Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach

Article abstract of DOI:10.1021/acscombsci.6b00010

An efficient discovery strategy by combining diversity-oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460_TaxR (EC₅₀ < 1.0 μM), which exhibits much less toxicity toward normal cells (EC₅₀ > 100 μM against normal human fibroblasts). The most active hits also exhibited drug-like properties suitable for further preclinical research. This redeployment of antidepressing compounds for anticancer applications provides promising future prospects for treating drug-resistant tumors with fewer side effects.

Full text of DOI:10.1021/acscombsci.6b00010

Research Article
pubs.acs.org/acscombsci
Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-
Resistant Cancer Agents by Combining Diversity-Oriented Synthesis
and Converging Screening Approach
Jinbao Xiang,† Zhuoqi Zhang,† Yan Mu,‡ Xianxiu Xu,† Sigen Guo,† Yongjin Liu,‡ Daniel P. Russo,§
Hao Zhu,§,# Bing Yan,*,‡ and Xu Bai*,†
†The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical Sciences, and The College of
Chemistry, Jilin University, Changchun, Jilin 130021, P. R. China
‡School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, P. R. China
§The Rutgers Center for Computational and Integrative Biology, Camden, New Jersey 08102, United States
#Department of Chemistry, Rutgers University, Camden, New Jersey 08102, United States
S
* Supporting Information
ABSTRACT: An efficient discovery strategy by combining diversity-
oriented synthesis and converging cellular screening is described. By a
three-round screening process, we identified novel tricyclic pyrido[2,3-
b][1,4]benzothiazepines showing potent inhibitory activity against
paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 μM), which exhibits
much less toxicity toward normal cells (EC50 > 100 μM against normal
human fibroblasts). The most active hits also exhibited drug-like
properties suitable for further preclinical research. This redeployment
of antidepressing compounds for anticancer applications provides
promising future prospects for treating drug-resistant tumors with
fewer side effects.
KEYWORDS: tricyclic thiazepine, H460TaxR, selective cytotoxicity, antidepressing, redeployment
Tricyclic compounds have been widely used for antipsychotic
drugs like tianeptine and anti-HIV or antiplatelet agents.12−14
These tricyclic derivatives were also reported to exhibit
anticancer activity.15,16 In the last few years, we have developed
synthetic methodologies to access a large library of novel
diversified tricyclic derivatives.17 To minimize the effort
required and maximize the information obtained, we have
developed a strategy to apply converging screening to the
discovery of anticancer agents from a library of heterocyclic
compounds. As depicted in Figure 1, we initially selected 28
leukemia cell lines and 245 representative compounds from 23
novel heterocyclic scaffolds for initial screening. Then, EC50
values of compounds with anticancer activities were deter-
mined. Anticancer activities of compounds with the optimal
scaffold against other solid tumor cell lines and normal human
fibroblasts (NHFB) were investigated. After the second round
of screening, the most active scaffold of compounds was paired
with its target cancer cell line of interest. On the basis of the
information obtained, a new round of design and synthesis was
conducted, and the compounds were evaluated for their
anticancer activity against the most active cell line and
INTRODUCTION
■
Non-small cell lung cancer (NSCLC) is the most frequent
subtype (accounting for over 80%) of lung cancer, which
remains the leading cause of cancer death worldwide.1 Despite
improvements in multidisciplinary therapeutic approaches, the
five-year survival rate for NSCLC patients is still disappoint-
ingly low at less than 20%.1−3 Multidrug resistance (MDR) has
been a huge barrier for cancer therapy and is responsible for
treatment failure in 90% of patients with metastatic cancer,
including NSCLC.4−9 Novel anticancer agents that can
overcome MDR are urgently needed. Therefore, a strategy
combining efficient screening and chemical synthesis methods
may facilitate the development of new agents and be of great
interest in the field.
High-throughput screening (HTS) of chemical libraries,
which may contain hundreds of thousands to millions of
compounds, has become a routine effort for the discovery of
tool compounds and drug leads.10 However, this method
requires robotics and other sophisticated equipment to increase
the scale and speed of assays. It still takes a highly specialized
and expensive screening lab to run an HTS operation.
