT (26) was 3-fold more potent than its 3R-
methyl ether analogue 38 and 6-fold more potent than
its 3R-ethyl ether analogue 39. Since the 3R-n-propyl
ether analogue 40 and the 3R-n-hexyl ether analogue
41 showed only 60% and 24% of inhibition at 0.3 µM,
the IC50 value was not determined. In the same experi-
ment, 3â-phenylethyl-ADT (29) gave an IC50 value of
99 nM. In the 3â-phenylmethyl-3R-ether series, the
inhibitory activity decreased when the size of the ether
increased (see compounds 38-41). Indeed, the percent-
age of inhibition dropped from 91% for 38 to 24% for 41
at 0.3 µM. Moreover, the 3â-cyclohexylethyl-ADT (28)
was 6-fold more potent than its 3R-methyl ether ana-
logue 43. A slight gain of inhibitory activity was,
however, observed for the 3â-phenylethyl 3R-methyl
ether ADT (42), which showed an IC50 value of 73 nM.
21
22
CH3(CH2)5
23
cyclohexyl
24
phenyl
25
cyclohexyl-CH2
phenyl-CH2
CH3(CH2)7
26
27
28
cyclohexyl-(CH2)2
phenyl-(CH2)2
phenyl-(CH2)3
CH3(CH2)11
HO(CH2)3
(CH2)3O (cycloether)
(CH2)2CO (lactone)
29
30
31
ndb
33
ndb
35
ndb
37
50
24
ndb
∆4-dionec
758 ( 139
a Compounds were tested at two concentrations (0.3 and 3 µM),
and the error was (10%. b Not determined. c Unlabeled 4-andros-
tene-3,17-dione.
series of saturated linear alkyl groups, the inhibitory
activity at 0.3 µM increased with the length of the chain
and reached a maximum value for the 3â-n-hexyl-ADT
(22) with 93% of inhibition. The activity then decreased
to reach a minimum for 3â-n-dodecyl-ADT (31) with 50%
(see 15, 17, 19, 22, 27, and 31). The 3â-(n, s, and t)-
butyl-ADTs (19, 20, and 21, respectively) showed about
the same activity, slightly higher for the 3â-s-butyl (20,
IC50 ) 73 nM). Switching from 3â-n-hexyl-ADT (22) to
3â-cyclohexyl-ADT (23) did not increase the inhibitory
Conclusion
The design of ADT 3R-ether and/or 3â-substituted
derivatives as inhibitors of type 3 17â-HSD was suc-

5262 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Ngatcha et al.
(TLC) was performed on 0.20 mm silica gel 60 F254 plates (E.
Merck, Darmstadt, GE), and 230-400 mesh ASTM silica gel
60 (E. Merck) was used for flash chromatography. Infrared
spectra (IR) are expressed in cm-1 and were obtained on a
Perkin-Elmer 1600 (FT-IR series) spectrophotometer. Nuclear
magnetic resonance spectra (NMR) were obtained at 300 MHz
for 1H and at 75.5 MHz for 13C with a Bruker AC/F 300
spectrometer. The chemical shifts (δ) are expressed in ppm
and are referenced to residual chloroform (7.26 ppm for 1H
and 77.00 ppm for 13C). For 1H NMR, only specific signals were
reported. For 13C NMR, all signals were reported. Elemental
analyses were performed by Robertson Microlit Laboratories
(Madison, NJ). When necessary, complementary mass spectra
(MS) and high-performance liquid chromatography (HPLC)
analyses were carried out using an LCQ Finnigan apparatus
(San Jose, CA) and a Waters Associates system (Milford, MA),
respectively.
cessful. Indeed, the inhibitory activity of most of them
is higher than that of ∆4-dione, the natural substrate
of the enzyme, and that of ADT, the lead compound
previously identified. However, all epi-ADT derivatives
(3â-OH) tested show a very poor inhibitory activity, even
lower than that of ADT (3R-OH). Such data demonstrate
the importance of a hydroxy group at position 3R for
the inhibition of type 3 17â-HSD. Our most potent
inhibitors of type 3 17â-HSD belong to the series of 3â-
alkylated ADT derivatives; IC50 values of approximately
60 nM were obtained for 3â-n-propyl-ADT (17), 3â-
phenylmethyl-ADT (26), and 3â-cyclohexylethyl-ADT
(28). Blocking the ADT hydroxy group with an ether link
in combination with a 3â-alkyl group did not bring a
major increase of inhibitory activity. An exception in this
series, 3â-phenylethyl 3R-methyl ether ADT (42) has an
IC50 value of 73 nM, a value comparable to those of other
good 3â-alkylated derivatives. In fact, this class of ADT
derivatives might be more resistant to biological deg-
radation than the ADT derivatives that are only 3â-
alkylated.
The hydrophobicity of the group at position 3â seems
to be an important requirement for inhibition of type 3
17â-HSD. However, this is not the only parameter to
consider, as indicated by the drop of inhibitory potency
observed with a longer 3â-alkyl side chain. Considering
the series of alkyl groups tested in our SAR study, it is
possible to estimate the size of the hydrophobic pocket
that the 3â-oriented group occupies. Moreover, we
previously reported the synthesis through parallel
liquid-phase chemistry of ADT derivatives having di-
versified tertiary amide groups at position 3â. The
results of this study24 agree with the presence of a
medium-size hydrophobic pocket located close to position
3â, although its exact topography is not known. It could
be better defined by extending our SAR study to
additional diversified analogues of our best inhibitors.
Such a SAR study focusing on medium-sized alkyl
groups could also lead to the design of a more potent
inhibitor. Crystallizing a typical inhibitor with the
enzyme would also yield precious information about the
shape of this hydrophobic pocket. Unfortunately, the
crystallization of a membrane enzyme such as type 3
17â-HSD remains a great challenge.
Synthesis of ADT 3R-Ether Derivatives 1-5 (Scheme
1). 17,17-Ethylenedioxy-3R-hydroxy-5R-androstane (44).
Ethylene glycol (5.77 mL, 10 equiv) and p-toluenesulfonic acid
(197 mg, 0.1 equiv) were added to a solution of androsterone
(3.00 g, 10.34 mmol) in benzene (150 mL). The resulting
mixture was refluxed overnight on a Dean-Stark apparatus.
The reaction mixture was then cooled to room temperature,
washed with water and brine and then dried over MgSO4. The
colorless oil obtained after concentration under reduced pres-
sure was submitted to flash chromatography using a mixture
of hexanes and EtOAc (9/1) containing 1% of triethylamine.
The unreacted androsterone (10%) was removed, and ketal 44
was obtained as a white solid in 85% yield. Rf ) 0.35 (hexanes/
1
EtOAc, 7/3); IR (film) 3353 (OH, alcohol); H NMR (CDCl3) δ
0.77 (s, CH3-19), 0.82 (s, CH3-18), 3.81-3.94 (m, OCH2CH2O),
4.02 (tapp, J ) 2.6 Hz, CH-3â); 13C NMR (CDCl3) δ 11.13, 14.37,
20.14, 22.59, 28.41, 28.96, 30.69, 31.23, 32.17, 34.15, 35.73,
35.87, 36.11, 39.08, 45.94, 50.32, 54.06, 64.50, 65.11, 66.46,
119.47.
General Procedure for the Synthesis of 3R-Ethers 45-
49. Ketal 44 was dissolved in dry THF, and NaH (10 equiv)
was added. The mixture was stirred under an argon atmo-
sphere at refluxing temperature for 1 h. The appropriate iodide
or bromide (8 equiv) was added: methyl iodide for 45, ethyl
iodide for 46, propyl iodide for 47, n-hexyl iodide for 48, and
allyl bromide for 49. The reaction mixture was stirred at
refluxing temperature overnight and then cooled to room
temperature before addition of water and extraction with
EtOAc. The organic phase was washed with brine, dried over
MgSO4, and evaporated to dryness under reduced pressure.
The yellow oil obtained was purified by flash chromatography,
using a mixture of hexanes and EtOAc (9.5/0.5) containing 1%
of triethylamine. The reaction was complete, and the pure
ether was obtained with a yield generally above 95%. The
chemical data of compounds 45-49 are reported in Supporting
Information.
General Procedure for Hydrolysis of the Ketal Group
(Synthesis of 1-5). A 5% aqueous H2SO4 solution was added
to ketals 45-49 dissolved in 1,4-dioxane. The resulting
mixture was stirred at room temperature, and the reaction,
monitored by TLC, was generally completed after 2-3 h. The
solution was then neutralized by addition of a saturated
NaHCO3 solution, and the extraction was done with EtOAc.
The organic phase was washed with water and brine, dried
over MgSO4, and concentrated under reduced pressure. The
concentrate obtained was purified by flash chromatography
using a mixture of hexanes and EtOAc as eluent. All the
hydrolyses proceeded quantitatively, and the pure ketones 1-5
were obtained as a white solid or white foam.
In conclusion, compounds 17, 26, and 28 are potent
inhibitors and also constitute valuable lead compounds
for pursuing the optimization of this new family of type
3 17â-HSD inhibitors. Although they likely inhibit the
enzyme in a reversible fashion, further experiments
have to be carried out in order for us to understand their
mechanisms of action and to ascertain the type of
inhibition. These results and the degree of selectivity
of this new type 3 17â-HSD inhibitors among 17â-HSDs
will be reported in due time.
