The expedient synthesis of 1,5-benzothiazepines as a family of cytotoxic drugs

Article abstract of DOI:10.1016/j.bmcl.2007.11.002

The expedient synthesis of 1,5-benzothiazepines using LaY zeolite under stirring condition is reported and synthesized compound screened for cytotoxic activity. The reaction produces the product in relatively low yields and requires a long time when they were performed in various solvents under conventional and microwave irradiation. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions.

Full text of DOI:10.1016/j.bmcl.2007.11.002

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 114–119
The expedient synthesis of 1,5-benzothiazepines
as a family of cytotoxic drugs
Kapil Aryaa,* and Anshu Dandiab
aIndian Oil Corporation Limited, R&D Centre, Faridabad, Haryana 121007, India
bDepartment of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 26 July 2007; revised 12 October 2007; accepted 1 November 2007
Available online 5 November 2007
Abstract—The expedient synthesis of 1,5-benzothiazepines using LaY zeolite under stirring condition is reported and synthesized
compound screened for cytotoxic activity. The reaction produces the product in relatively low yields and requires a long time when
they were performed in various solvents under conventional and microwave irradiation. Thus, the procedure provides a simple and
green synthetic methodology under environmentally friendly conditions.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The versatile chemotherapeutic applications of 1,5-ben-
zothiazepines especially that of diltiazem in the treat-
ment of ailments of the cardiovascular system such as
coronary vasodilation,1 hypertension,2 etc. enthused
great interest in a detailed study of this class of com-
pounds. While carrying out drug design, it was found
that an important number of fluorinated 1,4- and 1,5-
benzodiazepines had been introduced as pharmacologi-
cal and cardiovascular agents, such as fluorodiazepam,
triflubazam, etc. Incorporation of fluorine atoms on
1,5-benzothiazepines or analogous nuclei enhances
pharmacological properties by increasing the solubility
in lipid materials and fat deposits in the body when com-
pared to their non-fluorinated analogs.3 It was also re-
phase transformations is greatly utilized in industry.10
Several organic reactions like alkylation, polymeriza-
tion, cyclization,11 photoreduction,12 or preparation of
nitroalkenes13 occur in gas phase or with reactants
sorbed within zeolite in inert solvent. Recently, several
reports on the use of acidic zeolites (HY) in macrolact-
onization,14 acetalization,15 acetylation,16 and gem-
diacetalization,17 as well as the synthesis and application
of the first organic-functionalized zeolite-beta18
prompted us to investigate the new catalytic possibilities
of Y zeolite.
It has been extensively studied by various workers that
the reaction between a,b-unsaturated carbonyl com-
pounds and 2-aminobenzenethiols takes place in two
steps19,20 involving the previous formation of the Mi-
chael adduct as an intermediate20,21 which readily
undergoes dehydrative cyclization to give 1,5-ben-
zothiazepines. It was observed that the formation of
the intermediate and the final cyclized product is affected
by the reaction conditions,22 catalyst,23 and type of
groups or substituents present24 on the compounds
(Scheme 1).
ported that Cl,4 Me,5 CF3 or a free COOH group7
6
when present on different positions in the 1,5-ben-
zothiazepine nucleus act as potential pharmacophores.
A series of 1,5-benzothiazepines bearing fluorine and
4-fluorophenyl groups have been found to be effective
for treatment of cancer metastasis8 and recently 8-flu-
oro-1,5-benzothiazepine reported from our laboratory
has been found to be a promising anti-AIDS agent in
preliminary screening.9
RE exchanged Y Zeolites are reported as effective cata-
lysts in organic chemistry and their specificity in gas
The use of various zeolite catalysts in organic transfor-
mations is a growing area of interest.25,26 The Na form
of faujasites (Y), a class of zeolite catalysts, is almost
neutral in nature. However, a basic character can be
introduced by increasing the alumina content of the cat-
alyst framework, thereby increasing the population of
counter cations and their radii.27,28 Furthermore, the
Keywords: Zeolite; Microwaves; Benzothiazepines; Catalyst;
Photocytotoxicity.
