Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription

Article abstract of DOI:10.1016/j.bmcl.2016.12.078

cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15. 666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demonstrated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation accessible in 666-15 is critically important.

Full text of DOI:10.1016/j.bmcl.2016.12.078

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of regioisomers of 666-15
as inhibitors of CREB-mediated gene transcription
Fuchun Xie a,1, Bingbing X. Li a,1, Xiangshu Xiao a,b,c,
⇑
a
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
Knight Cardiovascular Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated
in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule
inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing
cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15.
Received 3 November 2016
Revised 28 December 2016
Accepted 28 December 2016
Available online xxxx
666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity
without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe
the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demon-
strated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical
for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation acces-
sible in 666-15 is critically important.
Keywords:
CREB
Cancer
6
66-15
Regioisomer
Bioactive conformation
Ó 2016 Elsevier Ltd. All rights reserved.
Cancer is a heterogeneous group of complex and multigenic
disease. Numerous oncogenes and tumor suppressor genes have
been identified to directly contribute to the development and
initiated by recruiting CREB-binding protein (CBP) and its closely
related paralog p300 and other proteins in the transcription
9
,10
machinery to the gene promoters.
Similar to other phosphory-
1
maintenance of transformed cellular states. During the past three
lated proteins, CREB phosphorylation is dynamic and tightly
regulated to ensure its transcription activity is tightly coupled to
the environment cues. Three protein phosphatases have been
identified to be able to dephosphorylate CREB to inactivate its tran-
decades, various types of targeted therapies (e.g. kinase inhibitors
and hormonal therapies) have been developed for various types of
2
cancers. However, most of these therapies face a formidable chal-
11
lenge of rapidly developed drug-resistance through up-regulating
alternative cellular survival pathways.3 Therefore, identifying
and targeting novel regulators of cancer development and
maintenance have been the subject of intense cancer biology and
chemical biology studies including those from the Cancer Genome
scription activity. These are protein phosphatase 1 (PP1), protein
,4
12
13
phosphatase 2A and phosphatase and tensin homolog (PTEN).
Mechanistically, the kinases that can phosphorylate and activate
CREB are proto-oncogenes that are often overactivated in tumor
cells while those phosphatases that can dephosphorylate CREB
are known as tumor suppressors that are often inactivated or
deleted in tumor cells. As a consequence, CREB is often overacti-
vated in cancer cells to drive tumor development and maintenance.
Indeed, this overactivation has been observed in numerous cancer
5
Atlas (TCGA) project. Among these novel targets are transcription
factors that are deregulated in various cancer cells.6
Cyclic-AMP response element (CRE) binding protein (CREB) is a
7
stimulus-activated transcription factor. CREB normally resides in
8
9,14–16
the nucleus in an inactive state. Upon phosphorylation at Ser133
tissues.
by various kinases including protein kinase A (PKA), protein kinase
B (PKB/Akt), p90 ribosomal S6 kinase (pp90 ) and Ras-activated
mitogen activated protein kinases, CREB’s transcription activity is
Because CREB sits at a signaling hub of multiple oncogenic
signaling pathways and is overactivated in many cancer tissues,
CREB has been recognized as an important oncology drug targets.9
We and others have been investigating small molecule inhibitors
RSK
9
,17–25
of CREB as potential cancer therapeutics.
Among these,
⇑
Corresponding author at: Program in Chemical Biology, Department of Phys-
iology and Pharmacology, Oregon Health & Science University, 3181 SW Sam
Jackson Park Rd, Portland, OR 97239, USA.
6
66-15 (Fig. 1) represents the most potent inhibitor of CREB-
mediated gene transcription with efficacious in vitro and in vivo
anti-breast cancer activity without harming normal cellular
E-mail address: xiaoxi@ohsu.edu (X. Xiao).
These authors made equal contribution to this paper.
1
20,26
homeostasis.
