Discovery of a novel class of aldol-derived 1,2,3-triazoles: Potent and selective inhibitors of human cytochrome P450 19A1 (aromatase)

Article abstract of DOI:10.1016/j.bmcl.2011.10.039

The discovery of a novel five-component 1,2,3-triazole-containing pharmacophore that exhibits potent and selective inhibition of aromatase (CYP 450 19A1) is described. All compounds are derived from an initial aldol reaction of a phenylacetate derivative

Full text of DOI:10.1016/j.bmcl.2011.10.039

Bioorganic & Medicinal Chemistry Letters 22 (2012) 718–722
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel class of aldol-derived 1,2,3-triazoles: Potent
and selective inhibitors of human cytochrome P450 19A1 (aromatase)
James McNulty a, , Jerald J. Nair a, Nesrin Vurgun a, Benjamin R. DiFrancesco a, Carla E. Brown a,
⇑
Bernice Tsoi b, Denis J. Crankshaw b, Alison C. Holloway b
a Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4M1
b Department of Obstetrics and Gynecology, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4K1
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery of a novel five-component 1,2,3-triazole-containing pharmacophore that exhibits potent
and selective inhibition of aromatase (CYP 450 19A1) is described. All compounds are derived from an
initial aldol reaction of a phenylacetate derivative with an aromatic aldehyde. Structure–activity data
generated from both syn- and anti-aldol adducts provides initial insights into the requirements for both
potency and selectivity.
Received 31 August 2011
Revised 6 October 2011
Accepted 11 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aromatase inhibition
Anticancer compounds
Aldol reaction
Triazoles
Cancer is a leading cause of mortality among women, with
breast cancer alone comprising 30%1,2 of all new cases (estimated
230,480 cases) diagnosed in the US in 2011.2 Currently, one out
of eight American women will develop breast cancer in her life-
time.2 Approximately 70–80% of postmenopausal breast cancer pa-
tients have hormone-dependent (estrogen-dependent) breast
O
NC
N
O
NH2
N
CN
HN
N
N
O
3. Anastrozole
2. Aminoglutethimide
CN
1. Tamoxifen
O
N
N
H
N
H
H
O
CN
4. Letrozole
5. Exemestane
Scheme 1. Commonly used drugs for the treatment of breast cancer, including the estrogen receptor antagonist tamoxifen 1, non-steroidal aromatase inhibitors
aminoglutethimide 2, Anastrozole 3 and Letrozole 4 as well as the steroidal aromatase inhibitor exemestane 5.
⇑
Corresponding author.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.039

J. McNulty et al. / Bioorg. Med. Chem. Lett. 22 (2012) 718–722
719
OH
2
OH
NH
HO
OH
OH
OH
OH
OH
1
3
4
10
10b
9
8
O
O
O
O
O
O
HO
4a
10a
NH
6a
6
7
OH
O
OH
O
OH
7. Pancratistatin
8. Narciclasine
6. Apigenin
Scheme 2. Flavonoid aromatase inhibitor apigenin 6, as well as cytotoxic alkaloid representatives of the Amaryllidaceae including pancratistatin 7 and narciclasine 8.
RO
Y
X
D:
9 (D=donor substituent)
OCH3
a
3
2
HO
O
O
HO
b
O
O
1
OCH3
O
O
O
OH
O
O
O
O
O
11a. Syn-adduct
10a. Syn-adduct
10b. Anti-adduct
c
12b
11b. Anti-adduct
Scheme 3. Anti-selective aldol reaction of methyl (3,4-methylenedioxy)phenylacetate and benzaldehyde. Reagents and conditions: (a) LiHMDS, THF, À78 °C to rt, 3 h, 90%;
(b) LiAlH4, THF, 0 °C to rt, 3 h, 95%; (c) BDMA, TsOH, DCM, rt, 1 h, 94%.