*
Corresponding author. Tel.: +91 9911317131; fax: +91 129
2294381; e-mail: aryakapil2001@yahoo.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.002

K. Arya, A. Dandia / Bioorg. Med. Chem. Lett. 18 (2008) 114–119
115
COOH
H
COOH
HC
S
CH
X
SH
X
O
C
+
La Y zeolite
neat, stirring
N
NH2
H3C
H3C
F
F
3(a-f)
X=8-OCH3 , 8-CH3 , 8-Cl, 6-Cl, 8-Br, 8-F
1(a-f)
2
Scheme 1.
electrostatic interaction between the metal cation and
the organic guests within the zeolite supercage has been
well studied.29,30 In this context, we have initiated a pro-
gram exploiting the interactions of exchanged rare-earth
cations of the faujasites with the included organic guest
molecules in the supercages. Our main aim is to identify
the conditions in which such an interaction could create
sufficient polarization of the organic guests inside the
supercages to facilitate chemical transformations. In line
with our expectations, when 2-aminobenzenethiols (1a–
f) with a,b-unsaturated ketones (2) were stirred at room
temperature in the presence of LaY zeolite, the 8-substi-
tuted-2-carboxy-2,3-dihydro-1,5-benzothiazepines 3a–f
were produced in 72–94% yield (Scheme 1).
for cytotoxic activities first on a cell line of human tu-
mor HL-60 (human promyelocytic leukemia). Hence,
in an attempt toward a non-traditional approach to
the experimental setup of organic reactions, and our
continuing interest in the synthesis of fluorine contain-
ing biodynamic heterocycles and as an extension of
our work on the reactions of 2-aminobenzenethiols with
a,b-unsaturated ketones and analogous compounds33,9
under solvent-free and ecofriendly conditions, we report
herein, for the first time, the synthesis of title com-
pounds 3a–f under solventless conditions (Scheme 1).
As an initial attempt to find an optimal reaction condi-
tion, a variety of experimental conditions were examined
for title compound 3a by changing catalyst, reaction
medium (MW irradiation, conventional, and stirring),
and temperature (Table 1). It was found that more
acidic LaY34 zeolite is the best choice of catalyst for
the preparation of 2-carboxy-2,3-dihydro-1,5-ben-
zothiazepines compared with CeY, NaY, and HY34 zeo-
lites (Table 1). Since the number and strength of acid site
in zeolite increase with metal cation exchanged in the or-
der of H+ < Na+ < Ce2 + < La3+, the increase in the
yield of 3a according to this order suggests that acid sites
on zeolite work as active sites for this reaction (Table 1).
For checking the catalyst amount’s effect on reaction
conditions, we have tried the reaction taking different
Traditional methods applied for the syntheses of 2-car-
boxy-2,3-dihydro-1,5-benzothiazepines involve the use
of volatile organic solvents under reflux and strong
acids/bases as catalyst, giving low yields due to the
extended reaction time which favors the formation of
the corresponding disulfides.31,32
As part of a program aimed at achieving simple and
environmentally compatible synthetic methodologies in
search of medicinally important heterocycles, we have
investigated the catalytic activity of LaY zeolite for or-
ganic syntheses and synthesized compounds were tested
Table 1. Comparative study of the synthesis of 3a (X = OMe)
Entry
Medium
Reaction conditions
Reaction temperature (ꢁC)
Time (min)
Yieldb (%)
1
2
Ethanol + dry HCl gas
Toluene + TFA
Methanol + gl. AcOH
LaY zeolitea
Reflux
Reflux
Reflux
MW
78
420
720
420
13
12
16
10
12
8
62
46
44
70
68
58
59
54
94
65
56
50
54
72
64
50
120
115
130
138
130
140
125
100
80
3
4
5
Montmorillonite KSF
CeY zeolitea
MW
MW
6
7
Neat + DMF (2–3 drops)
PTSA
MW
MW
8
9
LaY zeolitea
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
Stirring
10
11
12
13
14
15
16
LaY zeolitea
14
17
18
15
12
15
18
LaY zeolitea
60
rt
LaY zeolitea
Montmorillonite KSF
CeY zeolitea
NaY zeolitea
HY zeolitea
100
100
100
100
a 100 wt % catalyst used that means that the substrate:catalyst weight ratio is 1:1.
b Isolated yields.

116
K. Arya, A. Dandia / Bioorg. Med. Chem. Lett. 18 (2008) 114–119
Table 4. Synthesis of 8-substituted-2-carboxy-4-(4-fluoro-2-methyl-
phenyl)-2,3-dihydro-1,5-benzothiazepines (3a–f) using LaY zeolitea
amount’s of catalyst and found that 2 g of catalyst is
sufficient for activation of the synthesis of 3a. Higher
amount of catalyst produced lesser yield (Table 2).
