Isorhodanine and thiorhodanine motifs in the synthesis of fused thiopyrano[2,3-d ][1,3]thiazoles

Article abstract of DOI:10.1055/s-0030-1260765

Utilization of 4-thioxo-2-(thi)oxothiazolidines in the synthesis of new fused thiopyrano[2,3-d][1,3]thiazole derivatives under Knoevenagel and hetero-Diels-Alder reaction conditions has been studied. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260765

LETTER
1385
Isorhodanine and Thiorhodanine Motifs in the Synthesis of Fused
Thiopyrano[2,3-d][1,3]thiazoles
F
use
d
T
hiopyrano[
a
2,3-
d
][1,3]
n
thiazoles ylo Kaminskyy,a Olexandr Vasylenko,b Dmytro Atamanyuk,a Andrzej Gzella,c Roman Lesyk*a
a
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University,
Pekarska 69, Lviv 79010, Ukraine
Fax +380(322)757734; E-mail: dr_r_lesyk@org.lviv.net
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Murmanska 1, Kyiv 02094, Ukraine
Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland
b
c
Received 13 January 2011
S
O
S
Abstract: Utilization of 4-thioxo-2-(thi)oxothiazolidines in the
synthesis of new fused thiopyrano[2,3-d][1,3]thiazole derivatives
under Knoevenagel and hetero-Diels–Alder reaction conditions has
been studied.
H
N
NH
S
R1
R2
R1
R2
NH
X
X
S
X
S
S
R1 R2
Key words: iso(thio)rhodanine, condensation, Diels–Alder reac-
tion, heterocycles, antitumor agents
X = S, O
Scheme 1 General scheme for thiopyrano[2,3-d][1,3]thiazole syn-
thesis
Derivatives of thiazolidine (rhodanine, 2,4-thiazolidinedi-
one) have gained significant popularity in drug design as
privileged scaffolds possessing diverse biological activi-
ties. A wide range of lead compounds, drug candidates
and patented compounds have been identified on their ba-
sis.1 Fused heterocyclic systems based on 4-thioxo-2-thi-
azolidinone (isorhodanine) and 2,4-dithioxothiazolidine
(thiorhodanine) are especially promising among such de-
rivatives.2,3 The hypothesis that fused heterocyclic sys-
tems can imitate the biological activity of their synthetic
precursors, namely 5-ylidene-4-thiazolidinones, has been
proposed as a basis for their design. The critical influence
of the nature of C5-substituents on biological activity
should also be taken into consideration.1,4 This reasoning
makes 5-aryl(heteryl)idene-4-thioxothiazolidines attrac-
tive building blocks for the synthesis of complex hetero-
cyclic systems, especially as highly active heterodiene
components. Although 5-alkylidene-4-thioxothiazo-
lidines that include small lipophilic moieties are seldom
used, they may be of interest because of their possible use
in hetero-Diels–Alder type reactions.5
lowed us to synthesize 5-alkylidene-4-thioxo-2-
thiazolidinones 1a–c with acceptable yields. The appro-
priate isosters based on thiorhodanine were not formed
under the same conditions; instead, the series of 8,8-
R1,R2-5,8-dihydro-2H-[1,3]thiazolo[5¢,4¢:5,6]thiopyrano-
[2,3-d][1,3]thiazol-2,6(3H)-dithiones (3a and 3c) was ob-
tained (Scheme 2).8,9
Attempts to synthesize isosters 2 of compounds 3, based
on isorhodanine were undertaken to study the influence of
heteroatom substitution on biological activity. For the
synthesis of compounds 2a and 2b,10,11 we modified the
standard method: the reaction was performed in ethanol
medium with heating of the reaction mixture. The mecha-
nism of compounds 2 synthesis did not involve phase of
5-alkylidene-4-thioxo-2-thiazolidinones formation, prob-
ably because the reaction of compounds 1 with isorho-
danine did not allow us to get the target compounds 2. The
obtained tricyclic heterocyclic systems were new thiaz-
olodin(thi)one derivatives, and information on the synthe-
sis of such systems is sparse. However, the use of Cu-
nanoparticles as a recoverable catalyst for one-pot, three-
component coupling of 2,4-thiazolidinedione, amines,
and aldehyde derivatives yielding 8-R-5,8-dihydro-
3H,4H-bisthiazolo[4,5-b; 5¢,4¢-e]pyridine-2,6-diones was
described.12
Hence, we have established the synthesis of a series of
new thiopyrano[2,3-d][1,3]thiazoles using hetero-Diels–
Alder reactions based on 5-alkylideneiso(thio)rhodanines
(Scheme 1).
