Boron-based 4-hydroxytamoxifen bioisosteres for treatment of de novo tamoxifen resistant breast cancer

Article abstract of DOI:10.1021/ml3000287

Tamoxifen remains the first line therapy for estrogen receptor positive (ER+) breast cancer. However, polymorphisms of the gene encoding P450 2D6 could result in no protein expression or no CYP2D6 enzymatic activity and may significantly reduce the benefit of the hormone therapy. To address this issue, we designed and synthesized three 4-hydroxytamoxifen bioisosteres utilizing a boron-aryl carbon bond that can be oxidized under physiological conditions to yield 4-hydroxytamoxifen. We show that the bioisosteres inhibit the growth of two ER+ breast cancer cell lines, MCF-7 and T47D, with potencies comparable to or greater than that of 4-hydroxytamoxifen. We further demonstrate that after incubation with breast cancer cells, the majority of the bioisosteres has been converted to 4-hydroxytamoxifen. Our study suggests that boron-based 4-hydroxytamoxifen bioisosteres may be an effective therapeutic remedy for intrinsic tamoxifen resistance in breast cancer patients deficient in CYP2D6 metabolism.

Full text of DOI:10.1021/ml3000287

Letter
pubs.acs.org/acsmedchemlett
Boron-Based 4-Hydroxytamoxifen Bioisosteres for Treatment of de
Novo Tamoxifen Resistant Breast Cancer
Quan Jiang,† Qiu Zhong,† Qiang Zhang,‡ Shilong Zheng,*,‡ and Guangdi Wang*,†,‡
‡
†Department of Chemistry and RCMI Cancer Research Program, Xavier University of Louisiana, 1 Drexel Drive, New Orleans,
Louisiana 70125, United States
S
* Supporting Information
ABSTRACT: Tamoxifen remains the first line therapy for
estrogen receptor positive (ER+) breast cancer. However,
polymorphisms of the gene encoding P450 2D6 could result in
no protein expression or no CYP2D6 enzymatic activity and
may significantly reduce the benefit of the hormone therapy.
To address this issue, we designed and synthesized three 4-
hydroxytamoxifen bioisosteres utilizing a boron-aryl carbon
bond that can be oxidized under physiological conditions to
yield 4-hydroxytamoxifen. We show that the bioisosteres
inhibit the growth of two ER+ breast cancer cell lines, MCF-7
and T47D, with potencies comparable to or greater than that
of 4-hydroxytamoxifen. We further demonstrate that after
incubation with breast cancer cells, the majority of the
bioisosteres has been converted to 4-hydroxytamoxifen. Our study suggests that boron-based 4-hydroxytamoxifen bioisosteres
may be an effective therapeutic remedy for intrinsic tamoxifen resistance in breast cancer patients deficient in CYP2D6
metabolism.
KEYWORDS: 4-hydroxytamoxifen bioisosteres/4-hydroxytamoxifen prodrugs, CYP2D6, boron−carbon bond, breast cancer
amoxifen has been the mainstay hormonal therapy for
breast cancer that expresses the estrogen receptor (ER+)
responsible for this metabolic route of 4-OHT demethylation
leading to endoxifen formation. Thus, both endoxifen and 4-
OHT represent desirable alternatives to tamoxifen for breast
cancer patients lacking the active form of the P450 enzyme
CYP2D6.11−15
T
since the 1980s. Nearly 70% of all diagnosed breast tumors are
classified as ER+, most of which initially respond to tamoxifen
treatment.1 However, approximately 8% of breast cancer
patients present intrinsic resistance to tamoxifen2 mainly
because these patients do not have a functional P450 2D6
enzyme (CYP2D6) that is responsible for converting tamoxifen
to its more potent metabolites, 4-hydroxytamoxifen (4-OHT)
and endoxifen.3 Indeed, breast cancer mortality was signifi-
cantly increased in patients with CYP2D6-null allele as
compared to wild-type patients.4 Jordan and co-workers first
reported that high first-pass metabolism of tamoxifen led to a
significant increase in its activity and characterized the first
active primary metabolite, 4-OHT,5,6 which showed 30−100-
fold greater potency than tamoxifen in inhibiting estrogen-
dependent cell proliferation.7−9
The predominant biotransformation route, demethylation of
tamoxifen to form N-desmethyltamoxifen, is catalyzed by the
P450 enzyme CYP3A4/5.10 This major primary metabolite has
a potency similar to tamoxifen. It is then converted into the
more potent secondary metabolite endoxifen exclusively by
CYP2D6. On the other hand, the same CYP2D6 is required for