Experimental Section
Chemical Synthesis. Chemical reagents and starting
materials (androsterone and dihydrotestosterone) were pur-
chased from Aldrich Chemical Co. (Milwaukee, WI), Sigma
Chemical Company (St. Louis, MO), or Steraloids (Wilton,
NH). Dichloromethane and diethyl ether, 99.8% anhydrous
grade, were purchased from Aldrich Chemical Co. (Milwaukee,
WI). THF, used in anhydrous conditions, was distilled from
sodium benzophenone ketyl. Solvents for chromatography were
obtained from BDH Chemicals (Montreal, Canada) or Fisher
Chemicals (Montreal, Canada). Thin-layer chromatography
3R-Methoxy-5R-androstan-17-one (1). White solid; Rf )
1
0.21 (hexanes/EtOAc, 9/1); IR (film) 1738 (CdO, ketone); H
NMR (CDCl3) δ 0.80 (s, CH3-19), 0.84 (s, CH3-18), 2.42 (dd, J1
) 19.0 Hz and J2 ) 8.5 Hz, CH-16â), 3.28 (s, CH3O), 3.42 (tapp
,
J ) 2.5 Hz, CH-3â); 13C NMR (CDCl3) δ 11.37, 13.80, 20.00,
21.71, 24.98, 28.27, 30.77, 31.54, 32.51, 32.78, 35.01, 35.84,
36.00, 39.47, 47.80, 51.46, 54.32, 55.64, 75.39, 221.52. Anal.
(C20H32O2) C, H.

Inhibitors of 17â-Hydroxysteroid Dehydrogenase
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5263
3R-Ethoxy-5R-androstan-17-one (2). White solid; Rf )
3-(17′-Oxo-5′R-androstan-3′R-oxy)propanoic Acid (8).
To a stirred solution of alcohol 51 (0.150 g, 0.38 mmol) in
acetone (20 mL) at 0 °C was added dropwise a 2.7 M solution
of Jones’ reagent (1.5 mL). The reaction was monitored by TLC
and was completed after 30 min, and then isopropyl alcohol
was added dropwise until a persistent green color remained.
Organic solvents were removed under reduced pressure. The
resulting green concentrate was dissolved in water, and
extraction was done with EtOAc. Combined organic layers
were washed with brine, dried over MgSO4, and evaporated
to dryness. Purification by flash chromatography using a
mixture of hexanes and EtOAc (6/4) yielded the keto acid 8.
White solid; Rf ) 0.10 (hexanes/EtOAc, 6/4); IR (film) 3447
broad (OH, acid), 1738 (CdO, ketone and acid); 1H NMR
(CDCl3) δ 0.79 (s, CH3-19′), 0.84 (s, CH3-18′), 2.41 (dd, J1 )
19.0 Hz and J2 ) 8.8 Hz, CH-16′â), 2.61 (t, J ) 6.2 Hz, CH2-
2), 3.58 (m, CH-3′â), 3.65 (t, J ) 6.5 Hz, CH2-1); 13C NMR
(CDCl3) δ 11.39, 13.79, 20.01, 21.73, 25.55, 28.20, 30.74, 31.52,
32.57, 32.86, 35.00, 35.06, 35.84, 36.00, 39.51, 47.81, 51.45,
54.26, 62.90, 74.51, 175.41, 221.51. Anal. (C22H34O4) C, H.
1
0.26 (hexanes/EtOAc, 9/1); IR (film) 1741 (CdO, ketone); H
NMR (CDCl3) δ 0.80 (s, CH3-19), 0.85 (s, CH3-18), 1.19 (t, J )
7.2 Hz, CH3-2′), 2.43 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-
16â), 3.43 (q, J ) 6.6 Hz, CH2O), 3.53 (tapp, J ) 2.4 Hz, CH-
3â); 13C NMR (CDCl3) δ 11.43, 13.83, 15.73, 20.05, 21.76, 25.62,
28.31, 30.78, 31.59, 32.65, 33.33, 35.05, 35.86, 36.07, 39.52,
47.83, 51.53, 54.33, 62.92, 73.29, 221.51. Anal. (C21H34O2) C,
H.
3R-Propanoxy-5R-androstan-17-one (3). White solid; Rf
) 0.39 (hexanes/EtOAc, 9/1); IR (film) 1741 (CdO, ketone);
1H NMR (CDCl3) δ 0.80 (s, CH3-19), 0.85 (s, CH3-18), 0.92 (t,
J ) 7.4 Hz, CH3-3′), 2.42 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz,
CH-16â), 3.32 (t, J ) 6.6 Hz, CH2O), 3.51 (tapp, J ) 2.6 Hz,
CH-3â); 13C NMR (CDCl3) δ 10.75, 11.44, 13.83, 20.05, 21.76,
23.35, 25.62, 28.33, 30.82, 31.59, 32.68, 33.30, 35.07, 35.86,
36.05, 39.55, 47.83, 51.53, 54.37, 69.48, 73.39, 221.52. Anal.
(C22H36O2) C, H.
3R-Hexanoxy-5R-androstan-17-one (4). White foam; Rf
) 0.35 (hexanes/EtOAc, 9/1); IR (film) 1742 (CdO, ketone);
1H NMR (CDCl3) δ 0.80 (s, CH3-19), 0.85 (s, CH3-18), 0.88 (t,
J ) 7.0 Hz, CH3-6′), 2.43 (dd, J1 ) 19.0 Hz and J2 ) 8.8 Hz,
CH-16â), 3.35 (t, J ) 6.7 Hz, CH2O), 3.50 (tapp, J ) 2.5 Hz,
CH-3â); 13C NMR (CDCl3) δ 11.44, 13.83, 14.06, 20.05, 21.76,
22.66, 25.68, 25.93, 28.32, 30.13, 30.82, 31.59, 31.71, 32.70,
33.27, 35.07, 35.86, 36.05, 39.55, 47.83, 51.53, 54.39, 67.86,
73.40, 221.50. Anal. (C25H42O2) C, H.
3R-(Prop-2′-enoxy)-5R-androstan-17-one (5). White foam;
Rf ) 0.34 (hexanes/EtOAc, 9/1); IR (film) 1741 (CdO, ketone),
1651 (CdC, alkene); 1H NMR (CDCl3) δ 0.80 (s, CH3-19), 0.84
(s, CH3-18), 2.41 (dd, J1 ) 19.0 Hz and J2 ) 8.8 Hz, CH-16â),
3.57 (tapp, J ) 2.5 Hz, CH-3â), 3.93 (m, CH2-1′), 5.13 (d, J )
10.3 Hz, 1H of CH2-3′), 5.26 (d, J ) 17.2 Hz, 1H of CH2-3′),
5.92 (m, CH-2′); 13C NMR (CDCl3) δ 11.37, 13.80, 20.00, 21.71,
25.51, 28.26, 30.75, 31.54, 32.61, 33.18, 35.01, 35.82, 36.02,
39.49, 47.79, 51.48, 54.29, 68.80, 73.11, 116.09, 135.74, 221.44.
Anal. (C22H34O2) C, H.
Synthesis of ADT 3R-Ether Derivatives 6-9 (Scheme
2). To a stirred solution of 49 (0.796 g, 2.13 mmol) in dry THF
(80 mL) at 0 °C was added dropwise 16.7 mL (6.9 equiv) of a
1 M borane solution in THF. The mixture was allowed to react
under an argon atmosphere for 3 h, then 3.5 mL of a 3 N
NaOH solution and 1.5 mL of H2O2 (30% w/v) were added. The
resulting mixture was stirred at room temperature for 1 h
before addition of water and extraction with EtOAc. The
organic phase was washed with water and brine and dried over
MgSO4. After evaporation under reduced pressure, the crude
product was purified by flash chromatography using a mixture
of hexanes and EtOAc (8/2) containing 1% of triethylamine.
The two alcohols 50 and 51 were obtained, in a ratio of 1:3,
with a 76% global yield. The chemical data of compounds 50
and 51 are reported in Supporting Information. The keto
alcohols 6 and 7 were quantitatively obtained after hydrolysis
of 50 and 51 with a 5% H2SO4 solution in 1,4-dioxane according
to the procedure described above.
3R-(2′-Hydroxypropanoxy)-5R-androstan-17-one (6).
White solid; Rf ) 0.19 (hexanes/EtOAc, 7/3); IR (film) 3458
(OH, alcohol), 1740 (CdO, ketone); 1H NMR (CDCl3) δ 0.80 (s,
CH3-19), 0.85 (s, CH3-18), 1.14 (d, J ) 6.3 Hz, CH3-3′), 2.42
(dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â), 3.12 and 3.38
(2m, CH2-1′), 3.55 (m, CH-3â), 3.92 (m, CH-2′); 13C NMR
(CDCl3) δ 11.38, 13.80, 18.52, 20.00, 21.71, 25.54 (25.69), 28.22,
30.77, 31.50, 32.55 (32.64), 32.97 (33.06), 34.98, 35.84, 36.03,
39.53 (39.59), 47.80, 51.44, 54.32, 66.55 (66.61), 73.31 (73.40),
74.16 (74.30), 221.50. Anal. (C22H36O3) C, H.
