Antiproliferative activities and SAR studies of substituted anthraquinones and 1,4-naphthoquinones

Article abstract of DOI:10.1016/j.bmcl.2013.09.098

STAT3 is constitutively active in a large variety of cancers. The search for STAT3 inhibitors led to the discoveries of LLLs 3 and 12, which are substituted anthraquinones. LLL12 is an extremely potent compound that exhibits high levels of antiproliferative activity. Herein the synthesis and evaluation of compounds containing either an anthraquinone or 1,4-naphthoquinone moiety are reported. Analogs were evaluated in several cancer cell lines. Interestingly, it was found that the anthraquinones did not follow the same trends as the 1,4-naphthoquinones in regards to potency. LLL12, which contains a sulfonamide at position 1, was found to be the most potent of the anthraquinones. In contrast, the methyl ketone and methyl ester derivatives (LLLs 3.1 and 5.1) were found to be the most potent of the 1,4-naphthoquinones. Selected 1,4-naphthoquinones were also evaluated in the STAT3 fluorescence polarization assay in order to evaluate their abilities to bind to the STAT3 SH2 domain. They were found to have similar affinities, and their activities suggest that STAT3 is one of their molecular targets.

Full text of DOI:10.1016/j.bmcl.2013.09.098

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6864–6867
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antiproliferative activities and SAR studies of substituted
anthraquinones and 1,4-naphthoquinones
⇑
Deepak Bhasin , Jonathan P. Etter , Somsundaram N. Chettiar, May Mok, Pui-Kai Li
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Rm 338 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210-1291,
United States
a r t i c l e i n f o
a b s t r a c t
Article history:
STAT3 is constitutively active in a large variety of cancers. The search for STAT3 inhibitors led to the
discoveries of LLLs 3 and 12, which are substituted anthraquinones. LLL12 is an extremely potent
compound that exhibits high levels of antiproliferative activity. Herein the synthesis and evaluation of
compounds containing either an anthraquinone or 1,4-naphthoquinone moiety are reported. Analogs
were evaluated in several cancer cell lines. Interestingly, it was found that the anthraquinones did not
follow the same trends as the 1,4-naphthoquinones in regards to potency. LLL12, which contains a
sulfonamide at position 1, was found to be the most potent of the anthraquinones. In contrast, the methyl
ketone and methyl ester derivatives (LLLs 3.1 and 5.1) were found to be the most potent of the 1,
4-naphthoquinones. Selected 1,4-naphthoquinones were also evaluated in the STAT3 fluorescence
polarization assay in order to evaluate their abilities to bind to the STAT3 SH2 domain. They were found
to have similar affinities, and their activities suggest that STAT3 is one of their molecular targets.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 21 August 2013
Revised 25 September 2013
Accepted 30 September 2013
Available online 9 October 2013
Keywords:
STAT3 inhibitor
LLL3
LLL12
Signal transducer and activator of transcription 3 (STAT3) has
been implicated in numerous solid tumors and hematological
malignancies.1 It is activated in response to a number of cytokines
and hormones.2–5 Following the phosphorylation of a specific tyro-
sine residue, the STATs undergo homo- and/or hetero-dimerization
via the reciprocal interactions of the phosphotyrosine residues and
Src homology 2 (SH2) domains, translocate to the nucleus, and
activate the transcription of target genes.6,7 STAT3 is activated
led to the discovery of LLL12, which is a potent small molecule
inhibitor of STAT3 (Fig. 1).12 Over the past few years, LLL12 has
been extensively studied.13–23
Recently, the antiproliferative activities of substituted 1,4-
naphthoquinones were reported.24 Some of the most potent com-
pounds contained a sulfonamide substituent (PDs 13–15),24 which
is also present in LLL12. The compounds were found to inhibit the
STAT3 fluorescence polarization (FP) signal.24 The Ki values of PD9
upon phosphorylation at Tyr705 7
a STAT1–STAT3 heterodimer.8
.
It signals as a homodimer or as
and PD18 were derived to be 13.3 0.6 and 18.2 4.8 lM, respec-
tively (Table 1).24 Herein the synthesis and biological evaluation of
additional anthraquinone- and 1,4-naphthoquinone-containing
analogs that target STAT3 is reported.
There currently are not any STAT3 inhibitors on the market, but
strategies to target STAT3 have been directed toward its amino-
terminal, DNA-binding and SH2 domains. The SH2 domain has re-
ceived considerable attention, as it is involved in both receptor
binding and dimerization. STA-21 was the first reported small mol-
ecule inhibitor of the STAT3 SH2 domain.9 However, STA-21 is
structurally complex, making the synthesis of STA-21 analogs for
structure–activity relationship (SAR) studies difficult. As a result,
the structure was simplified in the design and synthesis of the ini-
tial LLL compounds.10 The anthraquinone moiety was retained,
while the fourth ring was discarded.10 The most potent analog
identified was LLL3, which was subsequently evaluated in glioblas-
toma.11 LLL3 was shown to inhibit STAT3 DNA-binding in both
U373 and MDA-MB-231 cells.11 Further structural modifications
The majority of the compounds contain the anthraquinone moi-
ety (Table 2). They were substituted at the 1, 2, 5 and 8 positions.
Position 1 was substituted with ester, amide, acid or sulfonamide
groups. Positions 5 and 8 were substituted with hydroxyl or ether
groups. This allowed for the capacity for hydrogen bond
O
OH
O
OH
O
O
OH
O
O
S
O O
O
O
NH2
LLL12
⇑
Corresponding author. Tel.: +1 (614) 688 0253; fax: +1 (614) 292 2435.
E-mail address: li.27@osu.edu (P.-K. Li).
STA-21
LLL3
These authors contributed equally to this work.
Figure 1. Structures of STA-21, LLL3 and LLL12.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.09.098