the formation of 4-OHT, which is equally or more potent than
endoxifen. While the hydroxylation at the 4C-position depends
on CYP2D6, the biotransformation from 4-OHT to endoxifen
does not. In fact, it has been shown that CYP3A4/5 is primarily
To achieve increased bioavailability of 4-OHT in CYP2D6
deficient breast cancer patients as well as enhanced drug
selectivity toward tumor cells, we sought to explore the utility
of a boron-based prodrug strategy. This strategy takes into
consideration the need to have an effective level of the active
form of tamoxifen and the preferential uptake of 4-OHT by
cancer cells. To this end, we have designed three boronic
derivatives of tamoxifen as 4-OHT prodrug candidates. Boronic
acid has been previously used in imaging and medicinal
chemistry offering unique advantages associated with its low
toxicity and stability.16 It is well-known that the boron-aryl
carbon bond is susceptible to oxidative cleavage by hydrogen
peroxide to form a phenol compound.17−20 Because tumor cells
have elevated concentration levels of hydrogen peroxide,21−23 it
is anticipated that upon entering breast cancer cells, these
prodrugs will undergo facile oxidization reaction to form 4-
OHT (Figure 1). This approach may thus have the potential to
increase the efficacy of hormone therapy by (1) increasing the
Received: January 29, 2012
Accepted: April 6, 2012
Published: April 6, 2012
© 2012 American Chemical Society
392
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ACS Medicinal Chemistry Letters
Letter
trifluoromethanesulfonic anhydride in CH2Cl2. The
PdCl2(dppf)-catalyzed borylation of the triflate 3 gave the
pinacolyl boronate ester of tamoxifen derivative 4 using a
diboron reagent in the presence of KOAc.25,26 The reaction of
the pinacolyl boronate ester 4 with potassium bifluoride formed
the potassium trifluoroborate of tamoxifen 5. The free boronic
acid prodrug 6 was obtained successfully via hydrolysis of 5
using trimethylsilyl chloride as an effective fluorophile.27
To determine the antiestrogenic effects of the prodrugs, we
performed breast cancer cell survival assays in which the ability
of the prodrugs to inhibit growth of MCF-7 and T47D cells was
measured. The 4-OHT treated cell survival data were used as
positive controls. MCF-7 and T47D breast cancer cells both
express the estrogen receptor, and their growth and
proliferation depend on estrogen. Antiestrogenic compounds
such as tamoxifen and ICI 182780 (Fulvestrant) are used to
treat hormone responsive breast cancer. Thus, MCF-7 and
T47D cell lines have been widely used as cellular models for ER
+ breast tumors.
As shown in Figure 2A, tamoxifen inhibited MCF-7 cell
survival and growth by 18 and 52% at 10−7 and 10−6 M,
respectively. 4-OHT, the active metabolite of tamoxifen, more
strongly inhibited growth of MCF-7 cells at these two doses
(by 56 and 63%, respectively). In comparison, the pinacolyl
boronate ester prodrug (4) showed 52% growth inhibition at
10−7 M and 63% at 10−6 M, similar to the efficacy of 4-OHT.
The trifluoroborate prodrug (5) demonstrated growth
inhibition on MCF-7 cells with 59% at 10−7 M and 76%
inhibition at 10−6 M concentration. The boronic acid prodrug
(6) was found to inhibit cell growth with efficacies comparable
to 5 at the two doses (51 and 75% inhibition, respectively).
Additional survival assays using T47D cells confirmed the
efficacies of the prodrugs (Figure 2B). Consistent with previous
Figure 1. Design of boron-based 4-OHT bioisosteres.
concentration of 4-OHT in cancer cells, (2) providing the
active and more potent form (4-OHT) of tamoxifen for
patients with defective CYP2D6 polymorphism, and (3)
allowing the formation of endoxifen as a downstream metabolic
product with equivalent potency as 4-OHT independent of
CYP2D6.
The three designed boron-containing derivatives of tamox-
ifen share the common boron-aryl carbon bond and are all
expected to be transformed to 4-OHT upon oxidization, but
each of them has its own feature. The boronic acid pinacol ester
(4) was designed for attenuated polarity as compared to 4-
OHT. The potassium trifluoroborate derivative (5) was
intended to afford greater solubility of the prodrug. The
boronic acid prodrug (6) was included for its increased stability.