3R-(3′-Bromopropanoxy)-5R-androstan-17-one (9). Al-
cohol 51 (0.142 g, 0.36 mmol), PPh3 (0.19 g, 2 equiv), and CBr4
(0.24 g, 2 equiv) in dry CH2Cl2 (50 mL) was stirred at 0 °C
under an argon atmosphere. The reaction was completed after
2 h. The crude mixture was then adsorbed on silica gel and
flash chromatography performed using a mixture of hexanes
and EtOAc (9/1) as eluent to afford the bromide 9. White solid
(88% yield); Rf ) 0.3 (hexanes/EtOAc, 9/1); IR (film) 1740 (Cd
1
O, ketone); H NMR (CDCl3) δ 0.80 (s, CH3-19), 0.85 (s, CH3-
18), 2.43 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â), 3.47-
3.56 (m, CH-3â, CH2-3′ and CH2-1′); 13C NMR (CDCl3) δ 11.41,
13.81, 20.03, 21.74, 25.73, 28.27, 30.82, 31.28, 31.54, 32.70,
32.97, 33.13, 35.02, 35.86, 36.03, 39.57, 47.83, 51.46, 54.37,
64.79, 73.77, 221.59. Anal. (C22H35O2Br) C, H.
Synthesis of epi-ADT and ADT Derivatives Substi-
tuted at Positions 3R and 3â (Compounds 10-31, Scheme
3). 17â-[(tert-Butyldimethylsilyl)oxy]-5R-androstan-3-one
(52). To a solution of dihydrotestosterone (10.00 g, 34.48 mmol)
in dry DMF (500 mL) were added 11.74 g (5 equiv) of imidazole
(11.74 g, 5 equiv) and tert-butyldimethylsilyl chloride (TBDMS-
Cl) (15.61 g, 3 equiv). The reaction mixture was stirred at room
temperature overnight. The mixture was then poured onto ice
and filtered. The resulting precipitate was washed with water
and dried over phosphorus pentoxide under reduced pressure
for 48 h. 17â-TBDMS-dihydrotestosterone (52) was obtained
as a white solid (91% yield). Rf ) 0.80 (hexanes/EtOAc, 8/2);
IR (KBr) 1720 (CdO, ketone); 1H NMR (CDCl3) δ -0.001 and
0.005 (2s, Si(CH3)2), 0.71 (s, CH3-18), 0.87 (s, SiC(CH3)3), 1.01
(s, CH3-19), 3.54 (t, J ) 8.2 Hz, CH-17R); 13C NMR (CDCl3) δ
-4.81, -4.48, 11.40, 11.51, 18.10, 21.13, 23.55, 25.86 (3×),
28.88, 30.94, 31.35, 35.53, 35.77, 37.12, 38.20, 38.64, 43.35,
44.73, 46.83, 50.54, 54.14, 81.78, 212.02.
General Procedure for Alkylation of C3-Carbonyl. To
a stirred solution of 17â-TBDMS-DHT (52) (0.500 g, 1.24
mmol) in dry THF (100 mL) at 0 °C were added dropwise 3
equiv of commercially available Grignard reagent in THF or
diethyl ether. The mixture was allowed to stir at 0 °C for 3 h
and left overnight at room temperature. A saturated solution
of NH4Cl was added, and the crude product was extracted with
EtOAc. The organic phase was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The two
stereoisomers C (53-69) and D (70-86) were easily separated
by flash chromatography using a mixture of hexanes and
EtOAc as eluent. Ratios, global yields, and some characteristic
data are given in Table 1. When the Grignard reagent was
generated in situ (as for 63 and 80 or 68 and 85), an amount
of 5 equiv was prepared using a well-known procedure
described by Smith,28 and the alkylation was done in dry
diethyl ether. Ketone 52 was then dissolved in dry diethyl
ether and added dropwise to the solution of Grignard reagent
generated in situ.
3R-(3′-Hydroxypropanoxy)-5R-androstan-17-one (7).
White solid; Rf ) 0.29 (hexanes/EtOAc, 7/3); IR (film) 3447
(OH, alcohol), 1739 (CdO, ketone); 1H NMR (CDCl3) δ 0.79 (s,
CH3-19), 0.83 (s, CH3-18), 2.41 (dd, J1 ) 19.1 Hz and J2 ) 8.7
Hz, CH-16â), 3.53 (tapp, J ) 2.2 Hz, CH-3â), 3.59 (m, CH2-1′),
3.78 (t, J ) 5.4 Hz, CH2-3′); 13C NMR (CDCl3) δ 11.37, 13.77,
19.99, 21.70, 25.42, 28.23, 30.69, 31.44, 31.95, 32.61, 32.91,
34.97, 35.84, 35.99, 39.67, 47.79, 51.35, 54.18, 63.04, 68.07,
74.45, 221.55. Anal. (C22H36O3) C, H.
In some cases, the Grignard reagent was replaced by the
corresponding lithium reagent (as for 58 and 75 or 59 and 76).
The commercially available lithium reagent (3 equiv) was

5264 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Ngatcha et al.
added to the ketone 52, exactly as in the case of commercially
available Grignard reagent. When the lithium reagent was
generated in situ (as for 66 and 83 or 67 and 84), an amount
of 8 equiv was prepared in a mixture of n-pentane and diethyl
ether (3/2, v/v) at -78 °C, using a well-known procedure
described by Bailey and Punzalan.29 Ketone 52 was then
dissolved in diethyl ether and added dropwise at 0 °C to the
freshly prepared lithium reagent (generated in situ).
(OH, alcohol), 1736 (CdO, ketone), 1601 and 1494 (CdC,
aromatic ring); 1H NMR (CDCl3) δ 0.57 (m, 1H), 0.83 (s, CH3-
18), 0.94 (s, CH3-19), 2.37 (m, 2H), 7.28 (t, J ) 6.9 Hz, CH-4′),
7.36 (t, J ) 7.5 Hz, CH-3′ and -5′), 7.53 (d, J ) 7.3 Hz, CH-2′
and -6′); 13C NMR (CDCl3) δ 12.39, 13.74, 20.38, 21.69, 28.19,
30.61, 31.43, 33.92, 34.91, 35.74, 35.99, 36.68, 41.03, 43.55,
47.72, 51.30, 54.28, 73.73, 126.18 (2×), 127.41, 128.48 (2×),
144.68, 221.22. Anal. (C25H34O2) C, H.
3â-Hydroxy-3R-phenylmethyl-5R-androstan-17-one (14).
White solid; 93% yield; Rf ) 0.38 (hexanes/EtOAc, 7/3); IR
(film) 3461 (OH, alcohol), 1736 (CdO, ketone), 1602 and 1495
(CdC, aromatic ring); 1H NMR (CDCl3) δ 0.86 (2s, CH3-18 and
CH3-19), 2.29 (m, 1H), 2.43 (dd, J1 ) 19.0 Hz and J2 ) 8.8 Hz,
CH-16â), 2.84 (s, CH2-Ph), 7.24 (m, 5H of Ph); 13C NMR
(CDCl3) δ 12.20, 13.82, 20.50, 21.78, 28.20, 29.68, 30.99, 31.58,
33.60, 35.11, 35.83, 36.15, 40.52, 43.36, 43.83, 47.82, 51.51,
54.72, 72.32, 126.51, 128.31 (2×), 130.53 (2×), 137.30, 221.23.
Anal. (C26H36O2) C, H.
3R-Hydroxy-3â-methyl-5R-androstan-17-one (15). White
solid; 91% yield; Rf ) 0.22 (hexanes/EtOAc, 7/3); IR (film) 3448
(OH, alcohol), 1739 (CdO, ketone); 1H NMR (CDCl3) δ 0.75 (s,
CH3-19), 0.83 (s, CH3-18), 1.17 (s, CH3-3â), 2.40 (dd, J1 ) 19.0
Hz and J2 ) 8.6 Hz, CH-16â); 13C NMR (CDCl3) δ 11.15, 13.76,
20.20, 21.70, 28.11, 30.80, 31.55 (2×), 33.93, 34.84, 35.05,
35.66, 35.77, 41.01, 41.70, 47.73, 51.45, 54.29, 69.59, 221.26.
Anal. (C20H32O2) C, H.
3R-Hydroxy-3â-vinyl-5R-androstan-17-one (16). White
solid; 91% yield; Rf ) 0.30 (hexanes/EtOAc, 7/3); IR (film) 3452
(OH, alcohol), 1738 (CdO, ketone), 1664 (CdC, alkene); 1H
NMR (CDCl3) δ 0.80 (s, CH3-19), 0.86 (s, CH3-18), 2.44 (dd, J1
) 19.0 Hz and J2 ) 8.7 Hz, CH-16â), 5.00 (d, J ) 10.5 Hz,
CH-2′), 5.22 (d, J ) 17.0 Hz, CH-2′), 5.92 (dd, J1 ) 17.3 Hz
and J2 ) 10.6 Hz, CH-1′); 13C NMR (CDCl3) δ 11.24, 13.84,
20.24, 21.78, 28.12, 30.85, 31.58, 33.22, 33.58, 35.12, 35.75,
35.86, 39.95, 40.65, 47.81, 51.50, 54.29, 72.02, 110.96, 146.74,
221.35. Anal. (C21H32O2) C, H.
3R-Hydroxy-3â-propyl-5R-androstan-17-one (17). White
solid; 87% yield; Rf ) 0.17 (hexanes/EtOAc, 8/2); IR (film) 3460
(OH, alcohol), 1737 (CdO, ketone); 1H NMR (CDCl3) δ 0.72 (s,
CH3-19), 0.81 (s, CH3-18), 0.87 (t, J ) 6.3 Hz, CH3-3′), 2.39
(dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â); 13C NMR (CDCl3)
δ 11.09, 13.73, 14.65, 16.24, 20.14, 21.66, 28.17, 30.77, 31.49,
33.00, 33.71, 34.99, 35.74, 35.92, 39.72, 40.71, 46.86, 47.70,
51.40, 54.25, 71.36, 221.26. Anal. (C22H36O2) C, H.