Preliminary structure-activity relationship (SAR)
http://dx.doi.org/10.1016/j.bmcl.2016.12.078
0
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Xie F., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.078

2
F. Xie et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
HO
studies identified the following (Fig. 1): (1) the naphthyl rings A
Cl
O
O
and B are critical for activity; (2) minor alterations of the two car-
bon linkers C and D can dramatically affect the CREB inhibition
activity; and (3) the primary amino group is essential for optimal
N
H
O
O
1
4
2
0
N
H
2
3
CREB inhibition. In this communication, we describe our investi-
gation on the SAR of region B with different regioisomers by vary-
ing one substitution at a time on naphthalene ring B. By keeping
the carboxamide substitution at position 2, two isomers 1a and
A
.HCl
D
2
H N
B
C
6
66-15
1
1
b (Fig. 2) were designed by moving the alkoxy group to position
and 4, respectively. On the other hand, by maintaining the alkoxy
Fig. 1. Chemical structure of 666-15.
group at position 3, isomers 1c and 1d (Fig. 2) were designed
through changing the carboxamide substitution to position 4 and
1, respectively.
HO
HO
Cl
Cl
O
O
O
The general strategy to the synthesis of regioisomers 1a-1d is
N
H
20
N
H
O
similar to our previously described synthesis of 666-15. The key
O
O
NH
2
1
1
O
is to synthesize building blocks 4a-4d (Scheme 1) and then couple
them to the same amine 8 (Scheme 2). The carboxylic acids 4a-4d
were synthesized according to Scheme 1. Compounds 2a-2c are
either commercially available or could be conveniently synthesized
from their corresponding acids by acid-catalyzed esterification
N
H
2
3
N
H
2
3
.HCl
.HCl
4
1
a
4
1b
H
2
N
O
HO
Cl
17
HO
reaction as described before. The Boc-protected aminopropyl side
Cl
4
O
O
O
O
chain was either installed by Mitsunobu reaction (for 3a) with an
alcohol or O-alkylation reaction with a bromide (for 3b and 3c) to
give ethers 3a-3c, which were further saponified by LiOH or NaOH
to generate required acids 4a-4c. A more elaborate scheme to
prepare 4d was needed (Scheme 1). The acid 7 was synthesized
N
H
N
H
O
O
1
N
N
H
2
4
H
3
1
3
O
.HCl
H
2
N
O
.HCl
2
H
N
2
2
7
by a reported procedure
1
with slight modifications. Briefly,
/H SO followed
1
c
1
d
,8-naphthoic anhydride was nitrated by HNO
3
2
4
by mercury-mediated decarboxylation of the resulting anhydride
(Pesci reaction) and acidic hydrolysis to give the mono-acid 6.
Fig. 2. Designed regioisomers 1a-1d by changing the substitution pattern on
naphthalene ring B of 666-15.
HO
NHBoc
P, DEAD
THF, rt, 6 h
LiOH
O
O
NHBoc
O
O
NHBoc
O
OH
Ph
3
2
THF/MeOH/H O
MeO
EtO
MeO
HO
rt, 12 h, 100%
8
2%
2
a
3a
4
a
O
O
O
LiOH
THF/MeOH/H O
2
Br
5
NHBoc
2 3
K CO , DMF
EtO
HO
rt, 12 h, 80%
0 oC, 12 h, 95%
BocHN
O
BocHN
O
OH
b
2
3b
4b
Br
NHBoc
3
, DMF
O
O
O
O
NaOH
K
2
CO
MeO
MeOH/H
O
HO
MeO
2
5
0 oC, 12 h, 61%
reflux, 12 h
BocHN
O
BocHN
HO
5
6%
2
c
3c
4c
O
O
O
i) HNO
3
/H
2
SO
4
i) SOCl2 then MeOH
O
O
8
8%
87%
HO
HO
ii) HgO, NaOH, H
reflux, 5 d; then
N HCl, reflux, 4 h
2
O
ii) Fe, NH Cl
4
EtOH/H O, 95%
2
OH
NO
2
5
iii) H
2
SO
62%
4 2
, NaNO
5
8%
6
7
5
i) HO
NHBoc
P, DEAD
THF, rt, 12 h
9%
O
O
i) MeOH, H
2
SO
4
Ph
3
reflux, 6 h, 90% MeO
HO
8
ii) LiOH
THF/MeOH/H
rt, 12 h, 93%
OH
BocHN
O
2
O
2
d
4d
Scheme 1. Synthesis of building blocks 4a-4d.