The synthesis of boron-based 4-OHT bioisosteres is outlined
in Scheme 1. 4,4′-(2-Phenylbut-1-ene-1,1-diyl)diphenol (1) was
obtained by McMurry reaction of 4,4′- dihydroxybenzophenone
with propiophenone. The monoalkylaton of 1 by 2-
(dimethylamino)ethylchloride hydrochloride in the presence
of cesium carbonate in DMF gave 4-OHT (2).24 Then, 4-OHT
was converted into the triflate 3 by reacting with
Scheme 1. Preparation of Boron-Based 4-OHT Bioisosteres
Reagents and conditions: (a) Propiophenone, TiCl4, Zn, THF, reflux. (b) 2-(Dimethylamino)ethylchloride hydrochloride, Cs2CO3, DMF, 70−80
°C. (c) (CF3SO2)2O, pyridine, CH2Cl2, 0 °C−rt. (d)
, PdCl2(dppf), KOAc, dioxane, reflux. (e) KHF2, MeOH/H2O, rt. (f)
(CH3)3SiCl, CH3CN, H2O, rt.
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Figure 2. Prodrugs of 4-OHT inhibit growth of (A) MCF-7 cells and (B) T47D cells.
reports on the sensitivity of T47D and MCF-7 to tamoxifen,28
T47D cells exhibited slightly higher survival ratios than MCF-7
cells when treated with 10−7 and 10−6 M 4-OHT except
tamoxifen at 10−7 M. For example, growth of T47D cells was
inhibited by 51% in 10−7 M 4-OHT as compared to the 56%
for MCF-7 cells. While the prodrugs were equally effective in
T47D as compared to 4-OHT, their overall potency was also
slightly lower than in MCF-7 cells. At 10−6 M, the prodrug 6
achieved 54% growth inhibitions of the T47D cells, lower than
the 75% inhibition of MCF-7 cells; treatment of T47D cells
with prodrugs 5 and 4 at 10−6 M dose resulted in 50 and 60%
inhibition, respectively, versus 76 and 63% in MCF-7 cells.
These results clearly demonstrate the effectiveness of the 4-
OHT prodrugs as antiestrogens in inhibiting the growth of ER+
breast cancer cells represented by MCF-7 and T47D cell lines.
Dose−response studies were performed to evaluate the
antiestrogenic effects of the prodrugs on MCF-7 and T47D
cells as compared with tamoxifen and 4-OHT. A dose−
response curve for each drug was obtained yielding IC50 values
as listed in Table 1. Consistent with previous studies,6 the IC50
69.6% (4-OHT), respectively, indicating that the majority of
the prodrug has been converted to 4-OHT in the media after
incubation with MCF-7 cells. This transformation was more
complete in T47D cells where the % peak area of 4-OHT
reached 79.1 versus 20.9% for the prodrug 6 (Figure 3B). For
prodrugs 4 and 5, the % peak areas of 4-OHT were 73.3 and
81.6%, respectively, in MCF-7 cells. Similar results were
observed when T47D cells were treated with prodrugs 4 and
5, where 69.9% of 4 and 86.3% of 5 were transformed into 4-
OHT.
We next sought to investigate the in vitro stability of the
boron prodrugs using MCF-7 cells. By monitoring the prodrug
and 4-OHT concentrations in the media at 11 time points (0−
144 h), the half-life of each prodrug, namely, the point where
half of the prodrug has been converted to 4-OHT, was
determined. The time-dependent oxidative conversion to 4-
OHT for each boron prodrug yielded a half-life of 96 h, or 4
days, for prodrug (6) as illustrated in the Supporting
Information, Figure 1S. Similar half-life data were obtained
for prodrug (4) (89 h) and prodrug (5) (84 h).
The modification of 4-OHT structure by incorporation of
boron may have improved the uptake of the prodrugs by breast
cancer cells. To compare the relative uptake of the prodrugs
versus 4-OHT, we measured the concentrations of the
remaining drugs in media after a 6 day period of incubation
with MCF-7 cells (Supporting Information, Figure 2S). Results
show that the concentration of 4-OHT in media is
approximately 2−4 times higher than those of prodrugs 4−6.
