Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs

Article abstract of DOI:10.1016/j.bmcl.2009.09.009

The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or imp

Full text of DOI:10.1016/j.bmcl.2009.09.009

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6459–6462
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs
Lita S. Suwandi , Gregory E. Agoston, Jamshed H. Shah, Arthur D. Hanson, Xiaoguo H. Zhan,
Theresa M. LaVallee, Anthony M. Treston *
EntreMed, Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The ana-
logs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead sub-
stituents were identified with similar or improved antitumor activities and reduced metabolic liability
compared to 2-methoxyestradiol.
Received 4 August 2009
Revised 2 September 2009
Accepted 4 September 2009
Available online 9 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Structure–activity relationships
2
-Methoxyestradiol analogs
2
-Methoxyestradiol (2ME2) is a naturally occurring metabolite
with potassium carbonate and methyl iodide in refluxing acetone
(90% yield). The 3-hydroxyl group of 2ME2 could also be selectively
converted to the triflic ester (2) using 4-nitrotrifluoromethane sul-
fonate and potassium carbonate (98%), which was used for syn-
thesis of compounds 3 to 8.
of estradiol which has been shown to have antitumor and antian-
giogenic activities in in vivo and in vitro models with little toxic-
1
7
ity. It is believed that 2ME2 exerts its antiproliferative activity
2
by inhibiting tubulin polymerization and inhibition of HIF-1
a.
2
ME2 has been evaluated in several clinical trials under the
Compound 2 was converted to nitrile 3 (70%) using potassium
cyanide via Pd-mediated catalysis. Pd-catalyzed CO insertion with
Ò
8
name Panzem . The clinical results showed that 2ME2 has low bio-
availability due to rapid metabolism via oxidation of the 17-hydro-
xyl group to estrone and conjugation of both 3- and 17-hydroxyl
moieties to form glucuronides.3 These data highlight the need for
modifications of 2ME2 that could reduce metabolic liability at
these sites and potentially increase the bioavailability of 2ME.
Numerous studies have reported structure–activity relation-
ships (SAR) of 2ME2, to increase antiproliferative activity and inhi-
potassium acetate led to the formation of the carboxylic acid 4
(60%). Esterification of 4 under acidic conditions in methanol pro-
vided methyl ester 5 (73%), and its subsequent reduction with lith-
ium aluminum hydride produced hydroxy methyl analog 6. Vinyl
analog 7 (33%) was prepared using vinyl tributyl tin and Pd cata-
8
lyst, and catalytic hydrogenation of 7 yielded ethyl analog 8
(quantitative).
4
bition of tubulin polymerization. These analogs do not address the
Compounds 10–13 were prepared from 2-methoxyestrone (9)
as shown in Scheme 2. Oppenauer oxidation of 2ME2 generated
metabolism issue identified in our clinical studies. Our analog pro-
gram focused on modification of the 3 and 17 positions of 2ME2 to
specifically block known sites of metabolism while maintaining or
improving the in vitro antiproliferative activity profile. This Letter
reports the SAR of 3-modified analogs and identification of lead
substituents at this position. SAR at the 17-position are being re-
4
b
9 (85%), which was converted to thiol analog 10 through the for-
mation of O-aryl thiocarbamate, followed by Newman–Kwart rear-
rangement, ester cleavage, and LAH reduction (12%, three steps).9
Triflic ester 11 was prepared from 9 using triflic anhydride in pyr-
idine (98%). Carboxamide analogs were synthesized by Pd-medi-
5
10
11
ported in a separate publication. The optimal 3- and 17-substitu-
ated CO insertion reaction with HMDS (12a), Me
2
NH (12b), or
ents from these two studies have been combined and their
antitumor activity and PK values are discussed in an accompanying
Letter.
MeNH (12c) as the nitrogen source, and selective 17-ketone
reduction with sodium borohydride (50–70%, two steps). 3-Amine
2
6
13 (74%) was prepared from 11 by Pd-catalyzed benzophenone
1
2
The analogs synthesized for this study were prepared as shown
imine formation followed by acid hydrolysis.
in Schemes 1–3. 2,3-Dimethoxy analog (1) was generated from
Scheme 3 depicts subsequent reactions of 3-amine 13. Sand-
2
ME2 by selective methylation of the 3-hydroxyl group of 2ME2
meyer reactions and 17-ketone reduction lead to the formation
1
3
14
of halogenated analogs 14a, 14b, and 14c (20–40%). Aminoni-
trile 15 (30%) was generated from 13 using cyanogen bromide,15
and sodium borohydride reduction. Additionally, 13 was converted
to sulfamide with sulfamoyl chloride, and to trifluoromethyl
*
Corresponding author. Tel.: +1 240 864 2600.
E-mail address: tonyt@entremed.com (A.M. Treston).
Principal author.
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.009

