Synthesis and in vitro antiproliferative activity of new substituted benzo[3′,2′:5,6]thiopyrano[4,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.5570450318

(Chemical Equation Presented) The synthesis of new planar benzo[3′,2′:5,6]thiopyrano[4,3-d]pyrimidine derivatives, carrying different side groups in the 2 position, is described. The novel substituted pyrimidines were obtained by reaction of the key intermediate 3-dimethylamino methylen-7-methoxy-2,3-dihydrobenzo[3′,2′:5,6]thiopyran-4(4H)-one, characterized by a reactive group adjacent to the C=O function, with the suitable binucleophile amidines in a basic medium. All the new compounds were evaluated for the antiproliferative ability by an in vitro assay on two human tumour cell lines (HL-60 and HeLa), and the 2-phenyl substituted derivative showed the capacity to inhibit cell growth on HL-60. Linear flow dichroism measurements indicated the inability to form a molecular complex with DNA.

Full text of DOI:10.1002/jhet.5570450318

May-Jun 2008
745
Synthesis and in vitro Antiproliferative Activity of New Substituted
Benzo[3',2':5,6]thiopyrano[4,3-d]pyrimidines
Anna Maria Marinia*, Federico Da Settimoa, Silvia Salernoa, Concettina La Mottaa,
Francesca Simorinia, Sabrina Taliania, Daniele Bertinia, Ornella Giab and Lisa Dalla Viab
aDipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
bDipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
Received June 8, 2007
R
O
N
S
N
H3CO
S
H3CO
The synthesis of new planar benzo[3',2':5,6]thiopyrano[4,3-d]pyrimidine derivatives, carrying different
side groups in the 2 position, is described. The novel substituted pyrimidines were obtained by reaction of
the key intermediate 3-dimethylamino methylen-7-methoxy-2,3-dihydrobenzo[3',2':5,6]thiopyran-4(4H)-
one, characterized by a reactive group adjacent to the C=O function, with the suitable binucleophile
amidines in a basic medium. All the new compounds were evaluated for the antiproliferative ability by an
in vitro assay on two human tumour cell lines (HL-60 and HeLa), and the 2-phenyl substituted derivative
showed the capacity to inhibit cell growth on HL-60. Linear flow dichroism measurements indicated the
inability to form a molecular complex with DNA.
J. Heterocyclic Chem., 45, 745 (2008).
INTRODUCTION
These results prompted us to synthesize the series of the
new tricyclic derivatives 2a-h, characterized by the
isosteric benzothiopyranopyrimidine system.
DNA is recognized as the primary target for several
clinically effective anti-tumour agents since drug-induced
DNA damage can inhibit cell proliferation and induce cell
death [1-4]. Despite their relative non selectivity, DNA-
damaging agents are still of interest and, among them,
DNA intercalating compounds are an important class of
clinically useful anti-tumour agents, due to their high
therapeutic potential [5].
R
N
S
N
H3CO
2a-h
The antineoplastic activity of these drugs is the result of
the interaction of their planar system between the DNA base
pairs of the target cells, which causes changes of the nucleic
acid structure and compromises its biological function [6,7].
In this field we have carried out extensive studies on
several heterocyclic systems endowed with a detectable
cytotoxic activity, characterized by a DNA intercalative
binding mode [8-10]. More recently we described two new
pyridothiopyranopyrimidine derivatives 1a (R=NH2) and 1b
(R=NHSO2C6H4-pCH3) [11], which, although endowed with
antiproliferative activity, showed the inability to interact with
the macromolecule. Nevertheless, these compounds were able
to alter the mitochondrial functionality through a mechanism
related to the induction of permeability transition [12], thus
appearing to offer an interesting chromophore system.