D. Bhasin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6864–6867
6865
Table 1
Table 3
Structures of previously reported 1,4-naphthoquinones
Structures of substituted 1,4-naphthoquinones
O
O
R2
R3
R1
O
R1
O
R1
R2
R3
Compound
R1
Compound
LLL3.1
LLL5.1
LLL6.1
LLL12.1
COCH3
PD9
OH
S(CH2)2OH
H
H
H
H
COOCH3
CONH2
SO2NH2
PD13
PD14
PD15
PD18
SO2NH2
SO2NH2
SO2NH2
OH
NHPh(3-OCH3)
NHPh
NHPh(4-OCH3)
S(CH2)2OH
CH3
stitution reactions between LLL3 or LLL3a with propyl iodide or
benzyl bromide (Scheme 3). Treatment of naphthalene-1-sulfonyl
chloride with methylamine hydrochloride produced N-methyl-
naphthalene-1-sulfonamide (Scheme 4). Oxidation and subsequent
addition using a reaction protocol that was similar to the synthetic
procedure for LLL6 produced LLL14. DCC coupling of b-alanine
ethyl ester hydrochloride with anthraquinone-2-carboxylic acid
and subsequent hydrolysis of the ester intermediate yielded LLL15.
The antiproliferative and FP assays were carried out according
to previously reported procedures.24 The analogs were evaluated
in breast (MDA-MB-231), prostate (DU-145 and PC-3) and colon
acceptance/donation at the two positions and its effects on activity
to be studied. With the exception of LLL15, which was substituted
at the 2 position, all of the anthraquinones were substituted at
either the 5 or 8 position, but not at both. The majority of the
1,4-naphthoquinones were generated as intermediates in the syn-
theses of the anthraquinones (Table 3). They are less structurally
complex than the corresponding anthraquinones. Since they lack
the third ring, the contributions to activity of only the substituted
1,4-naphthoquinone portions were able to be evaluated.
The synthetic procedures for several of the LLL compounds have
been previously reported (LLLs 3, 3a, 3.1, 12 and 12.1).10,12 Many of
the novel analogs presented here were synthesized in a similar
fashion. The condensation of methyl crotonate with bis(dimethyl-
amino)methoxymethane yielded tert-aminodienylester, according
to an established procedure (Scheme 1).25 The combination of
the intermediate with juglone produced LLL5 as the single isomer.
The ester was then hydrolyzed to produce LLL4. LLL5.1 was synthe-
sized by esterification and subsequent oxidation of 1-naphthoic
acid. The oxidation of commercially available 1-naphthalene car-
boxamide produced LLL6.1, which underwent a regioselective
Diels–Alder type reaction with 3-hydroxy-2-pyrone to produce
LLL6 (Scheme 2). DCC coupling of LLL4 with b-alanine ethyl ester
hydrochloride or glycine methyl ester hydrochloride yielded LLL7
ester or LLL9 ester, respectively, which upon hydrolysis produced
LLLs 7 and 9. LLLs 11, 11a, 13 and 13a were produced by the sub-
(HT-29) cancer cell lines at concentrations of 0.5, 5 and 50 lM.
The relative potencies of the compounds were fairly consistent
across all cell lines (Supplementary Fig. S1–S4). However, there
were a few exceptions. At a concentration of 50
10 were more active in DU-145 and HT-29 cells. At a concentration
of 5 M, this trend was also observed for LLL14. LLLs 13 and 12.1
lM, LLLs 9 and
l
were less active in HT-29 cells. Some compounds, including LLLs
4, 7, 7 ester, 11, 11a and 15, showed minimal activity in all cell
lines at all tested concentrations. In contrast, with the exception
of LLL12.1 in HT-29 cells, all of the substituted 1,4-naphthoqui-
nones (LLLs 3.1, 5.1, 6.1 and 12.1) nearly abrogated cell growth
at a concentration of 50
pound in all cell lines.
lM. LLL12 was by far the most active com-
The IC50 values of the analogs were also determined in HT-29
and DU-145 cell lines (Tables 4 and 5). The derived values were
in line with the observed activities at 0.5, 5 and 50 lM. LLL12
was the most active compound in both cell lines, achieving IC50
values of <200 nM. LLL14 was the next most potent compound of
those that featured an anthraquinone moiety. However, the meth-
ylation of the sulfonamide was clearly not advantageous, as LLL14
was roughly 40 to 60 times less potent than LLL12. Interestingly,
Table 2
Structures of substituted anthraquinones
R2
5
O
2
R4
1
8
R1
O
R3
O
N
N
Compound R1
R2
R3
R4
O
O
LLL3
LLL3a
LLL4
LLL5
LLL6
LLL7
COCH3
COCH3
COOH
COOCH3
CONH2
CONH(CH2)2COOH
OH
H
OH
OH
OH
OH
H
OH
H
H
H
H
H
H
H
H
H
H
N
O
O
reflux, 4 h
Juglone,
xylene, rt, 2 h
LLL7 ester CONH(CH2)2COOCH2CH3 OH
H
H
LLL9
CONHCH2COOH
OH
OH
H
H
H
H
O
OH
O
OH
LiOH.H2O
LLL9 ester CONHCH2COOCH3
LLL11
LLL11a
LLL12
LLL13
LLL13a
LLL14
LLL15
COCH3
COCH3
SO2NH2
COCH3
COCH3
SO2NHCH3
H
OC3H7
H
OH
OCH2Ph
H
H
OC3H7
H
H
OCH2Ph
H
H
H
H
H
H
H
H
H2O, MeOH
rt, 48 h
O
O
O
O
HO
O
LLL4
LLL5
OH
H
CONH(CH2)2COOH
Scheme 1. Syntheses of LLLs 4 and 5.