6
460
L. S. Suwandi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6459–6462
OH
OH
OH
MeO
HO
MeO
TfO
MeO
NC
b
c
2
3
2
ME2
g
d
a
OH
OH
OH
OH
MeO
MeO
MeO
MeO
MeO
HO
1
4
5
6
7
O
e
OH
OH
h
MeO
MeO
8
O
f
MeO
HO
Scheme 1. Reagents and conditions: (a) K
acetone)dipalladium(0)–chloroform adduct; (d) Pd(OAc)
2
CO
3
, MeI, acetone, reflux; (b) p-nitrophenyl triflate, K
2
CO
3
, DMF; (c) KCN, dppf, 1-methyl-2-pyrrolidinone, tris(dibenzylidene-
2
, MeOH, reflux; (f) LiAlH , THF, 50 °C; (g) Pd(PPh Cl , Bu SnCHCH ,
2
, dppf, KOAc, CO, DMSO, 60 °C; (e) concd H
2
SO
4
4
)
3 2
2
3
DMF, 90 °C; (h) Pd/C, H
2
, 2:1 MeOH:dioxane.
O
Reaction of amine 13 with sodium cyanate under acidic condi-
1
6
tions gave urea 17 (58%), while LAH reduction generated analog
8, which was converted to 19 (71%) using formic acid and formal-
1
MeO
17
dehyde. Formamide 20a (86%) was prepared by amide coupling
of amine 18 with activated formyl imidazolidine generated
2ME2
H N
17
2
in situ from formic acid and carbonyl diimidazole. Amine 18
13
was converted to acetamide 20b (82%) with acetic anhydride under
basic conditions, or to methyl carbamate 20c (65%) with methyl
a
O
e
d
O
1
8
chloroformate and DMAP. Also, compound 21 (3-deoxy-2ME2,
structure not shown) was purchased from a commercial source.
All 3-modified 2ME2 analogs were screened in vitro for antipro-
liferative activity using human breast carcinoma MDA-MB-231
cells, for antiangiogenic activity using human umbilical vein endo-
thelial cells (HUVEC), and by stimulation of proliferation of estro-
MeO
HO
MeO
TfO
c
9
11
b
OH
OH
gen-dependant MCF-7 cells as
activity. Results are listed in Table 1, sorted by MDA-MB-231
antiproliferative activity.
a surrogate for estrogenic
1
9
MeO
HS
MeO
Generally the most active substituents for antiproliferative
activity are hydrogen donors. Analogs with activity <1 lM, such
as aminonitrile 15, urea 17, formamide 20a, amine 18, carboxam-
ide 12a, and acetamide 20b are all H-donors.
1
2
R R N
1
0
12
O
Scheme 2. Reagents and conditions: (a) Al(i-PrO)
3
, cyclohexanone, toluene, reflux;
Hydrogen donor ability appears to be critical for antiprolifera-
tive activity. For example, isosteric substitution of the hydroxyl
group of 2ME2 with thiol (10) leads to substantial loss of activity,
which may be explained by thiol’s diminished ability to hydrogen
bond. Alkylation of an amine or a hydroxyl group, and subsequent
loss of H-donor ability, significantly decreases antitumor activities.
(
b) (1) NaH, dimethylthiocarbamoyl chloride, DMF; (2) mineral oil, 280 °C; (3)
2
NaOH, EtOH, reflux; (4) LAH, THF, À78 °C; (c) Tf O, pyridine, DCM, 0 °C to rt; (d) (1)
2 2 3
Pd(OAc) , rac-BINAP, Cs CO , dppp, HMDS, DMF, CO, 100 °C; (2) MeOH then acidic
1 2
workup; (3) NaBH
CO, 57 °C; (2) NaBH
MeNH (in THF), CO, 70 °C; (2) NaBH
, rac-BINAP, benzophenone imine, Cs
4
, MeOH for R = H, R = H (12a) or (1) PdCl
2
, dppp, Me
, MeOH for R = Me, R = Me (12b) or (1) PdCl , dppp, DMF,
, MeOH, rt for R = Me, R = H (12c); (e) (1)
CO , toluene, reflux; (2) 2 M HCl,
2
NH, DMF,
1
2
4
2
1
2
2
4
Pd(OAc)
THF, rt.
2
2
3
2
ME2, for example, shows good activity against MDA-MB-231 (IC50
of 0.69 M). However, when the 3-hydroxyl group is methylated
1) there is a significant drop in antitumor activity. A similar trend
l
(
sulfonamide with triflic anhydride and triethylamine. Reduction of
the ketone at 17-position resulted in 16 (54%, two steps).
can be observed in compounds 12a, 12b, and 12c and amine series
18 and 19. Unsubstituted carboxamide 12a and amine 18 are ac-