cancer.3 For over two decades tamoxifen 1 (Scheme 1) has been
used as the standard anti-estrogen in treating such tumors.4a–f
Tamoxifen and its metabolites function as selective estrogen recep-
tor modulators (SERM).4f Their antagonist action in breast tissue
prevents estrogen binding and resulting downstream effects that
include cancer cell proliferation and the activation of survival
and anti-apoptosis pathways.4d,e Estradiol, the most potent endog-
enous estrogen, is biosynthesized from androgens by the cyto-
chrome P450 19A1 enzyme complex (CYP19A1) called
aromatase.5 Aromatase activity has been demonstrated in breast
tissue in vitro and expression of aromatase shown to be highest
in or near breast tumor sites.5d–f Aromatase inhibitors (AIs) have
emerged over the last 15 years as modulators of the growth-stim-
ulatory effects of estrogens in estrogen-dependent breast cancer.
Nonsteroidal aromatase inhibitors can be divided into three classes
(Scheme 1) as aminoglutethimide-like 2 molecules, imidazole/tria-
zole derivatives, and flavonoids.6 Anastrozole 3 and Letrozole 4 are
currently approved AIs for the treatment of metastatic estrogen-
dependent breast cancer.6e–j Steroidal inhibitors that have been
developed to date, such as Exemestane 5, build upon the basic
androstenedione nucleus and incorporate substituents at varying
positions on the steroid.6k Use of an aromatase inhibitor as initial
therapy, or after treatment with tamoxifen is now recommended
as adjuvant hormonal therapy for postmenopausal women with
hormone-dependent breast cancer.3 Despite their clinical success,
negative side effects and partial selectivity of existing AIs are sig-
nificant issues which must be addressed. AIs are associated with
osteoporosis, reproductive problems and androgenic side effects.
These compounds also partly inhibit cytochromes 1A1, 1A2, 2D6,
2C8/9 and 3A4, all of which are involved in the metabolism of
xenobiotics, thus increasing the likelihood of drug–drug interac-
tions in patients. These factors in combination necessitate the
development of more selective AIs for the treatment of ER positive
breast cancer. The activity of flavonoids as aromatase inhibitors
has been demonstrated both in vitro and in vivo.6l,m We recently
Figure 1. X-ray structure of syn-aldol derived 1,3-diol 11a.
Figure 2. X-ray structure of anti-aldol derived benzylidene 12b.

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J. McNulty et al. / Bioorg. Med. Chem. Lett. 22 (2012) 718–722
reported the non-selective aromatase inhibitory activity of several
structure 9 (Scheme 3). This novel composition consists of five
independent fragments (two functionalized aryl rings, one oxygen-
ated substituent, one donor-substituent and a core unit of unde-
fined stereochemistry). In this letter, we report the synthesis of a
range of derivatives of this structural type and the development
of potent and selective AIs based on this scaffold.
We elected to pursue an aldol-based approach to compounds of
type 9, based on earlier work involving anti-7i,k and syn-selective7n
directed aldol reactions of phenylacetates. The selective generation
of (E)- or (Z)-enolates of phenylacetic esters9 and aldol reaction with
aromatic aldehydes leads to the respective anti- or syn-aldol adduct-
s.9h,i In the present case, we wished to access both syn- and anti-
diasteromers in order to assess activity in both series. The reaction
of the lithium enolate of methyl 3,4-methylenedioxyphenylacetate
flavonoids, with apigenin 6 (Scheme 2) being the most active (Ki
1.0 l
M).6n
Our research group has been involved in several areas of
research pertaining to alkaloids of the Amaryllidaceae,7 including
the polyhydroxylated isoquinolines pancratistatin 7 and narcicla-