Please cite this article in press as: Xie F., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.078

F. Xie et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
HO
Cl
O
N
4a-d
+
H
NH
2
HCl
O
8
EDCI,HOBt
CH
2
Cl
2
or DMF
HO
HO
Cl
Cl
O
O
O
O
N
H
N
H
O
O
O
NHBoc
1
1
N
H
2
3
N
H
2
3
4
9
a
4
9b
BocHN
O
(50%)
(51%)
HO
HO
Cl
Cl
O
O
O
N
H
N
H
O
O
O
O
1
4
N
H
N
2
H
3
4
1
3
BocHN
2
BocHN
9d
(33%)
O
9
c
(69%)
2N HCl/Et
2
O
MeOH-CHCl
3
1
a (81%); 1b (91%); 1c (91%); 1d (63%)
Scheme 2. Synthesis of regioisomers 1a-1d.
Direct reduction of the nitro group in 6 with iron resulted in only
low yield of the corresponding aniline. However, reduction of the
methyl ester of 6 gave 95% yield of the corresponding aniline, which
was further converted into naphthol 7 through a diazonium salt and
concomitant hydrolysis of the methyl ester. The requisite building
block 4d was prepared by Mitsunobu reaction followed by saponi-
Table 1
Biological activities of regioisomers 1a-d.
Compd
IC50
(l
M)a
GI50 (l
M)b
CREB inhibition
MDA-MB-231
MDA-MB-468
666-15
0.081 ± 0.04
23.98 ± 16.02
17.25 ± 3.90
18.94 ± 5.35
19.03 ± 10.96
0.073 ± 0.04
3.12 ± 0.13
2.68 ± 0.06
4.31 ± 0.73
3.82 ± 0.95
0.046 ± 0.04
1.93 ± 0.06
0.55 ± 0.16
1.70 ± 0.03
1.65 ± 0.53
1a
fication (Scheme 1). With all the building blocks 4a-4d in hand, they
were each coupled to amine 820 with EDCI/HOBt as the coupling
1b
1
1
c
d
reagents to give Boc-protected amides 9a-9d (Scheme 2). Final
removal of Boc protecting group from 9a-9d provided desired com-
a
pounds 1a-1d in good to excellent yields.28
The CREB inhibition refers to the activity of the compounds in the CREB tran-
scription reporter assay in HEK 293T cells. The cells were transfected with a renilla
luciferase reporter under the control of three copies of CRE. Then the cells were
treated with increasing concentrations of different compounds for 30 min followed
With the designed regioisomers 1a-1d in hand, we first evalu-
ated their potency in inhibiting CREB-mediated gene transcription
in living HEK 293T cells using our previously described CREB tran-
by stimulation with forskolin (10 lM) for 6 h before luciferase measurement. The
scription reporter assay.29 This reporter assay involved transfecting
IC50 was calculated through non-linear regression analysis of the dose-response
curves with normalized luciferase activity. The normalization was carried out
through the cell lysate protein concentration in individual samples.
HEK 293T cells with a reporter construct, which expresses renilla
luciferase with three tandem copies of CRE sequence in the
promoter region to report CREB’s transcription activity in living
cells. Then the transfected cells were treated with increasing con-
b
The GI50 was from the MTT assay after incubating the drugs with the indicated
cells for 72 h. The activities of 666-15 are included for comparison purpose and are
from Ref. 20.
centrations of different compounds (50 nM to 50
lM) followed by
stimulation with forskolin (10 M) to stimulate CREB phosphoryla-
l
tion and transcription activity. The relative luciferase activity was
used to report CREB’s transcription activity. We have previously
shown that 666-15 had an IC50 of ꢀ80 nM in this transcription
mers 1a-1d also adopt such a compact conformation at their global
energy minimum, a conformational search was performed for com-
pounds 1a-1d using the same protocol as we did before.20 Similar
to 666-15, the positively charged ammonium group in 1a-1d all
forms a hydrogen-bond with the carbonyl oxygen (Fig. 3B–E).
2
0
reporter assay. As shown in Table 1, moving the aminopropoxy
group from position
3.98 ± 16.02 M) or 4 (1b, IC50 = 17.25 ± 3.90
nificantly decreased CREB inhibition activity. Similarly, relocation
of the carboxamide from position 2 in 666-15 to 4 (1c, IC50
8.94 ± 5.35 M) or 1 (1d, IC50 = 19.03 ± 10.96 M) also dramati-
3
in 666-15 to position
1 (1a, IC50 =
2
l
lM) resulted in sig-
The naphthalene ring B in 1a-1d also forms
with the chlorophenyl ring, effectively forming
p
-stacking interaction
compact
a
=
conformation similar to what is observed in 666-15. However, as
the substitution pattern in the naphthalene B changes, the relative
orientation of the two-carbon linker D and naphthalene ring B vary
greatly compared to 666-15 (Fig. 3F). These results suggest that the
unique arrangement of different groups in 666-15 forming the
potential bioactive pharmacophore can not be altered without
losing bioactivity.