L. S. Suwandi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6459–6462
6461
OH
OH
OH
MeO
R3
MeO
NC
N
H
1
4
15
OH
OH
b
a
MeO
O
MeO
O
c
d
1
3
S
O
R4
N
H N
N
H
2
H
16
1
7
e
OH
g
OH
MeO
N
MeO
MeO
O
f
H N
R5
N
H
2
19
18
20
3
Scheme 3. Reagents and conditions: (a) (1) NaNO
2
in H
CuBr, 0 °C to rt; (3) LAH, THF, À78 °C for R = Br (14b) or (1) NaNO
BrCN, Et O, DCM, 0 °C to rt; (2) NaBH , MeOH, rt; (c) (1) sulfamoyl chloride, Et
NaBH , MeOH, rt; (3) 1 N HCl for R = CF (16b); (d) NaOCN, H O, AcOH; (e) LiAlH
1) formic acid, 80 °C; (2) NaOH, MeOH, rt for R = H (20a) or Ac O, NaOH (10 M aqueous), 0 °C to rt for R = Me (20b) or methyl chloroformate, Et
2
O, HCl, EtOH, 0 °C; (2) CuCl, 0 °C to rt; (3) LAH, THF, À78 °C for R = Cl (14a) or (1) NaNO
in H O, HBF
N, THF, rt; (2) NaBH
(1 M in THF), THF, À78 °C; (f) formic acid, formaldehyde (36% aqueous), toluene, 80 °C; (g)
2
in H
2
O, HBr, EtOH, 0 °C; (2)
3
3
2
2
4
, EtOH, 0 °C; (2) isolate; (3) 80 °C, vacuum oven; (4) LAH, THF, À78 °C for R = F (14c); (b) (1)
, MeOH, rt; (3) 1 N HCl for R4 = NH
(16a) or (1) Tf O, Et N, DCM, 0 °C; (2)
4 2 2 3
2
4
3
4
4
3
2
4
5
5
(
R
2
3
N, DCM, 0 °C to rt for
5
= OMe (20c).
Table 1
In vitro activity of 3-modified 2ME2 analogs, sorted by activity against MDA-MB-231
which determine antiproliferative activities for this compound ser-
ies. For example, most of the best analogs contain electrons,
either as part of carbonyl or a nitrile. Size of the 3-substituent is
also important. In the 3-halogen series, 3-fluoro analog 14c is the
most potent while bromo 14b and chloro 14c are roughly
equipotent.
HUVEC cell proliferation was used as an in vitro surrogate for
antiangiogenic activity. In general, HUVEC antiproliferative activity
follows the trends discussed above for antitumor activity. The most
active substituents in MDA-MB-231 were also active in HUVEC.
There were differences in sensitivities between assays. Vinyl 7
and nitrile 3 substituents have modest antitumor activities on
p
#
3-
MDA-MB-231
M)
HUVEC IC50
M)
MCF7 SI relative to
2ME2
Substituent IC50
(
l
(l
1
1
2
2
1
1
1
2
7
3
1
2
2
1
1
1
8
6
1
2
1
1
1
1
4
5
5
7
NHCN
NHCONH
0.62 ± 0.23
0.65
0.47 ± 0.21
0.59
0.92 ± 0.16
0.32 ± 0.12
1.00
b
b
2
ME2 OH
0.79 ± 0.08
0.78 ± 0.01
2.36 ± 0.24
2.48 ± 0.50
2.94 ± 0.80
3.95 ± 1.06
8.93 ± 0.61
8.98 ± 3.17
0.68 ± 0.15
0.07 ± 0.02
2.59 ± 0.08
2.32 ± 0.38
2.10 ± 0.23
1.65 ± 0.13
1.96 ± 0.05
2.65 ± 0.25
0a
2a
8
4c
0b
NHCOH
CONH
0.15 ± 0.04
0.85 ± 0.04
1.60 ± 0.29
2.13 ± 0.02
0.93 ± 0.16
0.84 ± 0.04
1.37 ± 0.06
2
NH
F
2
NHCOMe
CH@CH
CN
2
b
b
a
MDA-MB-231 (IC50 of 8.9
(IC50 values of 2–3 M). Ethyl 8 and dimethylamino 19, on the
other hand, have antiangiogenic activity (5.4 M and 2.8 M,
respectively) but show little antitumor activity (46.9 M and
03.0 M, respectively). These differences may be driven by varia-
tions in the cellular composition of tubulin isoforms, as has re-
lM), but are more active against HUVEC
6a
0c
NHSO
2
NH
2
9.47
3.88
na
na
b
b
a
NHCOOMe
17.61
5.92
l
OSO
Cl
2
CF
3
21.35 ± 0.81
26.93 ± 3.96
27.49 ± 1.99
43.68 ± 1.14
46.88 ± 1.98
55.59 ± 17.31
56.19 ± 3.47
62 ± 0.82
103.03 ± 11.55
>10
3.27 ± 2.21
7.45 ± 1.01
9.13 ± 0.37
31.47 ± 5.11
5.44 ± 0.18
28.25 ± 5.46
12.87 ± 7.36
22.1 ± 0.7
2.82 ± 1.71
>10
0.43 ± 0.13
2.19 ± 0.21
2.74 ± 0.16
0.73 ± 0.12
0.73 ± 0.23
1.26 ± 0.23
1.85 ± 0.38
1.80 ± 0.28
0.63 ± 0.07
l
l
4a
4b
l
Br
OMe
Et
1
l
2
0
CH
SH
H
2
OH
cently been reported for other antitubulin agents.
0
1
9
2b
6b
2c
Similar to the effect seen on antitumor activity, methylation of
the3-hydroxyl group of 2ME2 resulted in 40-fold decrease in antian-
giogenic activity. Additionally, alkylated carboxamide 12b showed a
substantial drop in activitycompared to unsubstituted amide 12a. In
contrast, dimethylation of the amine 18 to 19 did not result in signif-
icant changes to antiangiogenic activity (1.4-fold change, compared
to 41-fold change in antitumor activity). Following the general SAR
observed for antitumor activity, in addition to being hydrogen do-
NMe
CONMe
NHSO CF
2
a
2
na
na
na
na
a
2
3
>100
>100
>100
>100
46.19 ± 5.26
>100
>100
a
CONHMe
COOH
COOMe
a
>100
0.99 ± 0.23
a
na = not assayed.
b
Standard deviation not available where results are reported from a single
nors, the most antiangiogenic analogs also have
p electrons.
experiment.
Studies have shown that 2ME2 is significantly less estrogenic
2
1
than estradiol. Given the known pro-carcinogenic effect of estro-
gens it is desirable for new analogs to maintain or have further re-
duced estrogenicity compared to 2ME2. The estrogen-dependent
MCF-7 cell line was used as an in vitro surrogate for estrogenicity,
expressed as a simulation index relative to 2ME2 (SI). Values less
than 1.0 are desirable, representing less estrogenicity than 2ME2.
The results in Table 1 show that for this series of analogs estrog-
enicity does not follow the same trend seen for antiproliferation or
antiangiogenic activity. The data suggest that substituent size is an
tive against MDA-MB-231 proliferation. However when 12a and 18
are methylated to give carboxamides 12b and 12c and dimethyl
amine 19, antitumor activity diminishes significantly in each case.
Not all hydrogen donors show good antiproliferative activities.
Methyl alcohol 6, for example, is a hydrogen donor but is weakly
active against MDA-MB-231 proliferation (IC50 of 56
lM). Though
the ability to donate a proton is important, there are other factors