sine 8 (Scheme 2).8 Both compounds exhibit potent antiprolifera-
tive activity to a number of cancer cell lines.8c In addition to
cytotoxic activity, we have monitored P450 activities in order to
gauge off-target effects, for example we demonstrated several
pancratistatin and seco-analogs to exhibit potent human cyto-
chrome P450 3A4 inhibitory activity.7l–p Structural analysis of
compounds 2–4, 6–8 and our synthetic SAR studies7 revealed to
us a possible common pharmacophore, depicted as the general
O
HO
O
O
OCH3
b
H
H
OCH3
OCH3
O
a
O
O
14
13b. Anti-adduct
O
O
O
O
O
O
c
e
d
H
TMS
H
H
H
f
N3
OTos
OH
17
16
15
HO
O
O
O
O
O
H
H
H
h
i
g
N
N
N
N
N
N
N
N
N
N
N
N
20
19
21
Me3Si
18
k
j
17
25
27
3"
2"
4"
5"
m
AcO
3
BzO
O
O
1"
6"
6'
H
H
H
1'
5'
4'
1
l
2
2'
5'''
16
O
O
O
H
N
N
N
O
N
N
N
N
3'
22
4'''
24
23
NH2
n
p
o
O
O
O
O
H
H
O
H
NHAc
NHTos
28
26
NHBz
Scheme 4. Synthesis of functionalized 1,2,3-triazoles and derivatives in the anti-aldol series. Reagents and conditions: (a) LiHMDS, À78 °C to rt, 3 h, 90%; (b) MOMCl, DIPEA,
DCM, 0 °C to rt, 8 h, 95%; (c) LiAlH4, THF, 0 °C to rt, 3 h, 91%; (d) TosCl, py, DCM, rt, 5 h, 93%; (e) NaN3, DMF, rt, 6 h, 83%; (f) Cu(I)I, THF, rt, 8 h, 83%; (g) TBAF, THF, rt, 8 h, 98%;
(h) 5 M HCl, THF, rt, 7 h, 86%; (i) Swern, DCM, À78 °C to rt, 3 h, 96%; (j) BzCl, py, DCM, rt, 3 h, 98%; (k) Ac2O, py, DCM, rt, 3 h, 95%; (l) morpholine, 60 °C, 6 h, 82%; (m) 10% Pd/C,
H2, rt, 7 h, 94%; (n) Ac2O, TEA, DCM, rt, 3 h, 98%; (o) BzCl, TEA, DCM, rt, 3 h, 98%; (p) TosCl, TEA, DCM, rt, 3 h, 98%.

J. McNulty et al. / Bioorg. Med. Chem. Lett. 22 (2012) 718–722
721
with benzaldehyde yielded a 40:60 mixture of the syn- and anti-al-
dol adducts 10a and 10b, in 90% isolated yield (Scheme 3).9j The al-
dol adducts were readily separated on silica-gel on a gram scale and
the stereochemistry of both adducts proven through X-ray analysis.
The adducts were independently reduced to the corresponding 1,3-
diols 11a and 11b. The relative configuration of 11a as the syn-aldol
derivative was proven directly (Fig. 1), while conversion of 11b to its
crystalline benzylidene adduct 12b (Fig. 2) confirmed its origin from
the anti-aldol adduct. The slight anti-selectivity of this Li-mediated
aldol reaction was thus confirmed, in accord with prior studies.9f,j
We focused first on conversion of the major anti-aldol deriva-
tive 13b, prepared as outlined in Scheme 4, to the desired proto-
type 9. Protection of the 3-hydroxy group in 13b as the MOM
ether followed by LiAlH4 reduction of ester 14 gave alcohol 15 in
91% yield. The primary hydroxyl group in 15 was converted to tos-
ylate 16, which subsequently underwent smooth displacement
with sodium azide over 6 h at room temperature in DMF to give
azide 17 (83% isolated yield). Under ‘Click’ chemistry conditions,10
azide 17 was converted to the TMS-triazole 18 upon reaction with
ethynyl trimethylsilane. Desilylation with TBAF at room tempera-
ture then gave the free 1,2,3-triazole 19 efficiently. The hydroxy
triazole 20 was obtained directly from 19 after hydrolysis with
5 M HCl in THF and subsequently converted via Swern oxidation
to the oxo-triazole 21, and separately to the benzoate 22 and ace-
tate 23, all in near quantitative yields. Tosylate 16 was also easily
displaced with neat morpholine at 60 °C leading to 24. Reduction
of azide 17 with hydrogen over 10% palladium on carbon provided
the free amine 25 which was used without further purification in
the subsequent conversion to acetamide 26, benzamide 27 and
tosylamide 28, respectively.
converted to azide 32 via a similar reduction, tosylation azido-sub-
stitution sequence. Huisgen-cylization gave the TMS-protected tri-
azole 33 which was converted to derivatives 34, 35 and 36 using
the methods established in the anti-series.