While it is also possible that the boron prodrugs may have their
own antiestrogenic activities, our experimental data suggest that
the prodrugs were more efficiently uptaken by the cancer cells.
Finally, to confirm that the boron prodrugs, like their
resulting active form 4-OHT, exert the growth inhibitory effects
on breast cancer cells through the estrogen receptor expressed
in both MCF-7 and T47D, we tested the in vitro activity of the
prodrugs in an ER negative breast cancer cell line, MDA-MB-
231. Results (Supporting Information, Figure 3S) show that at
10−7 M, tamoxifen and 4-OHT both had minimal effect on cell
growth with greater than 95% survival ratio. The prodrugs 4−6
showed no inhibition of the growth of MDA-MB-231 cells
while appearing to stimulate growth to various degrees. In
contrast, the boron prodrugs all inhibited the growth of MCF-7
cells by over 60%. These data suggest that the inhibitory effect
of boron prodrugs on breast cancer cells is ER dependent.
In summary, we have synthesized three 4-OHT prodrugs by
linking a cleavable aryl carbon−boron bond to the tamoxifen
moiety. The utility of such prodrugs is based on the premise
that they can be converted rapidly to the active form of the
antiestrogen under favorable oxidative conditions in breast
Table 1. IC50 Values of Prodrugs in MCF-7 and T47D Cells
IC (μM)
50
drug
tamoxifen
MCF-7
T47D
0.794
1.13
4-OHtamoxifen
0.0291
0.148
0.210
0.144
0.260
0.228
boron prodrug (4)
boron prodrug (5)
boron prodrug (6)
0.00626
0.0420
concentration of 4-OHT in MCF-7 cells was observed at 0.029
μM, nearly 30 times more potent than that of tamoxifen (0.79
μM). In comparison, the boron prodrug 4 exhibited an IC50
concentration of 0.15 μM, about five times higher than 4-OHT
but five times lower than tamoxifen. The other two prodrugs, 5
and 6, had IC50 values of 0.0063 and 0.042 μM, respectively,
again comparable or more active than 4-OHT (0.029 μM).
To determine if the prodrugs undergo oxidative cleavage by
intracellular hydrogen peroxide present at elevated concen-
tration levels in the breast cancer cells, we analyzed the cell
culture media for concentrations of the prodrugs and the active
form of tamoxifen, 4-OHT. Using HPLC coupled to a linear
trap mass spectrometer, we were able to separate, identify, and
quantify the prodrugs and its active product, 4-OHT. As shown
in the total ion chromatogram (TIC) in Figure 3A, the boronic
acid prodrug of 4-OHT (6) was observed at 17.3 min, while the
desired active drug form, 4-OHT, eluted at 17.6 min. The
relative peak areas were measured at 30.4 (prodrug 6) and
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ACS Medicinal Chemistry Letters
Letter
Figure 3. Relative concentrations of prodrugs and their common oxidative product, 4-OHT, as determined by LC-MS/MS after incubation with (A)
MCF-7 cells and (B) T47D cells.
Funding
cancer cells with elevated levels of hydrogen peroxide. The cell
survival assay showed that the prodrugs were equally or more
effective in inhibiting the growth of MCF-7 and T47D breast
cancer cells, as compared to 4-OHT. Analysis of the prodrugs
and 4-OHT concentrations in the cell culture media suggests
that inhibition of the ER expressing breast cancer cells by the
prodrugs may be attributable to their increased uptake by the
cancer cells and efficient conversion into the active form of
tamoxifen, 4-OHT. Our study demonstrated the feasibility of
using boron chemistry as a prodrug strategy for 4-OHT. These
4-OHT prodrugs may significantly improve response to
antiestrogen therapy in patients with pharmacogenetic
variations or drug interactions that affect the activity of
CYP2D6. Further studies of the anticancer mechanism by
boron-based 4-OHT prodrugs are in progress.
This work was supported by a NIH RCMI program through
Grant 5G12RR026260-03, the Louisiana Cancer Research
Consortium (LCRC), Department of Agriculture Grant 58-
6435-7-019, and Office of Naval Research Grant N00014-99-1-
0763.
Notes
The authors declare no competing financial interest.
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AUTHOR INFORMATION
Corresponding Author
*Tel: 504-520-7824. E-mail: szheng@xula.edu (S.Z.). Tel: 504-
520-5076. E-mail: gwang@xula.edu (G.W.).
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