2a: R = H
2b: R = CH3
2c: R = Ph
2e: R = NHCH2COOH
2f: R = N(CH3)CH2COOH
2g: R = NH(CH2)3CH(NH2)COOH
2h: R = NHCH(CH3)2
2d: R = NH2
In the last years, the research on the benzothiopyrano-
pyrimidine system gave rise to the synthesis of a large
number of compounds endowed with interesting pharmaco-
logical properties [13] but, to date, the benzo-thiopyrano[4,3-
d]pyrimidine nucleus 2a, bearing a methoxy group in the 7-
position, was never investigated. In the 2-position of the fused
system, both lipophilic (compounds 2b,c) and protonable
groups (compounds 2d-h) were introduced with the aim of
enhancing the DNA-binding properties of the scaffold and/or
its antiproliferative activity. Indeed it seemed reasonable that
the presence of a pendant substituent might result in the
possibility of supporting the formation of a reinforced
complex with DNA, ascribable to electrostatic and/or to
hydrogen bonding interactions.
R
N
N
N
S
The ability of the new derivatives to exert an antipro-
liferative activity was evaluated by means of an inhibition
growth assay on two human tumour cell lines, human promy-
1a-b

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A. M. Marini, F. Da Settimo, S. Salerno, C. La Motta, F. Simorini,
S. Taliani, D. Bertini, O. Gia and L. Dalla Via
Vol 45
elocitic leukemic cells (HL-60) and human cervix adeno-
carcinoma cells (HeLa). Linear flow dichroism experiments
were performed to assess the occurrence of a molecular
complex with DNA [14].
methylthiopseudourea sulfate with isopropylamine in
aqueous solution, as described in literature [16]. The
subsequent condensation of
5
with the starting
intermediate 3 afforded the desired 2-isopropylamino-
pyrimidine derivative 2h (Scheme 2).
RESULTS AND DISCUSSION
Scheme 2
The synthetic procedure leading to the target 8-methoxy-
5H-benzo[3',2':5,6]thiopyrano[4,3-d]pyrimidine system 2a
takes advantage of the 1,3-bielectrophile reactivity of the
intermediate 3-dimethylaminomethylen-7-methoxy-2,3-di-
hydrobenzo[3',2':5,6]thiopyran-4(4H)-one 3 in the reaction
with a binucleophile amidine in a basic medium [9]. The
preparation of compound 3 was accomplished, with good
yields, using as starting compound the already described 7-
methoxy-2,3-dihydrobenzo[3',2':5,6]thiopyrano-4(4H)-one 4
[15], by reaction with an excess of dimethylformamide
dimethylacetal (DMF DMA) in refluxing toluene (Scheme
1). The 2-substituted analogues bearing the methyl (2b),
phenyl (2c), amino (2d) groups or the aminoacidic side
chains glycine (2e), N-methylglycine (2f) and ornithine (2g),
respectively, were also synthesized. Compounds 2b-g were
thus obtained by reacting 3-dimethylaminomethylen-7-
SCH3
C
NH2 H2SO4
CH3
HN
H2O
NH2CH
CH3
O
S
CH3
CH3
CH3
NHCH
C
CHN
+
CH3
NH2 H2SO4
HN
H3CO
5
3
EtONa, EtOH
!
CH3
NHCH
N
CH3
N
S
H3CO
methoxy-2,3-dihydrobenzo[3',2':5,6]thiopyran-4(4H)-one
3
2h
with the required amidine or aminoacidic derivative in an
ethanolic refluxing solution, in the presence of sodium
ethoxide (Scheme 1).
The crude target compounds were obtained as unique
products (tlc analysis) in modest (2e,g,h) to high (2a-d,f)
overall yields. This significant difference was ascribable
to the lower cyclization capability of the amidino
reactives bearing three instead of two amino groups [17].
All the derivatives were purified by crystallization and
the proposed structures were assigned on the basis of
analytical and spectral data (Tables I, II), which relied on
those of earlier studies performed by our group [9].
Scheme 1
O
OCH3
OCH3
H3C
H3C
+
N CH
H3CO
S
Toluene
!