6866
D. Bhasin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6864–6867
O
O
O
OH
OH
O
O
CrO3, 50% AcOH
AcOH, rt, o/n
O
triethylamine
CHCl3, -15 °C, o/n
H2N
O
H2N
O
H2N
O
LLL6
LLL6.1
Scheme 2. Syntheses of LLLs 6 and 6.1.
The activities of the four 1,4-naphthoquinones did not follow
the same pattern (Table 4). The major difference was that the
methyl ketone and methyl ester derivatives were the most active
(LLLs 3.1 and 5.1) of the 1,4-naphthoquinone series, while the sul-
fonamide-containing LLL12.1 was among the least active. Also,
LLL6 was more active than LLL5, while LLL5.1 was more active than
LLL6.1. LLL6.1, which contains a primary amide substituent, had
similar activities to LLL12.1. Interestingly, it also had similar activ-
ities to LLL6. In contrast, LLL3.1 was roughly twice as potent as
LLL3, and LLL5.1 was four to seven times as potent as LLL5. The
1,4-naphthoquinone derivatives of LLLs 4, 7, 7 ester, 9, 9 ester, 14
and 15 were not evaluated. LLLs 9 and 14 were the only com-
pounds of these that demonstrated noteworthy antiproliferative
activities. However, it would be interesting to see if the corre-
sponding 1,4-naphthoquinones would also lack activity, as identi-
cal trends were not observed for the analogs of the two series.
Since LLL12 is known to inhibit STAT3 phosphorylation, it was
evaluated in the FP assay along with LLLs 3.1, 5.1 and 12.1. As pre-
dicted, LLL12 inhibited the FP signal considerably. However, the
lone presence of LLL12 in the FP buffer also resulted in high and
anomalous FP readings, making it difficult to quantify its ability
to inhibit the FP signal. LLLs 3.1, 5.1 and 12.1 all inhibited the FP
signal to a similar extent (Fig. 2). This data demonstrates that the
evaluated 1,4-naphthoquinone derivatives are able to bind to the
STAT3 SH2 domain. However, their comparable activities make it
difficult to determine the SARs of these compounds in regards to
STAT3 inhibition. The calculated clogP values for these compounds
are all 1.9 or below (ChemDraw Ultra 12.0). As a result, solubility in
the aqueous FP buffer was not expected to be a limiting factor in
the evaluation of these 1,4-napthoquinones. That proved to be
the case.
O
O
OH
O
O
OR
I
OR
Br
silver oxide, rt, o/n
H3C
O
H3C
O
LLL3
LLL11 or LLL13
Scheme 3. Syntheses of LLLs 11, 11a, 13 and 13a. The syntheses of LLLs 11 and 13
are shown as examples.
LLLs 3 and 3a exhibited similar potencies in both cell lines. This
suggests that there is flexibility as to the position of the hydroxyl
substituent, at least as it concerns the methyl ketone analogs.
However, it is apparent that having a hydrogen bond donor is more
advantageous than substituting with ether substituents, as LLLs 11,
11a, 13 and 13a exhibited no antiproliferative activity. A lack of
activity was observed regardless of whether the ether was at the
5 or 8 position, or the identity of the substituent was a propyl ether
or benzyl ether. In comparing LLLs 3-6, 7, 7 ester, 9, 9 ester and 12,
it was found that besides the sulfonamide moiety, the methyl ke-
tone substituent at position 1 (LLL3) was the most active. Substitu-
tion with a carboxylic acid at this position (LLL4) resulted in a total
loss of activity. The presence of a methyl ester at this location was
not advantageous, as LLL5 was approximately four times less active
than LLL3. Amide substitution was somewhat tolerated; LLL6 was
roughly half as potent as LLL3. Extending the amide of LLL6 with
an acetic acid substituent did not appear to alter activity (LLL9),
while extension with methyl acetate resulted in a threefold reduc-
tion in activity (LLL9 ester). The presence of larger substituents re-
sulted in total losses of activity (LLLs 7 and 7 ester).
O
OH
CH3NH2.HCl
triethylamine
DCM, 0 °C, rt, 4 h
SO2
O
SO2Cl
SO2
N
H
N
H
LLL14
Scheme 4. Synthesis of LLL14.
Table 4
Antiproliferative activities (IC50 values in lM) of the anthraquinones and corresponding 1,4-naphthoquinones in DU-145 and HT-29 cells
R1
Anthraquinones
DU-145
1,4-Naphthoquinones
Compound
HT-29
Compound
LLL3.1
DU-145
6.4 0.5
HT-29
COCH3
LLL3
LLL3a
LLL5
LLL6
LLL12
11.5 1.8
10.2 2.4
45.7 7.5
17.7 2.2
0.19 0.01
10.4 0.8
8.5 0.6
37.3 1.9
24.7 1.2
0.11 0.01
4.2 0.8
COOCH3
CONH2
SO2NH2
LLL5.1
LLL6.1
LLL12.1
11.3 1.6
17.6 4.4
18.1 0.5
5.8 1.4
15.6 3.5
18.7 2.9
Cells were plated at 2500 cells/well and allowed to attach overnight. They were then treated with varying concentrations of compounds for 72 h. Antiproliferative activities
were determined through use of the MTS assay (Promega). Compounds were tested at least twice in triplicate.24