1
l
l
cally attenuated the inhibitory activity. These results show that
the substitution pattern on naphthalene ring B is absolutely critical
in determining the CREB inhibition activity. Previously, we have
shown that 666-15 adopted a compact conformation at its global
energy minimum (see also Fig. 3A).20 To investigate if the regioiso-
Please cite this article in press as: Xie F., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.078

4
F. Xie et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 3. Global conformational energy minima of 666-15 (A), 1a (B), 1b (C), 1c (D) and 1d (E). The yellow dotted line indicates a hydrogen bond and the corresponding
interatomic distance is shown in Å. In panel (F), the conformations of 1a-1d are superimposed onto that of 666-15.
We also assessed the cancer cell growth inhibition activities of
a-1d in breast cancer MDA-MB-231 and MDA-MB-468 cells. As
4. Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH. Cancer Lett. 2007;256:
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shown in Table 1, all four regioisomers showed significantly less
potent activity than 666-15. These results are consistent with their
reduced potency in inhibiting CREB-mediated gene transcription.
However, distinct difference exists for 1a-1d between the two
different assays. The growth inhibitory activity of 1a-1d in these
breast cancer cell lines is in general higher than their CREB
inhibition potency. This difference suggests that 1a-1d may be
endowed with activities independent of CREB inhibition in the
cells. This possibility is likely because the conformations accessible
for 1a-1d can be dramatically different from those of 666-15 due to
the differential substitution pattern in naphthalene ring B.
In this study, we designed, synthesized and evaluated regioiso-
mers of 666-15, a potent CREB inhibitor with robust anti-breast
cancer efficacy without harming normal body homeostasis. Our
results showed that the alkoxy and carboxamide substitution
pattern in naphthalene ring B of 666-15 is absolutely critical for
maintaining potent CREB inhibition and anti-proliferative activity
in breast cancer cells. These results reinforced that the unique
bioactive conformation accessible only in 666-15 is the key for
its potent activity. Further studies of SAR of 666-15 should keep
this unique pharmacophore intact.
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Acknowledgement
NMR (400 MHz, DMSO-d
.73 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.15-8.10 (m, 1 H), 8.06 (d, J = 8.0 Hz, 1 H),
8.00-7.95 (m, 4 H),7.94 (d, J = 8.5 Hz, 1 H), 7.74 (s, 1 H), 7.70 (d, J = 8.3 Hz, 1 H),
.64-7.56 (m, 4 H), 7.46 (td, J = 7.5, 1.2 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 6.89
dd, J = 8.7, 2.3 Hz, 1 H), 4.54 (t, J = 6.2 Hz, 1 H), 4.12 (t, J = 6.3 Hz, 2 H), 4.00 (q,
J = 6.1 Hz, 2 H), 4.03 (t, J = 5.5 Hz, 2 H), 3.04-2.94 (m, 2 H), 2.12 (quintet,
J = 6.9 Hz, 2 H); 13C NMR (100 MHz, DMSO-d
) d 167.35, 162.58, 153.63, 152.92,
48.38, 136.12, 135.61, 133.60, 129.40, 129.02, 128.46, 128.19, 128.09, 127.86,
6
) d11.02 (s, 1 H), 10.52 (s, 1 H), 8.75 (t, J = 5.5 Hz, 1 H),
8
This work was made possible through financial supports
provided by the United States National Institutes of Health
7
(
(
R01GM087305) and OHSU Office of Technology Transfer and
Business Development.
6
1
1
1
27.53, 127.24, 126.97, 126.69, 126.31, 125.29, 124.96, 124.16, 123.01, 123.00,
References
21.49, 119.19, 114.93, 108.84, 73.30, 67.93, 38.91, 36.91, 28.16. 1b: a white
1
solid, m.p. 198-199 °C. H NMR (400 MHz, DMSO-d
6
) d 11.03 (s, 1 H), 10.57 (s, 1
1.
2.
3.
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Higgins MJ, Baselga J. J Clin Invest. 2011;121:3797–3803.