4
The antiproliferative activity of compounds 2a-h was
evaluated by means of a cell growth inhibition assay on
two human tumour cell lines, HL-60 and HeLa using
Ellipticine as reference compound, in accordance with the
experimental procedures previously described [8]. The
results are expressed as IC50 values, i.e. the concentration
(µM) of a compound able to cause 50% of cell death with
respect to the control culture, and are reported in Table
III. The obtained values indicated that neither the scaffold
itself (2a) nor the derivatives (2b, 2d-h) substituted in the
2-position exert any cytotoxic activity, while the 2-phenyl
substituted compound, (2c), showed a significant anti-
proliferative effect on HL-60 cells.
Linear flow dichroism (LD) experiments were
performed, as reported in ref. [8], to assess the occurrence
of a molecular complex with DNA. Figure 1 showed the
LD spectra of DNA alone (continuous line) and in the
presence of 2c (dotted line) at [drug]/[DNA]=0.08. The
dichroic spectra revealed the absence of any detectable
signal in the region at wavelength higher than 300 nm,
where only the benzothiopyranopyrimidine chromophore
O
CH3
CH3
CHN
H3CO
S
3
R
C
EtONa, EtOH
!
HN NH2 HCl
R
N
S
N
H3CO
2a-g
a: R = H
b: R = CH3
c: R = C6H5
d: R = NH2
e: R = NHCH2COOH
f: R = N(CH3)CH2COOH
g: R = NH(CH2)3CH(NH2)COOH
The synthetic pathway utilized in the preparation of
compound 2h involved, as a first step, the preparation of
the isopropyl substituted amidine 5, by condensation of

May-Jun 2008
Synthesis and in vitro Antiproliferative Activity of New
Substituted Benzo[3',2':5,6]thiopyrano[4,3-d]pyrimidines
747
Table I
Physical and Analytical Data of Compounds 2a-h
Compound
R
Yield (%)
M. p. °C
Molecular
Formula
Analysis (%)
Calcd./Found
C
H
N
2a
2b
2c
2d
2e
2f
H
83
88
94
85
28
60
38
42
139-142
116-118
82-85
C12H10N2OS
C13H12N2OS
C18H14N2OS
C12H11N3OS
C14H13N3O3S
C15H15N3O3S
C17H20N4O3S
C15H17N3OS
62.59
62.25
63.91
63.84
70.56
70.22
58.77
58.69
55.44
55.15
56.77
56.43
56.66
56.19
62.72
62.34
4.35
4.18
4.95
4.73
4.61
4.57
4.49
4.23
4.29
4.46
4.73
4.68
5.55
5.23
5.92
5.79
12.17
11.99
11.47
11.56
9.14
CH3
C6H5
8.76
NH2
172-175
17.14
16.95
13.86
13.77
13.25
13.19
15.55
15.35
14.63
14.47
NHCH2COOH
CH3NCH2COOH
NH(CH2)3CH(NH2)COOH
NHCH(CH3)2
170-175
dec.
175-177
2g
2h
180-185
dec.
115-117
Table II
Spectral Data of Compounds 2a-h
1H nmr (δ ppm)
Compound
2a
R
ir
(cm-1)
Ms
m/z
H
1595, 1570, 1400, 1245,
3.83 (s, 3H, OCH3); 4.12 (s, 2H, CH2S); 6.95 (dd, 1H, 9-H J9-10 = 8.5 230
Hz J9-7 = 2.4 Hz); 7.01 (d, 1H, 7-H J7-9 = 2.4 Hz); 8.28 (d, 1H, 10-H
J10-9 = 8.5 Hz); 8.69 (s, 1H, 4-H); 9.07 (s, 1H, 2-H)
1220, 1035, 790
2b
CH3
1605, 1575, 1530, 1425,
1250, 1225, 1060, 790
2.63 (s, 3H, 2-CH3); 3.82 (s, 3H, OCH3); 4.07 (s, 2H, CH2S); 6.93 244