D. Bhasin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6864–6867
6867
Table 5
to bind to the STAT3 SH2 domain. However, it is possible that
the smaller sizes of the 1,4-naphthoquinone analogs results in
them binding to the SH2 domain with a slightly different geome-
try. This could make the sulfonamide-containing compounds no
longer the tightest binding of the monosubstituted 1,4-naphtho-
quinones. Still, the 1,4-naphthoquinone derivatives could be acting
through additional mechanisms of action (MOAs). Their resulting
effects on cellular signaling in cancer cell lines will need to be
determined to make further conclusions. Additional studies will
hopefully result in the discovery of more potent analogs and fur-
ther elucidation of their MOA(s).
Antiproliferative activities (IC50 values in
DU-145 and HT-29 cells
lM) of the remaining anthraquinones in
Compound
DU-145
HT-29
LLL4
LLL7
LLL7 ester
LLL9
LLL9 ester
LLL11
LLL11a
LLL13
LLL13a
LLL14
>100
>100
>100
>100
>100
>100
19.5 2.3
70.8 6.5
>100
20.6 1.4
67.6 9.1
>100
>100
>100
>100
>100
>100
>100
8.7 1.6
>100
6.5 1.4
>100
Acknowledgment
LLL15
Compounds were evaluated as it is described in Table 4.24
This research was supported in part by the Department of
Defense Prostate Cancer Research Program Award # W81XWH-
08-1-0555
100
90
80
70
60
50
40
30
20
10
0
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.bmcl.2013.09.098.
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Figure 2. Inhibitory activities of LLL compounds (500
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The differences in the structural characteristics that led to activ-
ity in the anthraquinone and 1,4-naphthoquinone series are
intriguing. These data suggest that the analogs of the two series
may be binding to biological targets through different interactions.
None of the analogs exhibited potencies similar to those of LLL12.
However, LLLs 3.1 and 5.1 were found to be relatively potent,
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