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H), 8.90 (t, J = 5.6 Hz, 1 H), 8.74 (s, 1 H), 8.42 (d, J = 8.7 Hz, 1 H), 8.20-8.16 (m, 1
H), 8.05 (d, J = 8.2 Hz, 1 H), 8.03-7.96 (m, 4 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.87-7.83
(m, 1 H), 7.74 (s, 1 H), 7.62-7.56 (m, 3 H), 7.45 (td, J = 7.5, 1.1 Hz, 1 H), 7.33 (s, 1
Please cite this article in press as: Xie F., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.078

F. Xie et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
H), 6.97 (d, J = 2.6 Hz, 1 H), 6.88 (d, J = 8.9, 2.6 Hz, 1 H), 4.55 (t, J = 6.3 Hz, 2 H),
.24 (t, J = 5.9 Hz, 2 H), 3.96 (q, J = 5.5 Hz, 2 H), 3.07 (t, J = 6.6 Hz, 2 H), 2.18
124.42, 124.35, 122.95, 122.33, 121.42, 119.18, 115.46, 114.90, 108.69, 67.93,
1
4
66.62, 39.02, 36.83, 27.34. 1d:
a
white solid. m.p. 145-146 °C.
H NMR
1
3
(
quintet, J = 6.9 Hz, 2 H); C NMR (100 MHz, DMSO-d
6
) d 167.31, 162.61,
(400 MHz, DMSO-d ) d 11.00 (s, 1H), 10.59 (s, 1H), 8.85 (t, J = 5.3 Hz, 1H), 8.74
6
1
1
1
1
54.27, 153.62, 148.28, 136.12, 133.60, 133.48, 132.47, 129.38, 129.07, 129.00,
28.17, 127.66, 127.54, 127.45, 126.92, 126.68, 126.50, 125.26, 123.05, 122.02,
(s, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.11 – 8.03 (m, 2H), 8.00 (brs, 3H), 7.92 (d,
J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 –
7.42 (m, 2H), 7.39 (d, J = 2.3 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 2.5 Hz,
1H), 6.99 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.7, 2.3 Hz, 1H), 4.57 (t, J = 5.7 Hz, 2H),
4.15 (t, J = 6.0 Hz, 2H), 3.99 (q, J = 5.3 Hz, 2H), 2.97 (q, J = 6.2 Hz, 2H), 2.06
21.60, 120.31, 119.26, 14.90, 108.87, 103.75, 67.86, 65.52, 38.98, 36.88, 27.35.
1
c: a white solid. m.p. 180-181 °C. H NMR (400 MHz, DMSO-d
6
) d 10.99 (s, 1
H), 10.53 (s, 1 H), 8.76 (t, J = 5.5 Hz, 1 H), 8.74 (s, 1 H), 8.44 (d, J = 8.4 Hz, 1 H),
.06 (d, J = 8.4 Hz, 1 H), 7.98-7.93 (m, 2 H), 7.91-7.82 (m, 4 H), 7.72 (s, 1 H), 7.67
d, J = 8.6 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.49-7.43 (m, 2 H), 7.32 (t, J = 7.5 Hz,
H), 7.17 (t, J = 7.8 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1 H), 6.90 (dd, J = 8.9, 2.3 Hz, 1
H), 4.58 (t, J = 5.9 Hz, 2 H), 4.23 (t, J = 5.9 Hz, 2 H), 4.02 (q, J = 5.5 Hz, 2 H), 2.96
8
(
1
(quintet, J = 6.0 Hz, 2H); 13C NMR (101 MHz, DMSO-d
6
) d 168.70, 162.56,
155.36, 153.78, 148.30, 136.57, 136.13, 135.02, 133.62, 129.42, 129.04, 128.14,
127.51, 127.45, 127.15, 126.90, 126.73, 125.80, 125.72, 125.24, 124.67, 122.98,
121.47, 119.22, 118.41, 114.84, 109.18, 108.68, 67.94, 65.33, 39.13, 36.73,
27.21.
1
3
(
q, J = 5.9 Hz, 2 H), 1.98 (quintet, J = 6.5 Hz, 2 H); C NMR (100 MHz, DMSO-d
d 167.45, 162.54, 153.75, 152.46, 148.34, 136.14, 133.63, 131.16, 130.64,
29.41, 129.02, 128.73, 128.30, 128.15, 127.44, 127.32, 127.00, 126.74, 125.26,
6
)
29. Li BX, Xiao X. ChemBioChem. 2009;10:2721–2724.
1
Please cite this article in press as: Xie F., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.078