(dd, 1H, 9-H J9-10 = 8.6 Hz J9-7 = 2.1 Hz); 6.99 (d, 1H, 7-H J7-9 = 2.1
Hz); 8.25 (d, 1H, 10-H); 8.57 (s, 1H, 4-H)
2c
C6H5
NH2
1595, 1570, 1420, 1250,
1215, 1045, 765, 730
3315, 3195, 1650, 1585,
1415, 1250, 1220, 1045,
790
3.84 (s, 3H, OCH3); 4.16 (s, 2H, CH2S); 6.96-7.03 (m, 2H, 9-H 7-H); 306
7.52-7.56 (m, 4H, ArH); 8.46-8.50 (m, 2H, ArH); 8.78 (s, 1H, 4-H)
3.80 (s, 3H, OCH3); 3.90 (s, 2H, CH2S); 6.57 (s, 2H, NH2, exch.); 245
2d
6.89 (dd, 1H, 9-H J9-10 = 8.8 Hz J9-7 = 2.4 Hz); 6.93 (d, 1H, 7-H J7-9
2.4 Hz); 8.13 (d, 1H, 10-H J10-9 = 8.8 Hz); 8.15 (s, 1H, 4-H)
=
2e
NHCH2COOH
3360, 3270, 3160, 1660,
1580, 1250, 1045, 1025,
790
3.50 (m, 2H, NHCH2); 3.80 (s, 3H, OCH3); 3.90 (s, 2H, CH2S); 6.21 303
(t, 1H, NH exch. J = 2.2 Hz); 6.86 (d, 1H, 7-H J7-9 = 2.2 Hz); 6.90
(dd, 1H, 9-H J9-10 = 8.4 Hz J9-7 = 2.2 Hz); 8.17 (s, 1H, 4-H); 8.19 (d,
1H, 10-H J10-9 = 8.4 Hz)
2f
CH3NCH2COOH
3390, 1720, 1595, 1505,
1220, 1050, 795
3.20 (s, 3H, NCH3); 3.81 (s, 3H, OCH3); 3.95 (s, 2H, CH2S); 4.31 (s, 317
2H, NCH2); 6.87-6.95 (m, 2H, 7-H 9-H); 8.16-8.28 (m, 2H, 10-H 4-
H); 12.57 (s, 1H, COOH, exch.)
2g
NH(CH2)3CH(NH2)COOH
3365, 3215, 1635, 1585,
1405, 1240, 1045, 790
1.61 (m, 4H, NCH2-CH2CH2); 3.12 (t, 1H, CH2CH J = 1.8 Hz); 3.32 360
(m, 2H, NHCH2); 3.80 (s, 3H, OCH3); 3.90 (s, 2H, CH2S); 6.86-6.94
(m, 2H, 7-H 9-H); 7.18 (t, 1H, NH exch. J = 2.1 Hz); 7.56 (bs, 2H,
NH exch.); 8.16-8.19 (m, 2H, 4-H 10-H)
2h
NHCH(CH3)2
3250, 1585, 1550, 1410, 1.16 (d, 6H, CH(CH3)2 J = 6.4 Hz); 3.81 (s, 3H, OCH3); 3.90 (s, 2H, 287
1300, 1245, 1170, 850, 790 CH2S); 4.04-4.14 (m, 1H, CH(CH3)2); 6.86-6.95 (m, 2H, 7-H 9-H);
8.16 (d, 1H, 10-H J = 8.4 Hz); 8.18 (s, 1H, 4-H)
Table III (continued)
absorbs, thus indicating its inability to give rise to a
molecular complex with the macromolecule.
Cellular lines IC50 (µM)
HL-60 HeLa
compound
2d
2e
>20
>20
>20
>20
Table III
2f
2g
>20
>20
>20
>20
Antiproliferative activity of compounds 2a-h
2h
ellipticine
>20
0,64± 0,02
>20
0,31± 0,01
Cellular lines IC50 (µM)
compound
HL-60
HeLa
2a
2b
2c
>20
>20
7,15 ± 0,01
>20
>20
>20
Thus, it is reasonable to assume that the observed
antiproliferative capacity (Table III) might ensue from the

748
A. M. Marini, F. Da Settimo, S. Salerno, C. La Motta, F. Simorini,
S. Taliani, D. Bertini, O. Gia and L. Dalla Via
Vol 45
dimethylaminomethylen-7-methoxy-2,3-dihydrobenzo[3',2':5,6]-
thiopyran-4(4H)-one 3 (0.200 g, 0.8 mmole) was added and the
reaction mixture was refluxed for 16 hours (tlc analysis). After
cooling, the solid was collected and the solution was evaporated
under reduced pressure. The solid and the residue were washed
with water and collected to give crude pyrimidine 2a, which was
purified by crystallization from ethanol (Table I).
effect on a different cellular target, which will be further
investigated.