Converging screening conducts screening in an iterative fashion
instead of attempting to find all the desirable hits in a single
round of screening. This approach has demonstrated its
efficiency and flexibility in several lead identification projects.11
Received: January 19, 2016
Revised: March 19, 2016
© XXXX American Chemical Society
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Supporting Information for the results of the other cell lines
and compounds). As shown in Table 1, our data demonstrated
that, among the 23 compounds tested, 5 compounds (1a, 1h,
1i, 1q, and 1w) exhibited antiproliferative activity with EC50
values below 100 μM. It was noteworthy that sulfone 1w (n =
2) showed a 23-fold increase of cytotoxicity compared with
sulfide analogue 1a, indicating that the sulfone moiety is pivotal
in the anticancer activity.
Second Round of Screening. We evaluated the most
active compound 1w from first round screening in several solid
tumor cancers, including lung (the most common male cancer,
causing 19.4% of all deaths from cancer), breast (the most
common female cancer, 25.2% of cancers diagnosed among
women), and colon cancer.21 Using CellTiter-Glo luminescent
cell viability assay (Promega, Madison, WI, USA), compound
1w was further evaluated for its anticancer activity against
HT29 (human colon adenocarcinoma cells), MCF-7/ADR
(adriamycin-resistant human breast cancer cells), H460
(human non-small cell lung carcinoma cells), and H460TaxR
(paclitaxel-resistant human non-small cell lung carcinoma cells)
cell lines (Table 2). Compound 1w displayed the most potent
inhibitory activity with EC50 values below 0.5 μM against H460
(entry 4) and H460TaxR (entry 5). It was noteworthy that
compound 1w showed less toxicity to normal human fibroblasts
NHFB (EC50 > 100 μM, entry 6). Taken together, compound
1w exhibits potent anticancer activities in both leukemia and
solid tumor cancers.
Figure 1. Discovery strategy.
NHFB. With this iterative process, we have discovered novel
anticancer agents with potent activity and low in vitro toxicity
(EC50 > 100 μM against NHFB). Herein, details of the
development of this strategy and its application in the discovery
of novel tricyclic thiazepine derivatives17e (representative
compound 1w, Figure 2) as anti-MDR cancer agents are
reported.
Third Round of Screening and SAR Studies. Synthesis
of Tricyclic Thiazepine Analogues. A series of novel tricyclic
thiazepine derivatives were designed and synthesized using
compound 1w as a lead (Figure 4). Compound 1w contains
three appendage-diversification sites, namely, (1) the pyridine
ring (A ring), (2) the benzene ring (C ring, R1), and (3) the p-
MePh group (R2). Our design sought to explore these sites by
altering the pyridine ring (A ring) or introducing other diverse
groups (R1 and R2) to investigate the SAR. The key synthesis
procedures included a cyclization reaction and sulfur oxidation
(see Supporting Information for details). Pyridine analogues
2−15, pyrazine analogues 20−22, and benzene analogue 27
were prepared according to our previously reported method.17e
Other analogues were synthesized following a similar procedure
to that of quetiapine22 and additional sulfur oxidation.
SAR of Tricyclic Thiazepines. On the basis of the results in
the second round screening, we decided to focus on evaluation
of the cancer cell lines with the most potent activity. All newly
synthesized compounds were examined for their antiprolifer-
ative activity against H460 and H460TaxR, which is highly
resistant to several anticancer drugs, including paclitaxel
(PTX).23−25 The EC50 values of the 27 tricyclic thiazepine
derivatives are presented in Table 3. As a result, compounds
1w, 9−12, and 14 exhibited an EC50 < 1.0 μM against both
H460TaxR and H460 cell lines while exhibiting minimal toxicity
RESULTS AND DISCUSSION
■
Selection of Representative Compounds. Our small-
molecule compound library was designed and built with
privileged structures to cover diverse chemical spaces.17,18 For
ensuring the selection of high quality compounds, 23 scaffolds
were selected based on novelty, availability, and empirical
relevance to the current drugs (Figure 3). These scaffolds were
classified into 6 monocyclic scaffolds, 5 bicyclic scaffolds, 11
tricyclic scaffolds, and 1 tetracyclic scaffold. All of these
scaffolds can be accessed in large numbers from commercially
available building blocks through parallel synthesis. Eventually,
245 representative compounds were selected based on
structural diversity.
First Round of Screening. Leukemia is the most
commonly diagnosed cancer in children, accounting for
approximately 35% of all pediatric cancers. Over 80% of
childhood leukemia cases are acute leukemia.19 Acute leukemia
can potentially cause death within a few weeks without timely
and appropriate treatment.20 In this work, we first selected 28
acute leukemia cell lines for screening (see Supporting
Information for details).
