Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives

Article abstract of DOI:10.1016/j.bmcl.2017.07.029

Novel N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives were designed, synthesized and their chemical structures were confirmed by ¹H NMR, ¹³C NMR and Mass spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including K562, Colo-205 and MDA-MB 231 by MTT assay. The screening results showed that five compounds (16b, 16d, 16i, 16p and 16q) exhibited potent cytotoxic activities with IC₅₀ values between 20 and 40 μM. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.

Full text of DOI:10.1016/j.bmcl.2017.07.029

Accepted Manuscript
Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiaze-
pin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl Derivatives
Mura Reddy Gudisela, N. Srinivasu, Chaitanya Mulakayala, Praveen Bommu,
M.V. Basaveswara Rao, Naveen Mulakayala
PII:
S0960-894X(17)30726-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.07.029
BMCL 25142
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 May 2017
5 July 2017
10 July 2017
Please cite this article as: Gudisela, M.R., Srinivasu, N., Mulakayala, C., Bommu, P., Rao, M.V.B., Mulakayala,
N., Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-
phenylpropan-2-yl Derivatives, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/
j.bmcl.2017.07.029
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Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]
thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenyl propan-2-yl Derivatives
Mura Reddy Gudisela, N. Srinivasu, Praveen Bommu,
Leave this area blank for abstract info.
Chaitanya Mulakayala, MV Basaveswara Rao, Naveen Mulakayala

Bioorganic & Medicinal Chemistry Letters
Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-
11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl Derivatives
Mura Reddy Gudisela,a N. Srinivasu,a Chaitanya Mulakayala,b Praveen Bommu,c M.V. Basaveswara Rao,
d Naveen Mulakayala e*
aDepartment of Chemistry, VFSTR, Vadlamudi, Guntur, 522213, India.
bDepartment of Biosciences, Sri Satya Sai Institute of Higher Learning, Anantapuram -515001, India.
c PS3 Laboratories LLC, Hyderabad -500072, India.
d Department of Chemistry, Krishna University, Machilipatnam – 521 00, India
e Clearsynth Labs Ltd, IDA Mallapur, Nacharam, Hyderabad-500076, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Novel
N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl
1
derivatives were designed, synthesized and their chemical structures were confirmed by H
NMR, C NMR and Mass spectra. The anticancer activities of the newly synthesized
13
Accepted
compounds were evaluated in vitro against three human cancer cell lines including HCT-116,
Available online
Hun7 and SW620 by MTT assay. The screening results showed that five compounds (
,
,
,
and ) exhibited potent cytotoxic activities with IC50 values between 20-40 μM.
Keywords:
dibenzo[b,f][1,4]thiazepin
Synthesis
Anticancer activity
Sirtuins
Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of
action of these molecules.
2009 Elsevier Ltd. All rights reserved.
Sunitinib
1. Introduction
anti-cancer,
antibacterial,
antifungal,
analgesic,
anti-
inflammatory, antiviral, anthelmintic, antipyretic and antiulcer
properties.5-13 The 1,5-benzothiazepine based drugs in clinical
applications against psychotic disorders were shown in Figure 1.
One of the fast growing diseases in the world was Cancer.
Cancer stood in the top 5 of the diseases which causes severe
health problems leading to death. As per WHO Cancer increases
rapidly to 15 million causes by 2020 worldwide. Now a days
researcher were extremely focusing in the develop new leads for
curing cancer.1
Recently many researchers were focused in the development
of new chemical entities (NCEs) which are having biological
importance. Many of the heterocyclic cores i.e. Indole,
Imidazole, triazole, benzimidazole and their fused compounds are
widely studied because of their significant biological activities.2
On the other hand benzothiazepine derivatives were considered
as lead molecules for different biological targets.2-4 Since
Dibenzothiazepines are considerably less exposed core compared
with other heterocyclic motifs which contains nitrogen and
sulphur with eminent biological activities in central nervous
system.
From the literature it was evident that some of the active
pharmaceutical ingredients (API) contains 1,5-benzothiazepine
scaffolds as core molecule. Benzodiazepines and their analogues
exhibit various biological activity such as anti-anxiety,
anticonvulsant, anti HIV-1, anticoagulant, calcium channel
blockers, cholecystokinin antagonists, antiobesity, anti-epileptic,
Fig-1: Representative pharmacologically active dibenzothiazepines