Synthesis of 5-alkylidene-4-thioxothiazolidines based on
aliphatic aldehydes or ketones under commonly em-
ployed Knoevenagel reaction conditions (acetic acid me-
dium in the presence of sodium acetate) gives low yields
in comparison with aromatic aldehydes.1,6 Therefore, we
adapted a method7 that involves use of an appropriate ke-
tone as a solvent and ethanolamine as a catalyst. This al-
Single crystal X-ray diffraction studies corroborated the
structures of compounds 2a and 2b.13 The molecular
structures of these compounds, with labeling schemes, are
shown in Figure 1 and Figure 2, respectively. Both com-
pounds consisted of a fused 5,8-dihydro-2H-[1,3]thiazo-
lo[5¢,4¢:5,6]thiopyrano[2,3-d][1,3]thiazol-2,6(3H)-dione
system in which the five-membered rings were planar,
while the six-membered ring had a flattened boat confor-
mation.
SYNLETT 2011, No. 10, pp 1385–1388
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260765; Art ID: B01211ST
© Georg Thieme Verlag Stuttgart · New York

1386
D. Kaminskyy et al.
LETTER
S
NH
S
R1
NH
R1
R2
O
S
R2
S
1a–c
S
S
i
i
NH
X
X = O
X = S
X
H
H
ii
S
S
N
H
N
H
N
S
N
S
S
O
O
S
S
S
S
R1 R2
R1
R2
2a,b
3a,c
a R1 = R2 = Me
b R1–R2 = (CH2)5
c R1–R2 = (CH2)4
Scheme 2 Synthesis of 5-alkylidene-4-thioxo-2-thiazolidinones (1) and 8,8-R1,R2-5,8-dihydro-2H-[1,3]thiazolo[5¢,4¢:5,6]thiopyrano[2,3-
d][1,3]thiazol-2,6(3H)-di(thi)ones (2 and 3). Reagents and conditions: (i) 4-thioxo-2-thiazolidinone or 2,4-dithioxothiazolidine (1.0 equiv),
R1COR2 (15–20 equiv), ethanolamine (2–3 drops), r.t., 1 h; (ii) 4-thioxo-2-thiazolidinone (1 equiv), R1COR2 (1.2 equiv), ethanolamine (2–3
drops), EtOH, reflux, 15 min.
Figure 1 X-ray crystal structure (ORTEP plot) of 2a
Figure 2 X-ray crystal structure (ORTEP plot) of 2b
The two compounds, 2a and 2b, differ in the substituents
at C12. In 2a, the C12 atom is substituted by two methyl
C(8), C(8), and, more interesting, higher-order rings
R2 (8) were demonstrated in both crystals.
groups, whereas in 2b this atom is shared between two
rings, 4H-thiopyrane and cyclohexane. The least-squares
planes through these rings are at an angle of 75.73(11)°.
In the crystal lattice of 2a, the molecules are connected by
N3–H3···O16i and N8–H8···O15ii hydrogen bonds, form-
ing chains parallel to the c axis, while in 2b chains of mol-
ecules linked by N3–H3···O19i and N8–H8···O18ii
hydrogen bonds, running parallel to the a axis, are ob-
served. Using graph-set notation14,15 first-order chains,
2
The possible use of compound from series 1 as effective
heterodienes in hetero-Diels–Alder reactions has been
shown with some dienophiles, namely 1-(4-bromophe-
nyl)pyrrole-2,5-dione, (3,5-dioxo-4-azatricyclo[5.2.1.02,6]-
dec-8-en-4-yl)acetic acid, and norbornene (Scheme 3).