Cmpd
X
Reaction
time (min)
Yieldb
(%)
Mp
(ꢁC)
Lit. mp
(ꢁC)
To check the general applicability of reaction in com-
monly available monomode reactor, reaction was per-
formed under three types of MW reactor and results
found with high reproducibility (Table 3).
3a
3b
3c
3d
3e
3f
8-OCH3
8-CH3
8-Cl
8
10
12
10
13
15
94
75
72
84
85
82
180
155
189
195
165
139
17837
15737
18637
19237
16637
13838
6-Cl
6-Br
6-F
As usual in the catalytic reaction, the increase of the
reaction temperature accelerated the conversion of the
substrate. It was also observed that MW irradiation
using different monomode reactor with focused rays
and a much more homogeneous electromagnetic field
and classical heating gave lower yield with higher reac-
tion time compared to reactions realized under stirring
conditions and interphase catalysis. In view of all these
results, we have synthesized all the compounds (3a–f)
using LaY zeolite under stirring at 100 ꢁC (Table 4).
a 100 wt % catalyst used that means that the substrate: catalyst weight
ratio is 1:1.
b Isolated yields.
Table 5. Photocytotoxicity of test compounds against HL-60 cell line
as Compounds, GI50 (mM)a
a
Compounds
GI50 (lm)
1.25b J cmÀ2
2.5 J cmÀ2
3a
3b
>10
>10
10
10
The phototoxicity of title compounds was investigated
first on a cell line of human tumor HL-60 (human pro-
myelocytic leukemia). Table 5 shows the extent of cell
survival expressed as GI50, which is the concentration,
expressed in mM, that induces 50% of inhibition of cell
3c
3d
>10
>10
6.8 2.0
6.9 1.9
0.9 0.2
0.8 0.1
1.45
3e
3f
Doxorubicin
2.5 0.6
6.6 0.9
2.36
a Concentration of compound required to inhibit the cell growth by
50% after 72 h of exposure as determined by MTT assay.
b UVA dose expressed in J cmÀ2 as measured at 365 nm with a Cole–
Parmer radiometer.
Table 2. Effect of LaY catalyst amounts on synthesis of 3a (X = OMe)
Entry
LaY catalyst
amount (g)
Time (min)
Yielda (%)
1
2
3
4
5
6
0
20
15
12
11
8
No reaction
Traces of product
growth, after irradiation at different UVA doses. Doxo-
rubicin was used as positive control.
0.5
1.0
1.5
2.0
3.0
20
58
94
92
Control experiments with UVA light or compounds
alone were carried out without significant cytotoxic ef-
fects (data not shown). The results, shown in Table 5,
indicate that compound 3a is not active, instead 3e,f
exhibited the highest activity. Interestingly, substitution
for a methyl group leads to an inactive derivative 3b.
From this preliminary screening the most active com-
pounds were also evaluated on a human intestinal ade-
nocarcinoma cell line (LoVo) and one line of
immortalized, not tumorigenic, human keratinocytes
(NCTC 2544). From Table 6 it appears that the
8
a Isolated yields.
Table 3. Synthesis of 3a using different available MW monomode
reactor
Entry Medium
MW Reaction
reactor temperature
Time/min Yielda
(%)
(ꢁC)
1
2
LaY zeolite
CEM
130
12.5
13
70
70
69
Prolobo 130
Biotage 130
13
Table 6. Photocytotoxicity of test compounds against NCTC 2544 and
LoVo cell linesa
Montmorillonite CEM
KSF
138
12
68
Prolobo 138
Biotage 138
12
13
68
68
b
Compounds
Cell line GI50 (lm)
NCTC 2544
LoVo
3
4
CeY zeolite
CEM
130
15
16
58
58
57
1.25c J cmÀ2 2.5 J cmÀ2 1.25b J cmÀ2 2.5 J cmÀ2
Prolobo 130
Biotage 130
16.5
3f
7.0 1.3
>20
>20
2.6 0.7 3.8 0.8
>20 >20
6.9 2.2 16.8 2.1
1.32 8.54
1.94 0.2
13.2 1.9
9.80 1.3
5.48
3e
3d
Neat + DMF
(2–3 drops)
CEM
140
10
58
Doxorubicin 3.04
Prolobo 140
Biotage 140
10
10.5
59
59
a Human cell lines: NCTC 2544 Human keratinocytes; LoVo intestinal
adenocarcinoma.
b Concentration of compound required to inhibit the cell growth by
50% after 72 h of exposure as determined by MTT assay.
c UVA dose expressed in J cmÀ2 as measured at 365 nm with a Cole–
Parmer radiometer.