Compounds 13a–36 were also screened against recombinant
human aromatase via kinetic monitoring of the conversion of O-dib-
enzylfluorescein benzyl ester (DBF) substrate to fluorescein by-
product.6n Fluorometric measurement of emission was made at
535 nm after excitation at 485 nm utilizing ketoconazole as a posi-
tive control, as recently reported.6n Azide 17 and TMS-triazole 18
proved to be inactive, while hydrolysis of the TMS group produced
the active deprotected triazole 19 with Ki 0.79 lM. Cleavage of the
MOM group from 19 gave hydroxy triazole 20 which was inactive,
while oxidation of 20 to the oxo-triazole 21 resulted in recovered
activity (Ki = 1.0
pronounced effect on AI activity. Conversion of 20 to the triazole
benzoate 22 (Ki 0.1 M) and the triazole acetate 23 (Ki 0.06 M)
lM). Acylation at C3 was observed to exert a
l
l
led to the discovery of potent inhibitors in the anti-series. These
results were not completely unexpected. Previous studies from
our group on cytochrome P450 3A4 inhibitory activities in the nat-
ural alkaloid series,7m,o as well as synthetic aldol-derived seco-ana-
logs7l,n revealed the importance of substituents at this position. In
moving to the syn-aldol series, all new compounds shown in
Scheme 5 were screened allowing us to identify the three deriva-
tives 34, 35 and 36 as potent aromatase inhibitors. The overall
SAR data showed that potent inhibitors can be realized in either
the syn- or anti- series, most likely due to conformational flexibility,
but that the magnitude is critically dependant on the C3 oxy-substi-
tuent. A free triazole is required at the C1 position in accord with the
expectation on the role of this substituent as a donor-group (9,
Scheme 3) binding to the Fe-core of the enzyme.
The anti-aldol derived derivatives 13–28 were screened for
activity against recombinant human aromatase allowing us to
identify the triazoles 19, 22 and 23 as active AI’s. We will return
to a full discussion on these activities shortly. The initial results
allowed us to focus on a more limited selection of syn-aldol derived
triazoles that were now accessed as outlined in Scheme 5. The syn-
aldol adduct 13a was protected as the MOM ether 29, and
In order to gauge selectivity, we also screened select active aro-
matase inhibitors 21, 22, 23, 34, 35 and 36 against cytochromes
P450 3A4, 1A1, and 2D6, results are summarized in Table 1. All
compounds proved to be non-inhibitors of CYP3A4 at the initial
10
lM concentration. Compounds 21 and 22 showed moderate
activity to CYP1A1, exhibiting pKi(M) values of 5.27 ( 0.04) and
O
HO
O
O
H
OCH3
b
H
H
OCH3
OCH3
O
a
O
O
29
13a. Syn-adduct
O
O
O
O
O
O
c
e
TMS
d
H
H
H
f
N3
OTos
OH
32
31
30
3"
6"
2"
4"
5"
O
O
HO
O
O
AcO
3
1"
H
H
H
6'
i
h
H
g
1'
5'
4'
36
1
2
N
N
N
N
N
N
N
N
N
N
2'
5'''
N
N
33
3'
35
34
Me3Si
4'''
Scheme 5. Synthesis of functionalized 1,2,3-triazoles in the syn-aldol series. Reagents and conditions: (a) LiHMDS, À78 °C to rt, 3 h, 90%; (b) MOMCl, DIPEA, DCM, 0 °C to rt,
8 h, 88%; (c) LiAlH4, THF, 0 °C to rt, 3 h, 90%; (d) TosCl, py, DCM, rt, 5 h, 85%; (e) NaN3, DMF, rt, 6 h, 86%; (f) Cu(I)I, THF, rt, 8 h, 80%; (g) TBAF, THF, rt, 8 h, 95%; (h) 5 M HCl, THF,
rt, 7 h, 70%; (i) Ac2O, py, DCM, rt, 3 h, 88%.