3R-Hydroxy-3â-(prop-2′-enyl)-5R-androstan-17-one (18).
White solid; 90% yield; Rf ) 0.39 (hexanes/EtOAc, 7/3); IR
(film) 3462 (OH, alcohol), 1739 (CdO, ketone), 1638 (CdC,
alkene); 1H NMR (CDCl3) δ 0.75 (s, CH3-19), 0.84 (s, CH3-18),
5.09 (d, J ) 15.7 Hz, 1H of CH2-3′), 5.13 (d, J ) 8.1 Hz, 1H of
CH2-3′), 5.86 (m, CH-2′); 13C NMR (CDCl3) δ 11.16, 13.78,
20.21, 21.73, 28.18, 30.81, 31.54, 33.05, 33.72, 35.06, 35.79,
39.83, 40.73, 44.53, 46.57, 48.69, 51.45, 54.25, 70.89, 118.72,
133.60, 221.28; MS calcd for C22H34O2 330.3, found 313.1 [MH
- H2O]+, 295.3 [MH - 2H2O]+ m/z.
3â-n-Butyl-3R-hydroxy-5R-androstan-17-one (19). White
solid; 89% yield; Rf ) 0.60 (hexanes/EtOAc, 8/2); IR (film) 3458
(OH, alcohol), 1734 (CdO, ketone); 1H NMR (CDCl3) δ 0.75 (s,
CH3-19), 0.84 (s, CH3-18), 0.89 (t, J ) 6.4 Hz, CH3-4′), 2.41
(dd, J1 ) 19.0 Hz and J2 ) 8.6 Hz, CH-16â); 13C NMR (CDCl3)
δ 11.15, 13.77, 14.08, 20.20, 21.72, 23.28, 25.25, 28.23, 30.81,
31.54, 33.06, 33.77, 35.04, 35.79, 35.97, 39.77, 40.80, 44.22,
47.76, 51.45, 54.29, 71.42, 221.33. Anal. (C23H38O2) C, H.
3â-s-Butyl-3R-hydroxy-5R-androstan-17-one (20). White
The chemical data of compounds 53-86 are reported in
Supporting Information.
General Procedure for Hydrolysis and Oxidation at
Position 17. The silylated ethers C and D of Scheme 3 were
dissolved in a methanolic solution of HCl (2%, v/v), and the
resulting mixture was stirred at room temperature for 3 h.
Water was added, MeOH was evaporated under reduced
pressure, and the residue was extracted with EtOAc. The
organic phase was washed with brine and dried over MgSO4.
The white concentrate obtained after evaporation under
reduced pressure was directly oxidized with Jones’ reagent
according to the procedure described above for the preparation
of compound 8. Purification of the final products was per-
formed by flash chromatography using a mixture of hexanes
and EtOAc as eluent.
For 13 (3R-phenyl), 16 (3â-vinyl), and 24 (3â-phenyl),
instead of the methanolic solution a TBAF solution was used
for hydrolysis of the silylated ether, and PCC instead of Jones’
reagent was used for the oxidation. Thus, to a solution of the
silylated ether in dry THF was added 1.5 equiv of a 1 M TBAF
solution, and the mixture was stirred at refluxing temperature
for 6 h. The reaction mixture was then cooled to room
temperature. A saturated NaHCO3 solution was added, and
the extraction was done with EtOAc. The combined organic
phase was washed with brine, dried over MgSO4, and evapo-
rated to dryness under reduced pressure. The crude residue
was dissolved in CH2Cl2 and added dropwise to a suspension
of PCC (1.5 equiv), NaOAc (3 equiv), and 4 Å molecular sieves
in CH2Cl2. The reaction mixture was stirred at room temper-
ature under argon for 3 h. Filtration was performed on a silica
gel column, using CH2Cl2 as eluent, and purification of the
final product was done by flash chromatography using a
mixture of hexanes and EtOAc as eluent.
3â-Hydroxy-3R-methyl-5R-androstan-17-one (10). White
solid; 90% yield; Rf ) 0.21 (hexanes/EtOAc, 7/3); IR (film) 3436
(OH, alcohol), 1738 (CdO, ketone); 1H NMR (CDCl3) δ 0.82 (s,
CH3-19), 0.84 (s, CH3-18), 1.24 (s, CH3-1′), 2.42 (dd, J1 ) 19.0
Hz and J2 ) 8.7 Hz, CH-16â); 13C NMR (CDCl3) δ 11.84, 13.79,
20.46, 21.74, 26.60, 28.34, 30.85, 31.55, 35.07, 35.79, 36.18,
36.33, 36.51, 43.19, 44.24, 47.78, 51.46, 54.57, 71.29, 221.21;
MS calcd for C20H32O2 304.2, found 305.1 [MH]+, 287.1 [MH
- H2O]+, 269.2 [MH - 2H2O]+ m/z; HPLC purity 97.7% (tR
)
12.3 min, YMC-Pak C4, 4.6 mm × 250 mm, CH3CN/H2O/
MeOH (30:40:30) at 1 mL/min flow rate).
3â-Hydroxy-3R-propyl-5R-androstan-17-one (11). White
solid; 92% yield; Rf ) 0.24 (hexanes/EtOAc, 8/2); IR (KBr) 3593
and 3450 (OH, alcohol), 1737 (CdO, ketone); 1H NMR (CDCl3)
δ 0.83 (s, CH3-18 and CH3-19), 0.91 (t, J ) 7.2 Hz, CH3-3′),
2.41 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â); 13C NMR
(CDCl3) δ 12.05, 13.75, 14.62, 16.00, 20.42, 21.71, 28.32, 30.83,
31.51, 34.30, 35.02, 35.77, 36.04, 36.10, 39.74, 40.92, 43.67,
47.76, 51.42, 54.55, 72.65, 221.24. Anal. (C22H36O2) C, H.
3â-Hydroxy-3R-(prop-2′-enyl)-5R-androstan-17-one (12).
White solid; 92% yield; Rf ) 0.41 (hexanes/EtOAc, 7/3); IR
(film) 3452 (OH, alcohol), 1738 (CdO, ketone), 1628 (CdC,
alkene); 1H NMR (CDCl3) δ 0.84 (s, CH3-19 and CH3-18), 2.32
(d, J ) 7.4 Hz, CH2-1′), 2.43 (dd, J1 ) 18.9 Hz and J2 ) 8.7
solid; 88% yield; Rf
) 0.14 (hexanes/EtOAc, 8/2); IR (film) 3468
(OH, alcohol), 1738 (CdO, ketone); 1
H NMR (CDCl3) δ 0.75 (s,
Hz, CH-16â), 5.11 (dapp, J ) 16.8 Hz, 1H of CH2-3′), 5.16 (dapp
,
CH3-19), 0.85 (s, CH3-18), 0.89 (d, J ) 6.6 Hz, CH3CH), 0.90
J ) 9.5 Hz, 1H of CH2-3′), 5.86 (m, CH-2′); 13C NMR (CDCl3)
δ 12.04, 13.76, 20.41, 21.71, 28.26, 30.83, 31.50, 33.87, 35.01,
35.77, 35.90, 36.02, 40.72, 41.81, 43.54, 47.75, 51.40, 54.56,
72.04, 118.82, 133.67, 221.22; MS calcd for C22H34O2 330.2,
found 331.1 [MH]+, 313.1 [MH - H2O]+, 296.3 [MH - 2H2O]+
m/z. Anal. (C22H34O2) C. H: calcd, 79.95; found, 77.86.
3â-Hydroxy-3R-phenyl-5R-androstan-17-one (13). White
solid; 88% yield; Rf ) 0.30 (hexanes/EtOAc, 7/3); IR (film) 3428
(t, J ) 7.0 Hz, CH3CH2), 2.42 (dd, J1 ) 19.0 Hz and J2 ) 8.7
Hz, CH-16â);
13C NMR (CDCl3) δ 11.15, 13.82, 20.23, 21.75,
23.31, 23.37, 28.38, 29.81, 30.21, 30.86, 31.57, 33.82, 35.09,
35.84, 36.53, 37.00, 40.79, 46.28, 47.80, 51.48, 54.29, 73.92,
221.42. Anal. (C23H38O2) C, H.
3â-tert-Butyl-3R-hydroxy-5R-androstan-17-one (21).
White solid; 92% yield; Rf ) 0.27 (hexanes/EtOAc, 8/2); IR
(film) 3545 (OH, alcohol), 1729 (CdO, ketone); 1H NMR

Inhibitors of 17â-Hydroxysteroid Dehydrogenase
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5265
(CDCl3) δ 0.74 (s, CH3-19), 0.85 (s, CH3-18), 0.92 (s, C(CH3)3),
2.42 (dd, J1 ) 19.0 Hz and J2 ) 8.8 Hz, CH-16â); 13C NMR
(CDCl3) δ 11.11, 13.82, 20.24, 21.75, 25.00 (3×), 26.99, 28.47,
30.88, 31.57, 33.91, 34.04, 35.09, 35.56, 35.84, 37.61, 40.96,
47.81, 51.46, 54.26, 75.37, 221.40. Anal. (C23H38O2) C, H.