Reactions were performed in glacial acetic acid medium
with a catalytic amount of hydroquinone (2–3 mg) to pre-
vent polymerization processes.16,17
O
O
Br
HO
O
H
H
N
S
N
O
O
H
N
O
Br
Br
N
O
S
HO
S
S
N
O
N
O
O
R1
H
NH
R1 R2
S
O
R1
R2
5a,b
+
O
O
O
S
H
R2
H
N
S
1a–c
H
N
N
O
S
S
O
H
R1 R2
S
4a–c
O
6a,b
R1
R2
a R1 = R2 = Me
b R1–R2 = (CH2)5
c R1–R2 = (CH2)4
Scheme 3 Synthesis of new thiopyrano[2,3-d][1,3]thiazol-2-one derivatives (4–6). Reagents and conditions: 1 (1.0 equiv), dienophile (1.2
equiv), hydroquinone, AcOH, reflux, 1 h.
Synlett 2011, No. 10, 1385–1388 © Thieme Stuttgart · New York

LETTER
Fused Thiopyrano[2,3-d][1,3]thiazoles
1387
The NMR data of compounds 417 revealed the presence of
a mixture of stereoisomers with diastereomeric ratios
from ~5:1 (4a) to ~12:1 (4c). However, spectral features
consistent with only one stereoisomer for compounds 5
and 6 were present in the NMR spectra, indicating that the
reaction is stereoselective, most probably due to steric
hindrance.2,17
recrystallized with ethanol or toluene for 1 or with mixtures
of DMF–EtOH or DMF–AcOH (1:2) for 3
(9) Spectral and analytical data for compounds 1 and 3 are as
follows. 5-Isopropylidene-4-thioxo-2-thiazolidinone (1a):
Yield: 90%; mp 152–154 °C (EtOH). 1H NMR (400 MHz,
DMSO-d6): d = 1.67 (s, 3 H, CH3), 2.17 (s, 3 H, CH3), 11.85
(s, 1 H, NH). 5-Cyclohexylidene-4-thioxo-2-thiazolidinone
(1b): Yield: 76%; mp 120–122 °C (EtOH). 1H NMR (400
MHz, DMSO-d6): d = 1.65 (m, 8 H), 2.30 (m, 2 H,
cyclohexylidene), 10.90 (s, 1 H, NH). 5-Cyclopentylidene-
4-thioxo-2-thiazolidinone (1c): Yield: 74%; mp 174–176 °C
(toluene). 1H NMR (400 MHz, DMSO-d6): d = 1.78 (quint.,
J = 6.8 Hz, 2 H), 1.89 (quint., J = 6.8 Hz, 2 H), 2.41 (t,
J = 6.4 Hz, 2 H), 3.03 (t, J = 6.4 Hz, 2 H, cyclopentylidene),
13.24 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d6): d =
192.83, 170.46, 166.64, 123.88, 39.71, 37.56, 27.69, 25.71.
LC-MS: m/z (%) = 200.1 (100) [M+ + 1]. 8,8-Dimethyl-5,8-
dihydro-2H-[1,3]thiazolo[5¢,4¢:5,6]thiopyrano[2,3-
d][1,3]thiazol-2,6 (3H)-dithione (3a): Yield: 52%; mp 190–
192 °C (DMF–AcOH). 1H NMR (400 MHz, DMSO-d6): d =
1.54 (s, 6 H, 2 × CH3), 13.53 (s, 2 H, NH). LC-MS: m/z (%)
= 305.2 (100) [M+ + 1]. Spiro[cyclopentane-1,8¢-(5,8-
dihydro-2H-[1,3]thiazolo[5¢,4¢:5,6]thiopyrano[2,3-
d][1,3]thiazol)]-2,6 (3H)-dithione (3c): Yield: 24%; mp
155–157 °C (DMF–EtOH). 1H NMR (400 MHz, DMSO-
d6): d = 1.55–2.03 (m), 2.10–2.45 (m, 8 H, cyclopentyl),
13.67 (s, 2 H, 2 × NH). LC-MS: m/z (%) = 331.1 (100)[M+ + 1]
(10) Preparation of 8,8-R1,R2-5,8-dihydro-2H-[1,3]thiazolo-
[5¢,4¢:5,6]thiopyrano[2,3-d][1,3]thiazol-2,6 (3H)-diones (2).