All 245 selected compounds were evaluated against leukemia
cell lines. The screening results of a tricyclic thiazepine scaffold
XIV against the OP-1 cell line are summarized in Table 1 (see
Figure 2. Structures of representative tricyclic thiazepine drugs and compound 1w.
B
DOI: 10.1021/acscombsci.6b00010
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Figure 3. Structures of selected scaffolds.
Table 1. Cytotoxic Activity of the Active Scaffold XIV against
Representative Cell Line OP-1
Table 2. Cytotoxic Activity of Compound 1w on Selected
Cancer Cell Lines and Normal Human Fibroblasts (NHFB)
cpd
X
Y
R1
R2
n
EC50 (μM)
entry
cell line
OP-1
EC50 (μM)
1a
1b
1c
1d
1e
1f
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
H
4-MePh
4-MeOPh
4-FPh
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
2
46.1
>100
>100
>100
>100
>100
>100
92.0
1
2
3
4
5
6
2.0
0.9
N
H
HT29
N
H
MCF-7/ADR
H460
1.2
N
H
4-NO2Ph
3-NO2Ph
4-F-3-NO2Ph
furan-2-yl
Ph
0.4
N
H
H460TaxR
NHFB
0.3
N
H
>100
1g
1h
1i
N
H
N
Me
Me
Me
Me
Me
Me
MeO
MeO
MeO
Cl
N
4-MePh
4-MeOPh
4-FPh
46.6
1j
N
>100
>100
>100
>100
>100
>100
>100
48.9
1k
1l
N
N
3-NO2Ph
furan-2-yl
Ph
1m
1n
1o
1p
1q
1r
N
N
N
3-MePh
4-FPh
N
N
4-MePh
3-NO2Ph
Ph
Figure 4. Design of tricyclic thiazepine analogues based on compound
1w.
N
Cl
>100
>100
>100
>100
>100
2.0
1s
1t
CH
CH
CH
N
Me
Me
Me
H
N
4-MeOPh
4-NO2Ph
Ph
4-MePh group of R2 was more active than those with other
substituents, including Ph (2), 4-MeOPh (5), 4-FPh (6), 4-
CF3Ph (7), and furan-2-yl (8). The position of methyl in the
MePh group was crucial because compounds 3 and 4 with 2-
and 3-methyl, respectively, were both inactive in NSCLC cells.
Clothiapine analogue 18 was not substantially toxic to either
H460TaxR or H460 cells. In contrast, the substituents including
1u
1v
1w
N
CH
CH
N
H
4-MePh
toward normal human fibroblasts (NHFB, EC50 > 100 μM)
(Figure 5). The substituent on thiazepine (B ring) played an
important role in cancer cell inhibition. Compound 1w with a
C
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a
Table 3. Cytotoxicity of 27 Tricyclic Thiazepine Derivatives against H460TaxR, H460, and NHFB Cell Lines
EC50 (μM)
cpd
X
Y
Z
R1
R2
H460TaxR
H460
NHFB
1w
2
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
H
H
H
H
H
H
H
H
4-MePh
Ph
0.3 0.1
>100
0.4 0.2
>100
>100
ND
N
N
N
N
N
N
N
N
N
N
N
N
N
CH
N
N
N
N
N
N
N
N
N
N
N
CH
3
2-MePh
3-MePh
>100
>100
ND
4
>100
>100
ND
5
4-MeOPh
4-FPh
>100
>100
ND
6
95.7 10.3
95.3 10.7
>100
>100
ND
7
4-CF3Ph
furan-2-yl
4-MePh
>100
ND
8
>100
ND
9
8-F
0.7 1.1
0.7 0.1
0.8 1.2
0.5 0.2
4.1 0.4
0.6 0.3
2.9 0.1
>100
0.4 0.3
0.4 0.2
0.8 1.1
0.5 0.1
3.0 0.1
0.5 0.1
3.6 2.8
>100
>100
>100
>100
>100
ND
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
PTX
8-Cl
4-MePh
8-Me
4-MePh
8-MeO
4-MePh
9-MeO
4-MePh
10-MeO
4-MePh
>100
ND
H
H
H
H
H
H
H
H
H
H
H
H
H
4-MePh
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
HO
ND
O(CH2CH2)2N
CH3N(CH2CH2)2N
(CH3)2N
Ph
>100
>100
ND
>100
>100
ND
>100
>100
ND
>100
>100
ND
N
4-FPh
>100
>100
ND
N
4-MePh
3.6 0.6
>100
3.3 1.0
>100
ND
N
HO
ND
N
O(CH2CH2)2(O)N
(CH3)2N(CH2)2O
(CH3)2N
4-MePh
>100
>100
ND
N
>100
>100
ND
N
>100
>100
ND
CH
1.5 1.8
0.8 0.4
4.3 1.5
0.006 0.002
ND
0.05 0.03
a
The results represent the mean SD with n = 3. ND means not determined.