3â-n-Hexyl-3R-hydroxy-5R-androstan-17-one (22). White
solid; 91% yield; Rf ) 0.19 (hexanes/EtOAc, 8/2); IR (film) 3507
(OH, alcohol), 1739 (CdO, ketone); 1H NMR (CDCl3) δ 0.76 (s,
CH3-19), 0.85 (s, CH3-18), 0.87 (t, J ) 8.0 Hz, CH3-6′), 2.42
(dd, J1 ) 19.0 Hz and J2 ) 8.6 Hz, CH-16â); 13C NMR (CDCl3)
δ 11.18, 13.80, 14.05, 20.24, 21.75, 22.60, 23.02, 28.26, 29.90,
30.85, 31.59, 31.84, 33.11, 33.82, 35.10, 35.82, 36.03, 39.83,
40.86, 44.56, 47.79, 51.49, 54.35, 71.49, 221.30. Anal. (C25H42O2)
C, H.
3â-Cyclohexyl-3R-hydroxy-5R-androstan-17-one (23).
White solid; 87% yield; Rf ) 0.15 (hexanes/EtOAc, 8/2); IR
(film) 3461 (OH, alcohol), 1736 (CdO, ketone); 1H NMR
(CDCl3) δ 0.74 (s, CH3-19), 0.85 (s, CH3-18), 2.42 (dd, J1 ) 19.0
Hz and J2 ) 8.7 Hz, CH-16â); 13C NMR (CDCl3) δ 11.15, 13.82,
20.23, 21.75, 26.59 (2×), 26.79 (3×), 28.38, 30.31, 30.86, 31.57,
33.85, 35.08, 35.84, 35.97, 37.08, 40.78, 47.82, 49.34, 51.46,
54.29, 73.30, 221.45. Anal. (C25H40O2) C, H.
3R-Hydroxy-3â-phenyl-5R-androstan-17-one (24). White
solid; 86% yield; Rf ) 0.31 (hexanes/EtOAc, 7/3); IR (film) 3442
(OH, alcohol), 1736 (CdO, ketone), 1591 and 1492 (CdC,
aromatic ring); 1H NMR (CDCl3) δ 0.88 (s, CH3-19), 0.91 (s,
CH3-18), 2.44 (dd, J1 ) 19.0 Hz and J2 ) 8.5 Hz, CH-16â),
7.25 (m, CH-4′), 7.35 (tapp, J ) 7.5 Hz, CH-2′ and 6′), 7.50 (d,
J ) 7.6 Hz, CH-3′ and 5′); 13C NMR (CDCl3) δ 11.37, 13.85,
20.29, 21.76, 28.13, 30.84, 31.59, 34.14, 34.89, 35.13, 35.74,
35.85, 41.20, 41.89, 47.82, 51.50, 54.30, 73.49, 124.37 (2×),
126.74, 128.21 (2×), 149.38, 221.28. Anal. (C25H34O2) C, H.
3â-Cyclohexylmethyl-3R-hydroxy-5R-androstan-17-
one (25). White solid; 92% yield; Rf ) 0.15 (hexanes/EtOAc,
8/2); IR (film) 3491 (OH, alcohol), 1726 (CdO, ketone); 1H NMR
(CDCl3) δ 0.76 (s, CH3-19), 0.85 (s, CH3-18), 2.43 (dd, J1 ) 19.0
Hz and J2 ) 8.6 Hz, CH-16â); 13C NMR (CDCl3) δ 11.23, 13.81,
20.22, 21.75, 26.25, 26.47 (2×), 28.27, 30.86, 31.55, 32.97, 33.79
(2×), 35.07, 35.63 (2×), 35.84, 35.93, 40.35, 40.81, 47.79, 51.46,
52.11, 54.32, 72.19, 221.38. Anal. (C26H42O2) C, H.
3R-Hydroxy-3â-phenylmethyl-5R-androstan-17-one (26).
White solid; 92% yield; Rf ) 0.31 (hexanes/EtOAc, 7/3); IR
(KBr) 3408 (OH, alcohol), 1732 (CdO, ketone), 1604 and 1500
(CdC, aromatic ring); 1H NMR (CDCl3) δ 0.75 (s, CH3-19), 0.84
(s, CH3-18), 2.41 (dd, J1 ) 18.9 Hz and J2 ) 8.8 Hz, CH-16â),
2.70 (s, CH2-Ph), 7.25 (m, 5H of Ph); 13C NMR (CDCl3) δ 11.18,
13.78, 20.20, 21.71, 28.16, 30.79, 31.52, 33.18, 33.70, 35.04,
35.79, 35.89, 39.94, 40.69, 47.75, 50.38, 51.41, 54.22, 71.12,
126.40, 128.09 (2×), 130.52 (2×), 136.92, 221.27. Anal.
(C26H36O2) C, H.
11.22, 13.82, 20.26, 21.76, 28.26, 29.55, 30.87, 31.59, 33.27,
33.80, 35.10, 35.84, 36.07, 39.89, 40.89, 46.43, 47.80, 51.49,
54.35, 71.42, 125.69, 128.31 (2×), 128.39 (2×), 142.70, 221.31.
Anal. (C27H38O2) C, H.
3R-Hydroxy-3â-phenylpropyl-5R-androstan-17-one (30).
White solid; 87% yield; Rf ) 0.44 (hexanes/EtOAc, 8/2); IR
(film) 3458 (OH, alcohol), 1736 (CdO, ketone), 1602 and 1496
(CdC, aromatic ring); 1H NMR (CDCl3) δ 0.75 (s, CH3-19), 0.85
(s, CH3-18), 2.43 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â),
2.61 (t, J ) 7.6 Hz, CH2-Ph), 7.24 (m, 5H of Ph); 13C NMR
(CDCl3) δ 11.19, 13.82, 20.23, 21.75, 25.05, 28.23, 30.83, 31.55,
33.11, 33.77, 35.07, 35.84, 36.01, 36.40, 39.78, 40.85, 44.09,
47.79, 51.46, 54.32, 71.43, 125.71, 128.28, 128.38 (2×), 142.44
(2×), 221.39. Anal. (C28H40O2) C, H.
3â-Dodecyl-3R-hydroxy-5R-androstan-17-one (31). White
solid; 89% yield; Rf ) 0.47 (hexanes/EtOAc, 7/3); IR (film) 3545
and 3462 (OH, alcohol), 1735 (CdO, ketone); 1H NMR (CDCl3)
δ 0.75 (s, CH3-19), 0.84 (s, CH3-18), 0.87 (t, J ) 6.4 Hz, CH3-
12′), 2.42 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â); 13C NMR
(CDCl3) δ 11.18, 13.80, 14.08, 20.23, 21.75, 22.66, 23.06, 28.26,
29.32, 29.63 (5×), 30.25, 30.85, 31.58, 31.90, 33.11, 33.82,
35.10, 35.82, 36.03, 39.83, 40.85, 44.56, 47.79, 51.49, 54.35,
71.47, 221.29. Anal. (C31H54O2) C, H.
Synthesis of Other epi-ADT and ADT Derivatives
Substituted at Positions 3R and 3â (Compounds 32-37,
Scheme 4). Formation of Ketals 87 and 88. The C17-
carbonyl of compounds 12 and 18 were respectively protected
as ketals 87 and 88, using p-toluenesulfonic acid and ethylene
glycol in CH2Cl2, according to the procedure described above.
17,17-Ethylenedioxy-3â-hydroxy-3R-(prop-2′-enyl)-5R-
androstane (87). White solid; 62% yield; Rf ) 0.54 (hexanes/
EtOAc, 7/3); IR (film) 3423 (OH, alcohol), 1638 (CdC, alkene);
1H NMR (CDCl3) δ 0.81 (s, CH3-18 and CH3-19), 2.30 (d, J )
7.4 Hz, CH2-1′), 3.86 (m, OCH2CH2O), 5.10 (d, J ) 16.9 Hz,
1H of CH2-3′), 5.14 (d, J ) 10.0 Hz, 1H of CH2-3′), 5.85 (m,
CH-2′); 13C NMR (CDCl3) δ 12.06, 14.38, 20.59, 22.58, 28.46,
30.64, 31.31, 33.95, 34.11, 35.72, 35.93, 35.99, 40.86, 41.86,
43.57, 45.93, 50.28, 54.29, 64.47, 65.11, 72.12, 118.72, 119.41,
133.79.
17,17-Ethylenedioxy-3R-hydroxy-3â-(prop-2′-enyl)-5R-
androstane (88). White solid; 75% yield; Rf ) 0.55 (hexanes/
EtOAc, 7/3); IR (film) 3494 (OH, alcohol), 1662 (CdC, alkene);
1H NMR (CDCl3) δ 0.73 (s, CH3-18), 0.82 (s, CH3-19), 2.16 (d,
J ) 7.5 Hz, CH2-1′), 3.83 (m, OCH2CH2O), 5.06 (d, J ) 19.1
Hz, 1H of CH2-3′), 5.13 (d, J ) 8.0 Hz, 1H of CH2-3′), 5.87 (m,
CH-2′); 13C NMR (CDCl3) δ 11.17, 14.40, 20.38, 22.62, 28.38,
29.68, 30.71, 31.24, 33.08, 33.82, 34.16, 35.78, 39.95, 40.76,
45.95, 48.72, 50.30, 53.92, 64.52, 65.14, 70.98, 118.62, 119.46,
133.73.
Oxidative Hydroboration of 87 and 88. Primary alcohols
89 and 90 were respectively obtained from alkenes 87 and 88
by an oxidative hydroboration with a 1 M borane solution, a 3
N NaOH solution, and H2O2 according to the procedure
described above.