5
PTSA
CEM
125
12.5
12
52
54
52
Prolobo 125
Biotage 125
12
a Isolated yield.

K. Arya, A. Dandia / Bioorg. Med. Chem. Lett. 18 (2008) 114–119
117
Table 7. Percentage of HL-60 in the different phases of the cell cyclea
catalysts. Thus, our method, compared with the re-
ported ones, shows very important advantages from
both ecological and economic point of view.
Treatment
G1
G2
9.0
S
Apoptotic cellsb
Non-irradiated cells
39.0
51.7
0.8
UVA irradiated cells without drug (2.5 J cmÀ2
)
Human promyelocytic leukemia cells (HL-60) were
grown in RPMI-1640 medium (Sigma Co Mo, USA),
human keratinocytes (NCTC 2544) were grown in
DMEM (Sigma Co Mo USA), and intestinal adenocar-
cinoma cells (LoVo) were grown in Ham’s F12 medium
(Sigma Co Mo, USA) all supplemented with 115 units/
mL of penicillin G (Invitrogen, Milano, Italy), 115 lg/
mL streptomycin (Invitrogen, Milano, Italy), and 10%
fetal bovine serum (Invitrogen, Milano, Italy). Individ-
ual wells of a 96-well tissue culture microtiter plate (Fal-
con BD) were inoculated with 100 mL of complete
medium containing 8 · 103 HL-60 cells or 5 · 103 NCTC
2544 and LoVo cells. The plates were incubated at 37 ꢁC
in a humidified 5% incubator for 18 h prior to the exper-
iments. After medium removal, 100 mL of the drug solu-
tion, dissolved in DMSO and diluted with Hanks’
Balanced Salt Solution (HBSS pH 7.2), was added to
each well and incubated at 37 ꢁC for 30 min and then
irradiated. Doxorubicin was used as positive control.
After irradiation, the solution was replaced with the
medium, and the plates were incubated for 72 h. Cell
viability was assayed by the MTT [(3-(4,5-dimethylthia-
zol-2-yl)-2,5-diphenyltetrazolium bromide)] test, as de-
scribed previously.42,43
24 h
48 h
72 h
35.9
49.6
34.8
12.4
10.2
11.9
50.1
40.5
55.1
8.2
10.9
9.1
3a 2.5 m MCUVA (2.5 J cmÀ2
)
24 h
48 h
72 h
28.9
44.5
43.5
10.8
10.3
12.0
58.4
45.0
43.8
13.5
28.7
42.5
3a 5.0 mMCUVA (2.5 J cmÀ2
)
24 h
48 h
72 h
33.9
51.7
58.7
11.8
11.2
5.9
55.3
37.8
35.4
20.4
28.2
47.9
a The percentage of each phase of the cell cycle (G1, S, and G2/M) was
calculated on living cells.
b The percentage of apoptotic cells is referred to cells population
characterized by the appearance of a sub G1 peak.
phototoxicity of the most active compounds, in particu-
lar 3f, is higher in the tumor cell lines in comparison to
the normal ones (NCTC 2544). In preliminary experi-
ments devoted to the search for a possible molecular tar-
get, compound 3f was evaluated for its potential
capability to induce single strand breaks in a plasmid
DNA, as a model.
For flow cytometric analysis of DNA content, 5 · 105
HL-60 cells in exponential growth were treated at differ-
ent concentrations of the test compounds for 24, 48, and
72 h. After the incubation period, the cells were centri-
fuged and fixed with ice-cold ethanol (70%), treated with
lysis buffer containing RNAseA, and then stained with
propidium iodide. Samples were analyzed on a Becton
Coulter Epics XL-MCL flow cytometer. For cell cycle
analysis, DNA histograms were analyzed using Multi
Cycle for Windows (Phoenix Flow Systems, San Diego,
CA).
The obtained results (data not shown) indicate that 3f,
after irradiation in the presence of DNA, is not able
to induce any significant damage to DNA thus suggest-
ing that another target at cellular level may be involved
in its phototoxic effect. In parallel to the cytotoxic eval-
uation, flow cytometry was employed to study cell cycle
variations upon irradiation. The effects of the most ac-
tive compound 3f were evaluated after 24, 48, and 72 h
from irradiation in the leukemic cell line. The percentage
of the cells in the different phases of the cell cycle is
shown in Table 7.