F (9), Cl (10), Me (11), and MeO (12) on the benzene ring
(C ring) were less important for the compounds’ cytoselective
toxicity. Replacement of the pyridine ring (A ring) with other
six-membered aromatic rings was also investigated. The
corresponding pyridine analogue 15 (Y = N), pyrazine
analogue 22, and benzene analogue 27 were all less potent
than compound 1w (X = N). The positive control paclitaxel
(PTX) has an EC50 value of 0.8 μM against the H460TaxR cell
line but exhibited high toxicity toward NHFB (EC50 = 0.05
μM).
We also examined images of NSCLC and NHFB cells treated
with compound 1w or DMSO. As shown in Figure S3, after
treatment with DMSO, both NSCLC cell lines proliferated fast.
After compound 1w treatment, NSCLC cells detached, became
rounded, and did not grow. However, a growth inhibitory effect
of compound 1w on NHFB cells was not observed. These
results demonstrate that these tricyclic thiazepine derivatives
exhibited selective cytotoxicity against H460TaxR and H460
cells.
drug-like properties. The parallel artificial membrane perme-
ability assay (PAMPA) was performed to evaluate cell
permeability of the active compounds. Generally, compounds
with a Pe > 200 cm/s are classified as highly permeable.
Representative compound 1w exhibited excellent potential cell
permeability (1081 cm/s). The Caco-2 assay was performed in
the P-gp-overexpressed Caco-2 cell line, which reflects the oral
absorption ability of the compounds in vivo. With an efflux
ratio greater than 2, a compound may be a substrate of P-gp
efflux and subject to poor oral absorption. Compound 1w had
an efflux ratio of 0.6, which predicted a good oral absorption for
this compound. The half-lives (T1/2) of the six hits in human
liver microsomes were determined, which reflect their
metabolic stability in vivo. A very small T1/2 suggests quick
metabolism in the liver, and a very long T1/2 (>24 h) may cause
cumulative toxicity. Compound 1w exhibited a suitable T1/2
value (5.2 h) in human liver microsomes, suggesting its
excellent metabolic stability in the liver. The high T1/2 value
(>50 h) of compound 1w in human plasma indicated a good
stability in vivo. Plasma protein binding influences the
distribution of drugs into body tissues, and compounds with
high plasma protein binding (>99%) are limited in terms of the
amount of free compound that are available to act on the
targeted tissue. Taken together, as indicated in Table 4,
Profiling the Most Active Compounds. To evaluate the
potential for the active hits to be applied in vivo, we performed
a panel of absorption, distribution, metabolism, and excretion
(ADME) in vitro assays to simulate their in vivo behaviors. As
shown in Table 4, six selected hits exhibited overall suitable
D
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00010.
Scaffolds, cytotoxicity assays, cell line images, descrip-
tions of biological assays, and NMR spectra of all of the
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: drbingyan@yahoo.com. Phone: +86-531-88380019.
*E-mail: xbai@jlu.edu.cn. Phone: +86-431-85619260.
Funding
This work was supported by a grant from the National Natural
Science Foundation of China (No. 90713008) and grants from
the Sci-Tech Development Project of Jilin Province in China
(Nos. 20140309010YY and 20106039). Additional support was
provided by Changchun Discovery Sciences, Ltd.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Drs. Guoqing Du and Lei Yang for their assistance in
the early phase of this project.
Figure 5. Dose-dependent cytotoxicity of six hits against H460TaxR
,
H460, and NHFB are shown along with their chemical structures.
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a
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DOI: 10.1021/acscombsci.6b00010
ACS Comb. Sci. XXXX, XXX, XXX−XXX