722
J. McNulty et al. / Bioorg. Med. Chem. Lett. 22 (2012) 718–722
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Effect of 1,2,3-triazoles on the catalytic ability of recombinant human aromatase
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Pharmacol. 2005, 56, 29; (f) McLachlan, A.; Kekre, N.; McNulty, J.; Pandey, S.
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E.; Pandey, S. Eur. J. Org. Chem. 2007, 5669; (h) McNulty, J.; Nair, J. J.; Codina, C.;
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Compound
Ki (
l
M)
pKia (M)
17
18
19
20
21
22
23
24
25
32
33
34
35
36
na
na
0.79
na
1.00
0.10
0.06
na
na
na
na
0.08
0.05
0.25
0.40
—
—
6.1 ( 0.3)
—
6.0 ( 0.3)
7.0 ( 0.5)
7.2 ( 0.3)
—
—
—
—
7.1 ( 0.1)
7.3 ( 0.1)
6.6 ( 0.1)
6.4 ( 0.3)
Ketoconazole
a
Values are means of three experiments, standard deviation is given in paren-
theses (na = not active at 10 M).
l
4.51 ( 0.12), respectively. In terms of 2D6 activity, only compounds
19 and 35 showed weak activity, exhibiting pKi(M) values of 2.95
and 3.15, respectively. Both Anastrozole 3 and Letrozole 4 are
known to inhibit the CYP3A4 isoenzyme,11a responsible for detoxi-
fication of the majority of xenobiotics such as drugs and environ-
mental toxins.11b The SAR-based results in this study validate our
initial hypothesis based on general structure 9 and highlight the po-
tential of this novel triazole aromatase inhibitory pharmacophore
towards the discovery of both potent and selective AI’s.
In summary, a novel class of 1,2,3-triazole was generated
through a concise synthetic strategy involving an aldol reaction
of methyl phenylacetate with benzaldehyde. Several triazoles de-
rived from both the syn- and anti-adducts were shown to be selec-
tive inhibitors of the enzyme aromatase, of significance in the
therapeutic approach towards breast cancer. The most potent of
these triazoles (anti-triazole acetate 23, and syn-triazole alcohol
35) exhibited selective aromatase inhibitory activity with potency
as low as 50 nM. Fragment-based refinement of the present inhib-
itors through functionalization of the aryl-residues in order to elu-
cidate this novel pharmacophore model further and the
investigation of in vivo activity in a cell-based model is currently
under investigation.
Acknowledgments
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Nat. Prod. 1993, 56, 1682; (b) Hudlicky, T.; Rinner, U.; Gonzales, D.; Akgun, H.;
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365; (e) Kornienko, A.; Evidente, A. Chem. Rev. 2008, 108, 1982.
We thank NSERC and McMaster University for financial support
of this work.
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Supplementary data
Experimental procedures and characterization data are pro-
vided. CCDC files 785411 and 785412 contain the supplementary
crystallographic data for compounds 11a and 12b. These data can
be obtained free of charge from The Cambridge Crystallography
Data Centre via www.ccdc.cam.ac.uk/data_requestcif.html.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.039.
10. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
11. (a) Buzdar, A. U.; Robertson, J. F. R.; Eiermann, W.; Nabholtz, J. Cancer 2002, 95,
2006; (b) de Graaf, C.; Vermeulen, N. P. E.; Feenstra, K. A. J. Med. Chem. 2005, 48,
2725.
References and notes
1. International Agency for Research on Cancer World Cancer Report 2008;
International Agency for Research on Cancer: Lyon, France, 2008.
2. Siegel, R.; Ward, E.; Brawley, O.; Jemal, A. CA Cancer J. Clin. 2011, 61, 212.