0,000
-0,005
General procedure for the synthesis of 2-Methyl- (2b), 2-
Phenyl- (2c) and 2-Amino-8-methoxy-5H-benzo[3',2':5,6]-
thiopyrano[4,3-d]pyrimidine (2d). Acetamidine hydrochloride,
benzamidine hydrochloride or guanidine hydrochloride (1.60
mmoles) was added, at room temperature, under nitrogen
atmosphere, to a stirred solution of sodium ethoxide (0.055 g,
2.4 mmoles of sodium in 8 mL of anhydrous ethanol). The
resulting suspension was stirred at room temperature for 15
minutes, then 3-dimethylaminomethylen-7-methoxy-2,3-di-
-0,010
LD
(deg)
-0,015
-0,020
-0,025
-0,030
250
300
350
400
450
500
hydrobenzo[3',2':5,6]thiopyran-4(4H)-one
3
(0.200 g, 0.8
wavelength (nm)
mmole) was added and the reaction mixture was refluxed for 8-
24 hours (tlc analysis). After cooling, the solid, if present, was
collected and the solution was evaporated under reduced
pressure. The solid and the residue were washed with water and
collected to give crude pyrimidines 2b-d, which were purified
by crystallization from ethanol (Tables I, II).
Figure 1. Linear flow dichroism spectra for compound 2c at [drug]/
[DNA]=0 (continuous line) and [drug]/[DNA]=0.08 (dotted line).
[DNA]=1.9x10-3 M in ETN buffer (10 mM TRIS, 10 mM NaCl, 1 mM
EDTA, pH=7)
General procedure for the synthesis of 2-Glycinyl- (2e), 2-
(N-methyl)glycinyl- (2f) and 2-(5N-ornithinyl)-8-methoxy-
5H-benzo[3',2':5,6]thiopyrano[4,3-d]pyrimidine (2g). The
required guanidineacetic acid, creatine monohydrate or arginine
hydrochloride (1.60 mmoles) was added, at room temperature,
under nitrogen atmosphere, to a stirred solution of sodium
ethoxide (0.092 g, 4.0 mmoles of sodium in 8 mL of anhydrous
ethanol). The resulting suspension was stirred at room
temperature for 15 minutes, then 3-dimethylaminomethylen-7-
methoxy-2,3-dihydrobenzo[3',2':5,6]thiopyran-4(4H)-one 3 (0.200
g, 0.8 mmole) was added and the reaction mixture was refluxed
for 8-24 hours (tlc analysis). After cooling, the solution was
acidified with concentrated hydrochloric acid (pH=6). The
precipitate was collected to give crude pyrimidines 2e-g, which
were purified by crystallization from ethanol (Tables I, II).
Isopropylguanidine sulphate (4). [16] Isopropylamine (1.70
mL, 20 mmoles) was added to a stirred suspension of 2-methyl-
2-thiopseudourea sulphate (2.780 g, 14.8 mmoles) in 2 mL of
ice-cooled water. The resulting suspension was stirred at room
temperature for 16 hours and then refluxed for 4 hours. After
cooling the solution obtained was evaporated to dryness and the
residue was purified by crystallization from ethanol, yield 35.0
%, m. p. 268-269°C, lit. m. p. 270-271°C. Anal. Calcd. for
C4H13N3O4S: C, 24.12; H, 6.53; N, 21.10; Found: C, 24.50; H,
6.33; N, 21.14.