After observing the biological importance of benzothiazepine
core in various API Molecules, we were encouraged to use
benzothiazepine as biologically active core from a well-known
API i.e Quetiapine. Then we diversified the core using an amino
acid linker to make a new target which can be used to test against
different biological activity. For this we have chosen 11-
(piperazin-1-yl)dibenzo [b,f][1,4]thiazepine core
A
from
Quetiapine and extended the chain using an amino acid such as
phenylalanine to improve the biological activity of the compound
B.
Reagents and conditions: a) Thiophenol, NaOH in MeOH,
78%; b) Fe powder, NH4Cl in water, 86%; c) PhOCOCl /
Na2CO3 solution in Toluene, 62%; d) PPA, 100-105oC, 8 h, 54%;
e) POCl3, Toluene, N,N,Dimethyl aniline, 92%; f) Piperazine,
toluene, IPA-HCl, 87%.
Fig. 2: Design of novel anticancer molecules B based on Quetiapine core
After the synthesis of 11-(piperazin-1-yl)dibenzo [b,f][1,4]
thiazepine 11 we wish to couple an amino acid linkage to
improve the solubility and binding capacity. For this we have
identified phenyl alanine as a suitable amino acid for this
reaction. Initially compound 11 was made free base using 1N
NaOH solution followed by coupling it with boc protected
phenyl alanine using TBTU to get compound 13. Initially the
coupling reaction was tried with EDC and HOBT in DMF.
But the reaction didn’t go for completion. Then we tried using
HATU and observed the presence of starting material after 12
h also. Finally the coupling went smoothly using TBTU and
DIPEA in DMF at room temperature within 12 h. Compound
13 was deprotected using aq HCl to get compound 14 which
on coupling with different carboxylic acids 15 to get the
desired product 16 in good yields (Scheme-2).
Quetiapine (Seroquel®, Astra Zeneca) (2, Fig. 1) belongs to
the dibenzothiazepine class is a dopamine antagonist and has
been used as a second generation atypical antipsychotic drug. It
has proven efficacy against schizophrenia14 and has shown anti-
emetic effects in the treatment of refractory nausea and vomiting
in advanced cancer.15
Our long standing interest in the identification of new anti-
cancer molecules16 prompted us to explore the use of
benzothiazepine core for the design of new anticancer inhibitors.
Thus, we hypothesized by picking up of active structural core of
A and incorporating the amino acid side chain using coupling
reaction followed by the amidation of terminal amine using
different carboxylic acids leads to a new class of compound B
(Fig. 2) which may be explored to test against anticancer activity.
After designing the molecules we were interested in the synthesis
of compound B and subsequent evaluation of their anticancer
properties in vitro.
Having the optimized reaction condition for the preparation of
compound 16 in hand we then examined the generality and scope
of this methodology. Thus a variety of aromatic/aliphatic/
heteroaryl/heterocyclic carboxylic acids (15) were reacted with
compound 14 using TBTU, DIPEA in DMF at room temperature
for 12 h produced the target compound 16 in good to excellent
yields and results are presented in Table 2. The reaction
proceeded well when aromatic carboxylic acids were used
compared with aliphatic carboxylic acids. In all these cases and
the substituents like Cl, I, CN, -CH3, -CH2CH3, and –OCHF2
present in the aromatic carboxylic acids (15) were well tolerated.
The reaction appeared to be clean and the desired product 16 was
isolated in good yield in each case.
Herein we report the synthesis and anticancer evaluation of N-
(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-
phenylpropan-2-yl derivatives starting from 11-(piperazin-1-
yl)dibenzo[b,f][1,4] thiazepine. For the synthesis of N-(1-(4-
(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-
phenylpropan-2-yl derivatives first we want to synthesize the
key starting material
11-(piperazin-1-yl)dibenzo[b,f][1,4]
thiazepine 11.
The
intermediate
11-(piperazin-1-yl)dibenzo[b,f][1,4]
thiazepine 11 was synthesized by following a known literature
procedure.17 Compound 5 which is commercially available
starting material was treated with thiophenol in presence of
NaOH, in MeOH to obtain compound 6. Compound 6 was
reduced with a mixture of iron powder and ammonium chloride
to yield the corresponding amine 7 which further converted into
their corresponding 2-(phenylthio) phenyl carbamate 8 with
phenyl chloroformate. Compound 8 on cyclization with poly
phosphoric acid (PPA) gives dibenzo [b, f] (1, 4) thiazepine- 11-
(10H)-one 9.18 Compound 9 on reaction with POCl3 to get chloro
compound 10 which is on reaction with piperazine yields
compound 11 (Scheme 1).
Scheme-2: Synthetic scheme of N-(1-(4-(dibenzo[b,f][1,4]
thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl
derivatives
Scheme-1: Synthetic scheme of 11-(piperazin-1-yl)dibenzo
[b,f][1,4]thiazepine