To a solution of 4-thioxo-2-thiazolidinone (5 mmol) and the
appropriate ketone (6 mmol) in EtOH (20 mL), a catalytic
amount of ethanolamine was added. The reaction mixture
was heated at reflux for 15 min. After cooling the reaction
mixture to room temperature, the product was filtered off,
washed with EtOH, and Et2O, and recrystallized (DMF–
EtOH, 1:2)
Newly synthesized compounds 2a, 3a, 4a, 5a, 6a, and 2b
were selected by the National Cancer Institute ‘Develop-
mental Therapeutic Program’ for in vitro cell line screen-
ing to investigate their anticancer activity. Anticancer
assays were performed according to the US NCI proto-
col.18–20 The tested compounds showed insignificant lev-
els of anticancer activity; having weak average values,
albeit with some specific influence on some cancer cell
lines.21 It was established that IGROV-1 (ovarian cancer)
and UO-31 (renal cancer) cell lines were sensitive to com-
pound 2b action as well as MOLT-4 (leukemia) cell line to
2a and Leukemia cell lines to 4a, correspondingly. Com-
parison of 2a and 3a activity levels showed that anticancer
activity of thiorodanine derivative 3a was lower than that
of the oxo-analogue. Compound 6a possessed the highest
level of anticancer activity among the tested compounds,
with lgGI50 = –4.66 (mean concentration of 50% growth
inhibition 21.9 mM) and could be considered to be a pro-
spective scaffold for further optimization.
Acknowledgment
We thank Dr. V.L. Narayanan from the Drug Synthesis and Chemi-
stry Branch, National Cancer Institute, Bethesda, MD, USA, for in
vitro evaluation of anticancer activity.
(11) Spectral and analytical data for compounds 2 are as follows.
8,8-Dimethyl-5,8-dihydro-2H-[1,3]thiazolo[5¢,4¢:5,6]-
thiopyrano[2,3-d][1,3]thiazol-2,6 (3H)-dione (2a). Yield:
45%; mp 210–212 °C (DMF–EtOH). 1H NMR (400 MHz,
DMSO-d6): d = 1.46 (s, 6 H, 2 × CH3), 11.53 (s, 2 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 170.14, 112.40,
112.33, 36.24, 31.59. LC-MS: m/z (%) = 273.0(100) [M+ + 1].
Spiro[cyclohexane-1,8¢-(5,8-dihydro-2H-[1,3]thiazolo-
[5¢,4¢:5,6]-thiopyrano[2,3-d][1,3]thiazol-2,6(3H)-dione
(2b): Yield: 45%; mp 235–237 °C (DMF–EtOH). 1H NMR
(400 MHz, DMSO-d6): d = 1.47 (br s, 2 H), 1.64 (br s, 4 H),
1.82 (t, J = 5.2 Hz, 4 H, cyclohexyl), 11.79 (s, 2 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 170.49, 114.67,
112.84, 39.66, 38.63, 24.84, 23.30. LC-MS: m/z (%) = 313.1
(100) [M+ + 1]
References and Notes
(1) Lesyk, R. B.; Zimenkovsky, B. S. Curr. Org. Chem. 2004,
1547.
(2) Lesyk, R.; Zimenkovsky, B.; Atamanyuk, D.; Jensen, F.;
Kiec-Kononowicz, K.; Gzella, A. Bioorg. Med. Chem. 2006,
5230.