3R-Hydroxy-3â-octyl-5R-androstan-17-one (27). White
solid; 89% yield; Rf ) 0.22 (hexanes/EtOAc, 8/2); IR (film) 3460
(OH, alcohol), 1739 (CdO, ketone); 1H NMR (CDCl3) δ 0.74 (s,
CH3-19), 0.83 (s, CH3-18), 0.85 (t, J ) 6.4 Hz, CH3-8′), 2.40
(dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â); 13C NMR (CDCl3)
δ 11.15, 13.76, 14.05, 20.20, 21.71, 22.60, 23.03, 28.22, 29.24,
29.58, 30.22, 30.81, 31.53, 31.83, 33.07, 33.77, 35.04, 35.78,
35.97, 39.77, 40.79, 44.53, 47.75, 51.44, 54.29, 71.42, 221.30.
Anal. (C27H46O2) C, H.
3â-Cyclohexylethyl-3R-hydroxy-5R-androstan-17-one
(28). White solid; 88% yield; Rf ) 0.35 (hexanes/EtOAc, 7/3);
IR (film) 3462 (OH, alcohol), 1740 (CdO, ketone); 1H NMR
(CDCl3) δ 0.76 (s, CH3-19), 0.86 (s, CH3-18), 2.43 (dd, J1 ) 19.0
Hz and J2 ) 8.8 Hz, CH-16â); 13C NMR (CDCl3) δ 11.22, 13.83,
20.25, 21.77, 26.40 (2×), 26.70, 28.27, 30.59, 30.87, 31.59,
33.15, 33.46 (2×), 33.83, 35.11, 35.86, 36.04, 38.22, 39.80,
40.88, 41.76, 47.83, 51.50, 54.33, 71.53, 221.43. Anal. (C27H44O2)
C, H.
17,17-Ethylenedioxy-3â-hydroxy-3R-(3′-hydroxypropyl)-
5R-androstane (89). White solid; 62% yield; Rf ) 0.13
1
(hexanes/EtOAc, 4/6); IR (film) 3348 (OH, alcohol); H NMR
(CDCl3) δ 0.82 (s, CH3-18 and CH3-19), 3.65 (t, J ) 4.6 Hz,
CH2-3′), 3.86 (m, OCH2CH2O); 13C NMR (CDCl3) δ 12.10, 14.38,
20.61, 22.61, 26.27, 28.51, 30.66, 31.30, 34.06, 34.14, 34.56,
35.74, 35.98, 36.24, 41.09, 43.76, 45.98, 50.29, 54.29, 63.29,
64.49, 65.13, 72.50, 119.43.
17,17-Ethylenedioxy-3R-hydroxy-3â-(3′-hydroxypropyl)-
5R-androstane (90). White solid; 72% yield; Rf ) 0.11
1
(hexanes/EtOAc, 4/6); IR (film) 3356 (OH, alcohol); H NMR
(CDCl3) δ 0.74 (s, CH3-19), 0.83 (s, CH3-18), 3.65 (t, J ) 6.0
Hz, CH2-3′), 3.86 (m, OCH2CH2O); 13C NMR (CDCl3) δ 11.19,
14.40, 20.39, 22.64, 26.37, 28.42, 30.72, 31.27, 33.24, 33.87,
34.19, 35.79, 35.93, 40.06, 40.94, 41.18, 45.97, 50.34, 54.03,
63.49, 64.53, 65.14, 71.16, 119.47.
3R-Hydroxy-3â-phenylethyl-5R-androstan-17-one (29).
White solid; 91% yield; Rf ) 0.14 (hexanes/EtOAc, 8/2); IR
(film) 3486 (OH, alcohol), 1737 (CdO, ketone), 1605 and 1495
(CdC, aromatic ring); 1H NMR (CDCl3) δ 0.79 (s, CH3-19), 0.86
(s, CH3-18), 2.43 (dd, J1 ) 18.9 Hz and J2 ) 8.6 Hz, CH-16â),
2.71 (m, CH2-Ph), 7.24 (m, 5H of Ph); 13C NMR (CDCl3) δ
Hydrolysis of Ketals 89 and 90. The deprotection of the
carbonyl groups of 89 and 90 was done with a 5% H2SO4
solution in 1,4-dioxane according to the procedure described
above, leading respectively to 32 and 33.

5266 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Ngatcha et al.
3â-Hydroxy-3R-(3′-hydroxypropyl)-5R-androstan-17-
one (32). White solid; 91% yield; Rf ) 0.23 (hexanes/EtOAc,
2/8); IR (film) 3359 (OH, alcohol), 1735 (CdO, ketone); 1H NMR
(CDCl3) δ 0.84 (s, CH3-18 and CH3-19), 2.43 (dd, J1 ) 19.1 Hz
and J2 ) 8.7 Hz, CH-16â), 3.66 (t, J ) 5.1 Hz, CH2-3′); 13C
NMR (CDCl3) δ 12.09, 13.80, 20.44, 21.74, 26.20, 28.32, 30.84,
31.53, 34.05, 34.47, 35.04, 35.80, 36.09, 36.14, 40.94, 43.73,
47.80, 51.45, 54.57, 63.26, 72.42, 221.35. Anal. (C22H36O3) C,
H.
45-49. The appropriate iodide was used in each case: methyl
iodide for 93, 97, and 98; ethyl iodide for 94; propyl iodide for
95; and n-hexyl iodide for 96. In all cases, 20-30% of the
starting material was recovered; the yields of compounds 93-
98 (80-88%) have been corrected accordingly. Chemical data
of these compounds are reported in Supporting Information.
Hydrolysis of TBDMS Group and Oxidation at Posi-
tion 17 (Synthesis of 38-43). A methanolic solution of HCl
(2%, v/v) was used for the hydrolysis of the silylated ether at
position 17 and the resulting alcohol was oxidized with Jones’
reagent, according to the procedure described above.
3R-Methoxy-3â-(phenylmethyl)-5R-androstan-17-one
(38). White solid; 92% yield; Rf ) 0.40 (hexanes/EtOAc, 8/2);
IR (film) 1739 (CdO, ketone), 1602 and 1496 (CdC, aromatic
ring); 1H NMR (CDCl3) δ 0.69 (s, CH3-19), 0.84 (s, CH3-18),
2.42 (dd, J1 ) 19.1 Hz and J2 ) 8.7 Hz, CH-16â), 2.63 and
2.77 (2d, J ) 13.7 Hz, AB system, CH2Ph), 3.29 (s, CH3O),
7.22 (m, 5H of Ph); 13C NMR (CDCl3) δ 11.52, 13.82, 20.23,
21.73, 28.13, 28.95, 30.85, 31.56, 33.71, 35.07, 35.54, 35.84,
36.69, 40.39, 43.16, 47.80, 48.48, 51.47, 54.35, 75.82, 126.02,
127.91 (2×), 130.26 (2×), 137.72, 221.39. Anal. (C27H38O2) C,
H.
3R-Ethoxy-3â-(phenylmethyl)-5R-androstan-17-one (39).
White solid; 88% yield; Rf ) 0.57 (hexanes/EtOAc, 8/2); IR
(film) 1739 (CdO, ketone), 1602 and 1496 (CdC, aromatic
ring); 1H NMR (CDCl3) δ 0.69 (s, CH3-19), 0.84 (s, CH3-18),
1.23 (t, J ) 7.0 Hz, CH3CH2O), 2.42 (dd, J1 ) 19.0 Hz and J2
) 8.7 Hz, CH-16â), 2.63 and 2.77 (2d, J ) 13.7 Hz, AB system,
CH2Ph), 3.48 (q, J ) 7.0 Hz, CH2O), 7.20 (m, 5H of Ph); 13C
NMR (CDCl3) δ 11.58, 13.79, 15.69, 20.20, 21.71, 28.04, 29.52,
30.82, 31.52, 33.80, 35.04, 35.50, 35.81, 37.03, 40.38, 43.95,
47.78, 51.43, 54.38, 55.45, 75.66, 125.93, 127.83 (2×), 130.28
(2×), 137.84, 221.40; MS calcd for C28H40O2 408.3, found 363.1
[MH - ethylOH]+, 345.1 [MH - ethylOH - H2O]+ m/z; HPLC
purity: 99.9% (tR ) 10.2 min, Nova-Pak C18, 3.9 mm × 150
mm, CH3CN/H2O/MeOH (30/15/55) at 1 mL/min flow rate).
Anal. (C28H40O2) C. H: calcd, 82.30; found, 81.31.
3R-Hydroxy-3â-(3′-hydroxypropyl)-5R-androstan-17-
one (33). White solid; 95% yield; Rf ) 0.14 (hexanes/EtOAc,
5/5); IR (film) 3378 (OH, alcohol), 1738 (CdO, ketone); 1H NMR
(CDCl3) δ 0.76 (s, CH3-19), 0.85 (s, CH3-18), 2.43 (dd, J1 ) 19.0
Hz and J2 ) 8.7 Hz, CH-16â), 3.65 (t, J ) 5.9 Hz, CH2-3′); 13
C
NMR (CDCl3) δ 11.19, 13.81, 20.24, 21.75, 26.31, 28.23, 30.84,
31.57, 33.24, 33.80, 35.08, 35.83, 36.03, 39.95, 40.89, 41.23,
47.79, 51.48, 54.35, 63.41, 71.05, 221.35. Anal. (C22H36O3) C,
H.
Bromination with Formation of Cycloethers 34 and
35. The bromination of 89 and 90 was performed, using PPh3
and CBr4 in CH2Cl2, according to the procedure described
above. Hydrolysis of the C17-ketal and cyclization at C3
occurred during this reaction, leading to a mixture of the two
C3 epimers. In both cases, the same result was observed on
TLC. Flash chromatography afforded a 50/50 epimeric mixture
of 34 and 35 in addition to a fraction of 35 alone. A 90% overall
yield was thus obtained.