4
76
15d
16d
5
85
15e
Reagents and conditions: a) 1N NaOH, EtOAC, 97%; b) Boc
protected Phenyl alanine, TBTU, DIPEA, DMF, RT, 12 h, 76%;
c) Aq HCl, Dioxane, RT, 12 h, 89%; d) carboxylic acid 15,
TBTU, DIPEA, DMF, RT, 12 h.After optimizing the reaction
conditions we underwent to synthesize several derivatives
including aliphatic, aromatic and heterocyclic.
16e
6
7
8
88
86
75
Table 1: Synthesis of N-(1-(4-(dibenzo[b,f][1,4] thiazepin-11-
yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives 16a
15f
Entry
1
Acid
Product
Yield
88
15a
16f
15g
16a
2
82
16g
15b
15h
16b
3
79
16h
9
84
15c
16c
15i
16i

10
76
16o
16
76
15j
15p
16j
16p
11
72
17
81
15k
16q
16k
12
79
16q
18
89
15l
15r
16l
13
76
15m
16r
a isolated yield
All the synthesized compounds were characterized by 1H
NMR, 13C NMR and Mass spectra. Several carboxylic acids were
used to synthesize compound 16. Several alkyl, aryl, heteroaryl
and heterocyclic carboxylic acids 15 were participated well in the
reaction affording the corresponding products in good yields
(Table 1, entries 1–18). The use of substituted aryl carboxylic
acids participated well in the reation yielding the desired product
in excellent yield (Table 1, entries 1,5-7, 9, 18). Alkyl, heteo aryl
and heterocyclic carboxylic acids employed were also well
tolerated (Table 1, entries 4, 8, 11, 13-16).
16m
14
82
15n
After synthesizing different molecules, we were interested to
check the anticancer properties of the synthesized compounds in
vitro. Since 11-(piperazin-1-yl)dibenzo [b,f][1,4]thiazepine
derivatives19 were active against anticancer activity in the
literature, we were interested to test anticancer properties of the
synthesized derivatives in vitro. We tested the synthesized
compounds against a number of cancer cell lines for example,
human chronic myeloid leukemia cells (K562), human colon
carcinoma cells (Colo-205), and human breast cancer cell line
(MDA-MB 231) for their anti-proliferative properties in vitro.
16n
15
85
15o
Table 2 : In vitro cytotoxic activity of the synthesized
compounds 16a–r against leukemia cells, K562, humancolon
carcinoma cells, Colo-205, human breast cancer cell line
(MDA-Mb 231)