(3) Lesyk, R.; Vladzimirska, O.; Holota, S.; Zaprutko, L.;
Gzella, A. Eur. J. Med. Chem. 2007, 641.
(4) Kaminskyy, D.; Zimenkovsky, B.; Lesyk, R. Eur. J. Med.
Chem. 2009, 3627.
(5) Matiychuk, V. S.; Lesyk, R. B.; Obushak, M. D.; Gzella, A.;
Atamanyuk, D. V.; Ostapiuk, Y. V.; Kryshchyshyn, A. P.
Tetrahedron Lett. 2008, 4648.
(12) Kumar, A.; Singh, P.; Saxena, A.; De, A.; Chandra, R.;
Mozumbar, S. Catal. Commun. 2008, 17.
(6) (a) Ohishi, Y.; Mukai, T.; Nagahara, M.; Yajima, M.;
Kajikawa, N.; Miyahara, K.; Takano, T. Chem. Pharm. Bull.
1990, 1911. (b) Ohishi, Y.; Mukai, T.; Nagahara, M.;
Yajima, M.; Kajikawa, N. Chem. Pharm. Bull. 1992, 907.
(7) Borisova, M. A.; Ginak, A. I.; Sochilin, Ye. G. Zh. Prikl.
Khim. (in Russian) 1970, 1886; Chem. Abstr. 1970, 520550.
(8) Preparation of 5-alkylidene-4-thioxo-2-thiazolidinone (1)
and 8,8-R1,R2-5,8-dihydro-2H-[1,3]thiazolo[5¢,4¢:5,6]thio-
pyrano[2,3-d][1,3]thiazol-2,6 (3H)-dithione (3). To a
solution of 4-thioxo-2-thiazolidinone or 2,4-dithioxo-
thiazolidine (5 mmol) in the appropriate ketone (20 mL),
2–3 drops of ethanolamine were added. The reaction mixture
was stirred at room temperature for 1 h, then diluted with
H2O and 2–3 drops of AcOH were added. The solid product
was filtered off, washed with H2O, EtOH, and Et2O, and
(13) Crystallographic data for 2a: Empirical formula:
C9H8N2O2S3; formula weight: 272.35; yellow, block; crystal
system: orthorhombic; space group: Pbca (#61);
a = 10.0548 (17), b = 13.7198 (17), c = 16.3093 (18) Å;
V = 2249.9 (5) Å3; Z = 8; Dcalc = 1.608 g/cm3;
F(000) = 1120; diffractometer: Kuma KM-4; residuals:
R[F2 > 2s(F2)], wR(F2): 0.048, 0.1347.
Crystallographic data for 2b: Empirical formula:
C12H12N2O2S3; formula weight: 312.42: colorless, lath;
crystal system: orthorhombic; space group: Pbca (#61);
a = 15.5909 (19), b = 10.2253 (9), c = 16.4741 (17) Å;
V = 2626.3 (5) Å3; Z = 8; Dcalc = 1.580 g/cm3;
F(000) = 1296; diffractometer: Kuma KM-4; residuals:
R[F2 > 2s(F2)], wR(F2): 0.040, 0.1329.
Synlett 2011, No. 10, 1385–1388 © Thieme Stuttgart · New York