It can be observed that treatment with 3f in combination
with UVA induces a reduction of the S phase at 48 and
72 h after irradiation especially for the highest dose uti-
lized. This is accompanied by a concomitant block in G1
phase. This event is followed at 48 and 72 h after the
irradiation by massive induction of apoptosis, as ob-
served by the appearance of a sub G1 peak (apoptotic
cells) that refers to cells with DNA content lower than
G1.35,36 In fact, apoptosis induces the activation of
endogenous nucleases, which are responsible for nucleic
acid degradation.
Acknowledgment
Author is thankful to IOCL, R&D Center, Faridabad,
Haryana, India, for financial support.
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41. Synthesis of 8/6-substituted-2-carboxy-2,3-dihydro-1,5-ben-
zothiazepines (3a–f): (i) Conventional method: (a) Using
ethanol + dry hydrogen chloride gas: An equimolar mix-
ture of 1 (1 mmol) and 2 (1 mmol) was refluxed for 7–10 h
with dry ethanol (25 mL) saturated with hydrogen chlo-
ride gas, whereupon the reaction mixture changed from
yellow to dark green. Excess of solvent was concentrated
by distillation under reduced pressure. The product so
obtained was recrystallized from methanol to give light
green crystals of compounds 3. Similarly 3 was prepared
by reflux with toluene and trifluoroacetic acid (2–3 drops)–
methanol containing traces of glacial acetic acid to check
the most effective method of synthesis; (ii) MW mediated
method: (a) Using different solid supports such as mont-
morillonite KSF, Neat in the presence of few drops of
DMF, p-toluenesulfonic acid (PTSA): An equimolar
mixture of 5-methoxy-2-aminobenzenethiol 1 (1 mmol)
and 3-(4-fluoro-2-methyl benzoyl)-2-propenoic acid
2
33. (a) Arya, K.; Dandia, A. Lett. Org. Chem. 2007, 4, 378; (b)
Arya, K.; Dandia, A. Bioorg. Med. Chem. Lett. 2007, 17,
3298; (c) Arya, K.; Dandia, A. J. Fluorine Chem. 2007,
128, 224; (d) Arya, K.; Dandia, A.; Dhaka, N. J. Chem.
Res. 2006, 192; (e) Dandia, A.; Arya, K.; Sati, M.;
Sarawgi, P.; Loupy, A. Arkivoc 2005, 105; (f) Dandia, A.;
(1 mmol) was introduced in a beaker and dissolved in
acetone (15 mL). Inorganic solid support (20% by weight
of the reactants) was then added and swirled for a while
followed by removal of the solvent under gentle vacuum.
The dry free flowing powder thus obtained was placed into
a sealed vessel and irradiated inside the microwave oven.

K. Arya, A. Dandia / Bioorg. Med. Chem. Lett. 18 (2008) 114–119
119
After completion of the reaction (monitored by TLC) the
recyclable inorganic solid support was separated by
filtration after eluting the product with methanol. The
combined filtrate was concentrated under reduced pres-
sure and the residue was purified by column chromatog-
raphy with silica gel (n-hexane/EtOAc = 20:1) giving pure
product (3); (iii) Using stirring method: To a stirred
heterogeneous mixture of 5-substituted-2-aminobenzen-
ethiols (1a–f) and 3-(4-fluoro-2-methylbenzoyl)-2-prope-
noic acid (1 mmol), 2 g of LaY zeolite was added at 80 ꢁC.
The resulting mixture was stirred at the same temperature
for 8–15 min (Table 4). After the completion of reaction
(TLC analysis), reaction mixture was filtered and zeolite
was washed with water (and/or methanol). When catalyst
was reused, it was dried in air overnight at 300 ꢁC.
Alternatively the reaction mixture was directly applied on
a silica gel column and eluted with hexane/CH2Cl2 (1:9) to
afford the pure product (3a–f).
42. Elisei, F.; Aloisi, G.; Latterini, L.; Mazzuccato, U.; Viola,
G.; Miolo, G.; Vedaldi, D.; Dall’Acqua, F. Photochem.
Photobiol. 2002, 75, 11.
43. Viola, G.; Facciolo, L.; Canton, M.; Di Lisa, F.;
Dall’Acqua, S.; Vedaldi, D.; Tabarrini, O.; Fravolini, A.;
Cecchetti, V. Toxicol. In Vitro 2004, 18, 581.