2-Isopropylamino-8-methoxy-5H-benzo[3',2':5,6]thio-
pyrano[4,3-d]pyrimidine (2h). Isopropylguanidine sulphate 4
(0.318 g, 1.6 mmoles) was added, at room temperature, under
nitrogen atmosphere, to a stirred solution of sodium ethoxide
(0.092 g, 4.0 mmoles of sodium in 8 mL of anhydrous ethanol).
The resulting suspension was stirred at room temperature for 15
minutes, then 3-dimethylaminomethylen-7-methoxy-2,3-dihy-
drobenzo[3',2':5,6]thiopyran-4(4H)-one 3 (0.200 g, 0.8 mmole)
was added and the reaction mixture was refluxed for 16 hours
(tlc analysis). After cooling the obtained solution was
evaporated to dryness and the residue was purified by
crystallization from ethanol (Table I, II).
EXPERIMENTAL
Melting points were determined using a Reichert Köfler hot-
stage apparatus and are uncorrected. Infrared spectra (ir) were
obtained on a NICOLET/AVATAR, 360 FT spectrophotometer
as Nujol mulls. Nuclear magnetic resonance spectra (nmr) were
recorded on a Varian Gemini 200 spectrometer, in dimethyl-d6
sulfoxide solution using TMS as the internal standard. Mass
spectra (ms) were obtained on a Finningan Polaris/GCQ Plus
spectrometer using an electron beam energy of 70 eV.
Magnesium sulfate was always used as the drying agent.
Evaporations were made in vacuo (rotating evaporator).
Analytical tlc were carried out on Merck 0.2 mm precoated
silica gel aluminium sheets (60 F-254). Elemental analyses were
performed by our Analytical Laboratory.
3-Dimethylaminomethylen-7-methoxy-2,3-dihydrobenzo-
[3',2':5,6]thiopyran-4(4H)-one (3). An excess of dimethylform-
amide dimethylacetal (2.60 mL, 19.3 mmoles) was added to a
stirred solution of 7-methoxy-2,3-dihydrobenzo[3',2':5,6]thio-
pyran-4(4H)-one 4 (1.500 g, 7.73 mmoles) in anhydrous toluene
(10 mL) and the mixture was refluxed for 12 hours. After
cooling, the solution obtained was evaporated under reduced
pressure, giving a residue which was treated with ethyl ether,
collected and purified by crystallization from toluene-petroleum
ether 60-80°C (quantitative yield). m. p. 115-120°C; ir (nujol,
cm-1): 1635, 1590, 1325, 1230, 1065, 975, 770; 1H-nmr
(dimethyl-d6 sulfoxide): δ 3.11 (s, 6H, N(CH3)2); 3.77 (s, 3H,
CH3O); 4.07 (s, 2H, CH2S); 6.75 (dd, 1H, 6-H J6-5 = 8.5 Hz J6-8 =
2.4 Hz); 6.80 (d, 1H, 8-H J8-6 = 2.4 Hz); 7.40 (s, 1H,
CHN(CH3)2); 7.83 (d, 1H, 5-H J5-6 = 8.5 Hz); ms: m/z = 249
+
(M ). Anal. Calcd. for C13H15NO2S: C, 62.65; H, 6.02; N, 5.62;
Found: C, 62.50; H, 6.33; N, 5.14.
8-Methoxy-5H-benzo[3',2':5,6]thiopyrano[4,3-d]pyrimi-
dine (2a). Formamidine hydrochloride (0.219 g, 1.60 mmoles)
was added, at room temperature, under nitrogen atmosphere, to a
stirred solution of sodium ethoxide (0.055 g, 2.4 mmoles of
sodium in 8 mL of anhydrous ethanol). The resulting suspension
was stirred at room temperature for 15 minutes, then 3-
Acknowledgments. This work was supported by grants from
MIUR (Research fund: Cofin 2006).

May-Jun 2008
Synthesis and in vitro Antiproliferative Activity of New
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749
Chem., 2002, 37, 475-486.
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*
To whom correspondence should be addressed. E-mail:
marini@farm.unipi.it; Tel: +39-050-2219555; Fax: +39-050-2219605.
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