1388
D. Kaminskyy et al.
LETTER
119.98, 116.91, 52.29, 49.48, 48.26, 47.98, 46.70, 41.87,
The supplementary crystallographic data have been
deposited at the Cambridge Crystallographic Data Centre
(CCDC), 12 Union ROAD, Cambridge CB2 1EZ (UK), Tel.:
(+44) 1223/336–408, Fax: (+44) 1223/336–033, E-mail:
deposit@ccdc.cam.ac.uk, World Wide Web: http://
www.ccdc.cam.ac.uk (CCDC for 2a: 780127, for 2b:
780128)
39.88, 36.01, 28.43, 25.99. LC-MS: m/z (%) = 395.21 (100)
[M+ + 1]. 2-{Spiro[cyclohexane-1,9¢-(6,13,15-trioxo-3,7-
dithia-5,14-diazapentacyclo[9.5.1.02,10.04,8.012,16]heptadec-4
(8)-en-14-yl)]}acetic acid (5b): Yield: 71%; mp >240 °C
(EtOH). 1H NMR (400 MHz, DMSO-d6): d = 1.27–1.35 (m,
2 H), 1.38–1.67 (m, 8 H), 1.83–1.89 (m, 2 H), 2.77 (dd,
J = 4.0, 14.6 Hz, 2 H), 3.19 (m, 3 H), 3.35 (d, J = 8.4 Hz,
1 H, norbornane and cyclohexyl), 3.99 (d, J = 17.3 Hz, 1 H,
NC2C), 4.11 (d, J = 17.3 Hz, 1H, NCH2C), 11.31 (s, 1 H,
NH), 13.21 (br. s, 1 H, COOH). 13C NMR (100 MHz,
DMSO-d6): d = 177.39, 177.04, 171.37, 169.51, 120.79,
51.03, 50.79, 49.74, 48.58, 46.27, 39.95, 39.50, 38.82,
26.01, 22.42, 22.27. LC-MS: m/z (%) = 435.2 (100) [M+ +
1]. 9,9-Dimethyl-3,7-dithia-5-azatetracyclo[9.2.1.02,10.04,8]-
tetradecen-4 (8)-one-6 (6a): Yield: 63%; mp 125–127 °C
(MeCN). 1H NMR (400 MHz, DMSO-d6): d = 1.21 (s, 6 ,
2 × CH3), 1.03 (d, J = 9.9 Hz, 1 H), 1.38 (m, 2 H), 1.46–49
(m, 3 H), 1.87 (d, J = 8.2 Hz, 1 H), 2.22 (m, 2 H), 3.37 (d,
J = 8.2 Hz, 1 H, norbornane fragment), 11.34 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 170.90, 120.65,
116.47, 58.06, 45.36, 38.94, 36.03, 35.02, 31.36, 28.75,
28.17, 24.70. LC-MS: m/z (%) = 268.0 (98.18) [M+ + 1].
Spiro[cyclohexane-1,9¢-(3,7-dithia-5-azatetracyclo-
[9.2.1.02,10.04,8]tetradecen-4 (8)]one-6 (6b): Yield: 52%; mp
195–197 °C (EtOH). 1H NMR (400 MHz, DMSO-d6): d =
0.93 (d, J = 9.7 Hz, 1 H), 1.17 (m, 3 H), 1.32 (m, 3 H), 1.45–
1.55 (m, 7 H), 1.79 (m, 1 H), 1.91 (m, 1 H), 2.17 (m, 2 H),
2.25 (d, J = 3.6 Hz, 1 H), 3.29 (d, J = 8.2 Hz, 1 H,
(14) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta
Crystallogr., Sect. B: Struct. Sci. 1990, 46, 256.
(15) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L.
Angew. Chem., Int. Ed. Engl. 1995, 1555.