6
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L. S. Suwandi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6459–6462
important factor in estrogenicity. Smaller substituents at position 3
in general were more estrogenic than larger substituents. All the ha-
lides (14a–c), 3-deoxy (21), thiol (10), and amine (18), for example,
had a SI value >1. Comparison of primary amine 18 and tertiary
amine 19 show that the smaller, unsubstituted amine is more estro-
genic. It seems that there is a steric constraint in the estrogen recep-
tor binding site, and the undesirable effect of estrogenicity can
thus be reduced by introducing a relatively bulky substituent.
These data indicate that by modification of the 3-position we
were able to enhance antitumor and antiangiogenic activity while
further reducing undesirable estrogenicity. The most active 3-posi-
tion analogs for antiproliferation are generally less estrogenic than
11, 6625; (b) Lakhani, N. J.; Sparreboom, A.; Xu, X.; Veenstra, T. D.; Venitz, J.;
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2
2
ME2. The fluoro analog (14c), with MCF7 SI of 2.13, was removed
from further consideration due to increased estrogenicity. Taking
into account the antitumor, antiproliferative, and estrogenic activ-
ities, there are several potential lead substituents for position 3
that warrant further investigation. They include aminonitrile 15,
urea 17, formamide 20a, carboxamide 12a, amino 18 and acetam-
ide 20b. Further work on these lead substituents is described in the
5
6
.
.
Shah, J. H.; Agoston, G. E.; Suwandi, L.; Zhan, X. H.; Swartz, G. M.; LaVallee, T.
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1
In conclusion, 25 novel analogs of 2ME2 modified at the 3-posi-
tion have been synthesized and screened for their antiproliferative,
antiangiogenic, and estrogenic activities. Structure–activity rela-
tionships of these compounds led to the identification of several
lead substituents, which maintain the antitumor activity of 2ME2
while blocking the 3-position towards conjugation. The lead sub-
stituents reported here have been combined with 17-position ana-
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