3R/3â-(Spirotetrahydrofuran-2-yl)-5R-androstan-17-
one (34). White solid; IR (film) 1741 (CdO, ketone); 1H NMR
(CDCl3) δ 0.79, 0.84 and 0.85 (s, CH3-18 and CH3-19), 2.43 (2m,
CH-16â), 3.80 (2m, CH2-3′); 13C NMR (CDCl3) δ 11.35, (11.76),
13.80, 20.21, (20.45), 21.74, 25.33, (25.95), 28.32 (28.54), 30.73,
(30.90), 31.56, 32.43, (33.24), (34.68), 34.89, 35.03, 35.60, 35.84,
(35.96), (36.92), 38.30, 39.65, (40.31), 42.00, (44.80), 47.80,
51.45, 54.21 (54.57), 66.28 (66.64), 81.60 (83.38), 221.44
(221.58). Anal. (C22H34O2) C, H.
3R-O-(Spirotetrahydrofuran-2-yl)-5R-androstan-17-
one (35). White solid; Rf ) 0.45 (hexanes/EtOAc, 8/2); IR (film)
1741 (CdO, ketone); 1H NMR (CDCl3) δ 0.80 (s, CH3-19), 0.85
(s, CH3-18), 2.42 (dd, J1 ) 19.1 Hz and J2) 8.5 Hz, CH-16â),
3.80 (t, J ) 6.7 Hz, CH2-3′); 13C NMR (CDCl3) δ 11.37, 13.83,
20.24, 21.77, 25.36, 28.36, 30.75, 31.60, 32.46, 34.92, 35.09,
35.63, 35.87, 38.34, 39.68, 42.02, 47.83, 51.51, 54.26, 66.65,
81.61, 221.52; MS calcd for C22H34O2 330.3, found 331.1 [MH]+,
313.3 [MH - H2O]+ m/z.
Lactonization. Compounds 12 and 18 were respectively
submitted to oxidative hydroboration conditions as described
above for compound 49. The obtained triols 91 and 92 were
submitted to an excess of Jones’ reagent, leading to the
corresponding lactones 36 and 37.
3R,3â-O-(1′-Oxo-1′,3′-propanediyloxy)-5R-androstan-17-
one (36). White solid; 80% yield; Rf ) 0.47 (hexanes/EtOAc,
6/4); IR (film) 1787 (CdO, lactone), 1738 (CdO, ketone); 1H
NMR (CDCl3) δ 0.85 (s, CH3-19), 0.86 (s, CH3-18), 2.43 (dd, J1
) 19.0 Hz and J2 ) 8.7 Hz, CH-16â), 2.56 (t, J ) 8.2 Hz, CH2-
2′); 13C NMR (CDCl3) δ 11.71, 13.77, 20.44, 21.70, 28.18, 28.53,
30.72, 31.26, 31.47, 32.28, 34.94, 35.46, 35.66, 35.75, 39.26,
43.33, 47.72, 51.36, 54.34, 87.21, 176.45, 220.98. Anal. (C22H32O3)
C, H.
3â,3R-O-(1′-Oxo-1′,3′-propanediyloxy)-5R-androstan-17-
one (37). White solid; 76% yield; Rf ) 0.21 (hexanes/EtOAc,
6/4); IR (film) 1768 (CdO, lactone), 1736 (CdO, ketone); 1H
NMR (CDCl3) δ 0.82 (s, CH3-19), 0.85 (s, CH3-18), 2.42 (dd, J1
) 19.0 Hz and J2 ) 8.9 Hz, CH-16â), 2.57 (t, J ) 8.4 Hz, CH2-
2′); 13C NMR (CDCl3) δ 11.42, 13.82, 20.23, 21.73, 27.93, 28.59,
30.57, 31.50, 33.21, 34.28 (2×), 35.03, 35.54, 35.81, 39.82,
41.29, 47.73, 51.35, 53.96, 86.13, 176.68, 221.09; HPLC
purity: 99.8% (tR ) 10.0 min, Nova-Pak C18, 3.9 mm × 150
mm, CH3CN/H2O/MeOH (30/37/33) at 1 mL/min flow rate).
Anal. (C22H32O3) C. H: calcd, 76.70; found, 76.07.
3R-Propanoxy-3â-(phenylmethyl)-5R-androstan-17-
one (40). White solid; 79% yield; Rf ) 0.26 (hexanes/EtOAc,
9/1); IR (film) 1740 (CdO, ketone), 1601 and 1496 (CdC,
1
aromatic ring); H NMR (CDCl3) δ 0.67 (s, CH3-19), 0.84 (s,
CH3-18), 0.97 (t, J ) 7.4 Hz, CH3-3′), 2.42 (dd, J1 ) 19.0 Hz
and J2 ) 9.0 Hz, CH-16â), 2.65 and 2.77 (2d, J ) 13.8 Hz, AB
system, CH2Ph), 3.37 (t, J ) 7.0 Hz, CH2O), 7.22 (m, 5H of
Ph); 13C NMR (CDCl3) δ 11.03, 11.61, 13.82, 20.24, 21.74, 23.50,
28.07, 29.47, 30.90, 31.56, 33.79, 35.07, 35.53, 35.85, 36.94,
40.39, 44.00, 47.82, 51.46, 54.48, 61.86, 75.45, 125.93, 127.85
(2×), 130.34 (2×), 138.00, 221.47. Anal. (C29H42O2) C, H.
3R-Hexanoxy-3â-(phenylmethyl)-5R-androstan-17-
one (41). White solid; 81% yield; Rf ) 0.58 (hexanes/EtOAc,
8/2); IR (film) 1741 (CdO, ketone), 1605 and 1496 (CdC,
1
aromatic ring); H NMR (CDCl3) δ 0.67 (s, CH3-19), 0.84 (s,
CH3-18), 0.90 (t, J ) 6.7 Hz, CH3-6′), 2.42 (dd, J1 ) 19.1 Hz
and J2 ) 8.7 Hz, CH-16â), 2.65 and 2.77 (2d, J ) 13.7 Hz, AB
system, CH2Ph), 3.40 (t, J ) 7.1 Hz, CH2O), 7.21 (m, 5H of
Ph); 13C NMR (CDCl3) δ 11.61, 13.83, 14.08, 20.24, 21.75, 22.73,
26.14, 28.08, 29.50, 30.28, 30.91, 31.56, 31.57, 33.80, 35.08,
35.53, 35.85, 36.94, 40.39, 43.97, 47.82, 51.49, 54.52, 60.15,
75.48, 125.93, 127.85 (2×), 130.34 (2×), 138.00, 221.48; MS
calcd for C32H48O2 464.4, found 363.1 [MH - hexylOH]+, 345.1
[MH - hexylOH - H2O]+ m/z; HPLC purity: 97.2% (tR ) 16.3
min, Nova-Pak C18, 3.9 mm × 150 mm, CH3CN/H2O/MeOH
(35/10/55) at 1 mL/min flow rate). Anal. (C32H48O2) C. H: calcd,
82.70; found, 81.60.
3R-Methoxy-3â-(2′-phenylethyl)-5R-androstan-17-one
(42). White solid; 80% yield; Rf ) 0.40 (hexanes/EtOAc, 8/2);
IR (film) 1739 (CdO, ketone), 1605 and 1496 (CdC, aromatic
ring); 1H NMR (CDCl3) δ 0.80 (s, CH3-19), 0.86 (s, CH3-18),
2.44 (dd, J1 ) 19.0 Hz and J2 ) 8.7 Hz, CH-16â), 2.61 (t, J )
8.6 Hz, CH2Ph), 3.17 (s, CH3O), 7.23 (m, 5H of Ph); 13C NMR
(CDCl3) δ 11.59, 13.83, 20.26, 21.77, 28.23, 29.17, 30.87 (2×),
31.59, 33.68, 35.12, 35.86 (2×), 37.02, 39.61, 40.42, 47.83,
48.13, 51.50, 54.36, 74.92, 125.65, 128.24 (2×), 128.36 (2×),
143.01, 221.42. Anal. (C28H40O2) C, H.
Synthesis of ADT 3R-Ether 3â-Substituted Derivatives
38-43 (Scheme 5). Ether Formation. The 3R-ethers 38-
43 were obtained from the corresponding alcohols 81, 84, and
83 according to the procedure described above for compounds

Inhibitors of 17â-Hydroxysteroid Dehydrogenase
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5267
(2) Vihko, P.; Harkonen, P.; Oduwole, O.; Torn, S.; Kurkela, R.;
Porvari, K.; Pulkka, A.; Isomaa, V. 17â-Hydroxysteroid Dehy-
drogenases and Cancers. J. Steroid Biochem. Mol. Biol. 2003,
83, 119-122.
(3) Labrie, F.; Luu-The, V.; Lin, S. X.; Simard, J.; Labrie, C. Role of
17â-Hydroxysteroid Dehydrogenases in Sex Steroid Formation
in Peripheral Intracrine Tissues. Trends Endocrinol. Metab.
2000, 11, 421-427.
(4) Sasano, H.; Suzuki, T.; Takeyama, J.; Utsunomiya, H.; Ito, K.;
Ariga, N.; Moriya, T. 17-Beta-Hydroxysteroid Dehydrogenase in
Human Breast and Endometrial Carcinoma. Oncology 2000, 59
(Suppl. 1), 5-12.
(5) Moghrabi, N.; Andersson, S. 17â-Hydroxysteroid Dehydrogena-
ses: Physiological Roles in Health and Disease. Trends Endo-
crinol. Metab. 1998, 9, 265-270.