IC50 a,b (M)
11-yl)piperazin-1-yl)-1-oxo-3-phenyl
(difluoromethoxy)benzamide was found to be promising
(IC50~12–39M, Table 2).
propan-2-yl)-4-
Compound
K562
26
14
28
16
24
35
21
39
16
36
32
27
19
20
35
17
12
27
14
Colo-205 MDA-MB 231
16a
16b
16c
28
17
32
15
29
40
25
34
12
45
33
16
28
36
24
14
10
16
8
55
34
56
38
61
37
44
54
34
59
52
49
64
48
52
37
39
59
32
To understand the mechanism of action of the few of the
synthesised derivatives, we were tested for their inhibitory
potential against sirtuins. Being considered as important targets
for cancer therapeutics sirtuins (class III NAD-dependent
deacetylases) are shown to upregulated in various types of
cancer.21 Inhibition of sirtuins allows re-expression of silenced
tumor suppressor genes, leading to reduced growth of cancer
cells.
16d
16e
16f
16g
16h
16i
The Sirt1 activity of test compounds was determined using
Sirt1 fluorescence activity assay using a known inhibitor of Sirt1
as a reference compound suramin. At the concentration of 10 M
compounds 16b. 16d, 16i, 16p and 16q showed 44%, 62, 54%,
51% and 71% inhibition, respectively, when compared to
suramin’s 79% inhibition indicating that the anticancer properties
of these molecules are possibly due to their sirtuin inhibiting
properties.
16j
16k
16l
16m
16n
16o
16p
16q
16r
To know the nature of interactions between the active
compounds and the hSir1 protein a molecular docking study was
performed using a representative compound 16q (Fig. 3). The
three dimensional model of hSirt1 (NCBI gi no: 7555471, 200–
500 amino acid residues) was developed by homology modeling
using the templates PDB: 2HJH and PDB: 1J8F in the
Modeller9v6. Six amino acid residues, Ser 67, Cys 68, Phe 112,
Gln 161, Asn 217 and Pro 219 were found to play important roles
in this interaction with the overall binding energy of 8.6
Kcal/mol indicating that molecule 16q interacts well with this
protein. Docking interactions showed that 16q showed docking
with binding pocket formed of Val 64, Ser 67, Cys 68, Ile 70,
Phe 112, Ala 113, Tyr 117, Leu 150, Gln 152, Gln 161, Gly 164,
Ala 167, Cys 180, Val 212, Phe 213, Asn 217. Leu 218 and Pro
219. Among all this six residues were involved in hydrogen
bonding interactions Ser 67, Cys 68, Phe 112, Gln 161, Asn 217
and Pro 219 with ligand and remaining were showed non
covalent interactions.
Sunitinib
aIC50 represent the concentration of compound that causes a
50% growth inhibition to untreated cells using the MTT assay.
bData represent the mean values of three independent
determinations.
The anticancer activity of all the synthesized compounds were
tested at different concentrations in a MTT (3-(4,5-dimethyl
thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and the
IC50 values obtained for each compounds are summarized in
Table 2. Sunitinib, a receptor protein-tyrosine kinase inhibitor, a
member of-carboline family of compounds showed cytotoxicity
against Colo-205 and K562 cell lines20 was used as a reference
compound. While most of these compounds showed inhibition of
leukemia cell growth as reflected by their IC50 values, however
16b. 16d, 16i, 16m, 16n, 16p and 16q showed good results (IC50
<20M, Table 2). All these compounds are derivatives of
substitued alkyl carboamides, substituted aryl carbomides and
also heterocyclic carboamides indicating that the N-(1-(4-
(dibenzo[b,f][1,4]
phenylpropan-2-yl framework played an important role in the
inhibition of leukemia cell growth. Interestingly, except
thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-
compounds 16c, 16f, 16h, 16j, 16k and 16n all other compounds
(IC50 <30M, Table 2) were found to be active against colon
carcinoma cells and compounds 16b, 16d, 16f, 16i, 16p, and 16q
(IC50 <40M, Table 2) showed good activities against breast
cancer cells. After observing the above results all these active
compounds are derivatives of aryl/heterocyclic substituted
carboxylic acids indicating that the aryl/ heterocyclic substituted
amides containing N-(1-(4-(dibenzo[b,f][1,4] thiazepin-11-
yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl framework played
a key role in the inhibition of leukemia cell growth. Overall,
compound 16q possessing a N-(1-(4-(dibenzo[b,f][1,4]thiazepin-
Fig 3: Docking of compound 16q into the active site of hSirt1.

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In summary,
a
series of novel
N-(1-(4-(dibenzo
[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-
2-yl derivatives were designed and explored against anticancer
activity. These derivatives were synthesized in high yields via the
amidation of different carboxylic acids with 2-amino-1-(4-
(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phenyl
propan-1-one using TBTU. Most of the synthesized compounds
were evaluated for their anti-proliferative properties in vitro
against three cancer cell lines, Promising anticancer properties
were shown by a number of compounds. In addition in vitro
studies showed that inhibition of sirtuins could be the possible
mechanism of action and was supported by a docking study.
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suggests
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2-yl framework could be an attractive template for the
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Acknowledgements
M R G and N S are thankful to the management of Vignan's
Foundation for Science, Technology & Research University.
MRG thankful to PS3 labs for providing necessary support.