(6) Labrie, F.; Luu-The, V.; Lin, S.-X.; Labrie, C.; Simard, J.; Breton,
R. The Key Role of 17â-Hydroxysteroid Dehydrogenases in Sex
Steroid Biology. Steroids 1997, 62, 148-158.
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ysteroid Dehydrogenases. Mol. Cell. Endocrinol. 2004, 218,
7-20.
3â-(2′-Cyclohexylethyl)-3R-methoxy-5R-androstan-17-
one (43). White solid; 92% yield; Rf ) 0.62 (hexanes/EtOAc,
8/2); IR (film) 1741 (CdO, ketone); 1H NMR (CDCl3) δ 0.77 (s,
CH3-19), 0.85 (s, CH3-18), 2.42 (dd, J1 ) 19.0 Hz and J2 ) 8.6
Hz, CH-16â), 3.07 (s, CH3O); 13C NMR (CDCl3) δ 11.57, 13.82,
20.24, 21.76, 26.39 (2×), 26.70, 28.23, 29.10, 30.10, 30.87,
31.59, 33.47 (2×), 33.70, 34.64, 35.11, 35.85 (2×), 37.00, 38.21,
40.36, 47.83, 47.92, 51.50, 54.35, 75.01, 221.43. Anal. (C28H46O2)
C, H.
Inhibition of Type 3 17â-HSD. Preparation of the
Enzyme Source. The expression vectors encoding type 3 17â-
HSD were transfected into human embryonic kidney 293
(HEK-293) cells using a calcium phosphate procedure as
reported previously.31 Cells were then sonicated in 50 mM
sodium phosphate buffer (pH 7.4) containing 20% glycerol and
1 mM ethylenediaminetetraacetic acid (EDTA) and centrifuged
at 10000g for 1 h to remove the mitochondria, plasma
membranes, and cells fragments. The supernatant was further
centrifuged at 100000g to separate the microsomal fraction,
which was used as a source of type 3 17â-HSD for the
enzymatic assay.
(8) Luu-The, V. Analysis and Characteristics of Multiple Types of
Human 17â-Hydroxysteroid Dehydrogenase. J. Steroid Biochem.
Mol. Biol. 2001, 76, 143-151.
(9) Adamski, J.; Jakob, F. J.
A Guide to 17â-Hydroxysteroid
Enzymatic Assay. The inhibition test was carried out at
37 °C in 1 mL of 50 mM sodium phosphate buffer, pH 7.4,
containing 20% glycerol, 1 mM EDTA, and 2 mM of cofactor
(NADPH) in the presence of 0.1 µM [14C]-∆4-dione ([4-14C]-4-
androstene-3,17-dione (New England Nuclear, Boston, MA)
and the indicated concentration of compound to be tested. The
reaction was stopped after 1 h by adding 2 mL of diethyl ether
containing 10 µM of unlabeled ∆4-dione and T. The metabolites
were extracted twice with 2 mL of diethyl ether, evaporated,
and then dissolved in CH2Cl2 before being applied on silica
gel 60 TLC plates. TLC was developed in a mixture of toluene
and acetone (4/1). Substrate [14C]-∆4-dione and metabolite
[14C]-T were identified by comparison with reference steroids
and revealed by autoradiography, then quantified using the
PhosphoImager system (Molecular Dynamics, Sunnyvale, CA).
The percentage of transformation (% transf) and the percent-
age of inhibition were calculated from eqs 1 and 2, respectively:
Dehydrogenases. Mol. Cell. Endocrinol. 2001, 171, 1-4.
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ysteroid Dehydrogenase (HSD)/17-Ketosteroid Reductase (KSR)
Family; Nomenclature and Main Characteristics of the 17HSD/
KSR Enzymes. J. Mol. Endocrinol. 1999, 23, 1-11.
(11) Poirier, D. Inhibitors of 17â-Hydroxysteroid Dehydrogenases.
Curr. Med. Chem. 2003, 10, 453-477.
(12) Smith, H. J.; Nicholls, P. J.; Simons, C.; Le Lain, R. Inhibitors
of Steroidogenesis as Agents for the Treatment of Hormone-
Dependent Cancers. Expert Opin. Ther. Pat. 2001, 11, 789-824.
(13) Penning, T. M. 17â-Hydroxysteroid Dehydrogenase: Inhibitors
and Inhibitor Design. Endocr.-Relat. Cancer 1996, 3, 41-56.
(14) Geissler, W. M.; Davis, D. L.; Wu, L.; Bradshaw, K. D.; Patel,
S.; Mendonca, B. B.; Elliston, K. O.; Wilson, J. D.; Russell, D.
W. Andersson, S. Male Pseudohermaphroditism Caused by
Mutations of Testicular 17â-Hydroxysteroid Dehydrogenase 3.
Nat. Genet. 1994, 7, 34-39.
(15) Andersson, S.; Geissler, W. M.; Patel, S.; Wu, L. The Molecular
Biology of Androgenic 17â-Hydroxysteroid Dehydrogenases. J.
Steroid Biochem. Mol. Biol. 1995, 53, 37-39.
(16) Le Lain, R.; Barrell, K. J.; Saeed, G. S.; Nicholls, P. J.; Simons,
C.; Kirby, A.; Smith, H. J. Some Coumarins and Triphenylethene
Derivatives as Inhibitors of Human Testes Microsomal 17â-
Hydroxysteroid Dehydrogenase (17â-HSD Type 3): Further
Studies with Tamoxifen on the Rat Testes Microsomal Enzyme.
J. Enzyme Inhib. Med. Chem. 2002, 17, 93-100.
(17) Le Lain, R.; Nicholls, P. J.; Smith, H. J.; Maharlouie, F. H.
Inhibitors of Human and Rat Testes Microsomal 17â-Hydrox-
ysteroid Dehydrogenase (17â-HSD) as Potential Agents for
Prostatic Cancer. J. Enzyme Inhib. 2001, 16, 35-45.
(18) Dufort, I.; Rheault, P.; Huang, X. F., Soucy, P.; Luu-The, V.
Characteristics of a Highly Labile Human Type 5 17â-Hydrox-
ysteroid Dehydrogenase. Endocrinology 1999, 140, 568-574.
(19) Luu-The, V.; Dufort, I.; Pelletier, G.; Labrie, F. Type 5 17â-
Hydroxysteroid Dehydrogenase: Its Role in the Formation of
Androgens in Women. Mol. Cell. Endocrinol. 2001, 171, 77-82.
(20) Verhoeven, G. Androgens and the testis. Verh.sK. Acad. Ge-
neeskd. Belg. 1992, 54, 299-327.
[14C]-T
[14C]-T + [14C]-∆4-dione
% transf )
× 100
(1)
(% transf without inhibitor) -
(% transf with inhibitor)
% transf without inhibitor
% inhibition )
× 100 (2)
When several concentrations of an inhibitor were used in
the enzymatic assay, an inhibition curve was plotted using the
percentage of transformation versus the concentration of
inhibitor. From this inhibition curve, the IC50 value (the
concentration of inhibitor that provokes 50% of enzyme inhibi-
tion) was calculated by computer (DE50 program, CHUL
Research Center, Que´bec, Canada).
Acknowledgment. We thank the Canadian Insti-
tute of Health Research (CIHR) for an operating grant
and Le Fonds de La Recherche en Sante´ du Que´bec
(FRSQ) for a fellowship (to D.P.). We are grateful to Guy
Reimnitz and Mei Wang for performing the enzymatic
assays. Careful reading of the manuscript by Sylvie
Me´thot is also greatly appreciated.
(21) Pittaway, D. E. Inhibition of Testosterone Synthesis in the
Canine Testis in Vitro. Contraception 1983, 27, 431-436.
(22) Poirier, D.; Labrie, F.; Luu-The, V. Inhibition de la 17â-
Hydroxyste´ro¨ıde De´shydroge´nase de Type 3 par des De´rive´s
Ste´ro¨ıdiens: EÄ tude Exploratoire (Inhibition of Type 3 17â-
Hydroxysteroid Dehydrogenase by Steroid Derivatives: Explor-
atory Study). Me´decine-Sciences 1995, 11 (Suppl. 2), 24.
(23) Tche´dam Ngatcha, B.; Luu-The, V.; Poirier, D. Androsterone
Derivatives Substituted at Position 16: Chemical Synthesis,
Inhibition of Type 3 17â-Hydroxysteroid Dehydrogenase, Binding
Affinity for Steroid Receptors, and Proliferative/Antiproliferative
Activity on Shionogi (AR+) Cells. J. Enzyme Inhib. Med. Chem.
2002, 17, 155-165.
(24) Maltais, R.; Luu-The, V.; Poirier, D. Synthesis and Optimization
of a New Family of Type 3 17â-Hydroxysteroid Dehydrogenase
Inhibitors by Parallel Liquid-Phase Chemistry. J. Med. Chem.
2002, 45, 640-653.
(25) Maltais, R.; Luu-The, V.; Poirier, D. Parallel Solid-Phase
Synthesis of 3â-Peptido-3R-hydroxy-5R-androstane-17-one De-
rivatives for Inhibition of Type 3 17â-Hydroxysteroid Dehydro-
genase. Bioorg. Med. Chem. 2001, 9, 3101-3111.
Supporting Information Available: Rf, IR, 1H NMR, and
13C NMR data of intermediate compounds 45-51, 53-86, and
93-98, elemental analysis results for final compounds, and
Tables 1-8 listing crystallographic details for compound 14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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