(16) General experimental procedure for the hetero-Diels–Alder
reaction yielding fused derivatives of thiopyrano[2,3-d]-
[1,3]thiazol-2-ones (4–6). A mixture of the appropriate
5-alkylidene-4-thioxo-2-thiazolidinone (10 mmol) and the
appropriate dienophile {1-(4-bromophenyl)pyrrole-2,5-
dione, (3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-
yl)acetic acid or norbornene} (12 mmol) was heated at reflux
for 1 h with a catalytic amount of hydroquinone (2–3 mg) in
glacial AcOH (10 mL), then left overnight at r.t. The
precipitated crystals were filtered off, washed with EtOH,
and recrystallized from the appropriate solvent
(17) Spectral and analytical data for compounds (4–6) are as
follows. 6-(4-Bromophenyl)-8,8-dimethyl-3,4a,7a,8-
tetrahydropyrrolo[3¢,4¢:5,6]thiopyrano[2,3-d]thiazol-2,5,7-
trione (4a): Yield 85%; mp >240 °C (DMF–EtOH). 1H
NMR (400 MHz, DMSO-d6): d = 1.39 (s, 3 H, CH3), 1.49 (s,
3 H, CH3), 3.50 (d, J = 8.7 Hz, 1 , 7a-H), 4.93 (d, J = 8.7 Hz,
1 , 4a-H), 7.19 (d, J = 8.7 Hz, 2 H, ArH), 7.68 (d, J = 8.7 Hz,
2 H, ArH), 11.55 (s, 1 H, NH, major isomer). 13C NMR (100
MHz, DMSO-d6): d = 174.53, 172.92, 170.92, 132.91,
131.53, 122.52, 117.48, 116.12, 52.87, 43.57, 36.31, 26.93,
23.94 major isomer. LC-MS: m/z (%) = 426.0 (91.59) [M+ +
1]. Spiro[cyclohexane-1,8¢-(6-(4-bromophenyl)-3,4a,7a,8-
tetrahydropyrrolo[3¢,4¢:5,6]thiopyrano[2,3-d]thiazol)]-
2,5,7-trione (4b): Yield: 74%; mp 236–238 °C (EtOH). 1H
NMR (400 MHz, DMSO-d6): d = 1.52–1.80 (m, 6 H), 2.03
(m, 3 H), 2.27 (m, 1 H, cyclohexyl), 4.14 (d, J = 8.4 Hz, 1 ,
7a-H), 4.67 (d, J = 8.4 Hz, 1 , 4a-H), 7.13 (d, J = 8.8 Hz, 2 ,
ArH), 7.67 (d, J = 8.8 Hz, 2 , ArH), 11.50 (s, 1 H, NH, major
isomer). Spiro[cyclopentane-1,8¢-(6-(4-bromophenyl)-
3,4a,7a,8-tetrahydropyrrolo[3¢,4¢:5,6]thiopyrano[2,3-
d]thiazol)]-2,5,7-trione (4c): Yield: 70%; mp 227–229 °C
(DMF–EtOH). 1H NMR (400 MHz, DMSO-d6): d = 1.48–
1.62 (m, 1 H), 1.64–1.82 (m, 4 H), 1.87–1.96 (m, 1 H), 2.06–
2.17 (m, 3 H, cyclopentyl fragment), 3.85 (d, J = 8.5 Hz, 1 ,
7a-H), 4.78 (d, J = 8.5 Hz, 1 , 4a-H), 7.06 (d, J = 8.5 Hz,
2 H, ArH), 7.69 (d, J = 8.5 Hz, 2 H, ArH), 11.62 (s, 1 H, NH,
major isomer). 13C NMR (100 MHz, DMSO-d6): d = 174.44,
174.37, 170.45, 132.61, 131.42, 129.07, 122.08, 118.44,
117.35, 53.68, 47.44, 44.65, 37.24, 36.84, 24.02, 23.42
major isomer. LC-MS: m/z (%) = 452.0 (90.64) [M+ + 1].
2-[9,9-Dimethyl-6,13,15-trioxo-3,7-dithia-5,14-diazapenta-
cyclo[9.5.1.02,10.04,8.012,16]heptadec-4 (8)-en-14-yl]acetic
acid (5a): Yield: 69%; mp >240 °C (EtOH). 1H NMR (400
MHz, DMSO-d6): d = 1.14 (s, 3 H, CH3), 1.17 (s, 3 H, CH3),
1.50 (d, J = 10.5 Hz, 1 H), 1.75 (d, J = 10.5 Hz, 1 H), 2.17
(d, J = 2.4 Hz, 1 H), 2.72 (dd, J = 4.7, 14.9 Hz, 2 H,), 3.23
(m, 1 H), 3.27–3.33 (m, 1 H), 3.38 (d, J = 8.2 Hz, 1 H,
norbornane), 4.00 (d, J = 18.2 Hz, 1 H, NCH2C), 4.08 (d,
J = 18.2 Hz, 1 H, NCH2C), 11.43 (s, 1 H, NH). 13C NMR
(100 MHz, DMSO-d6): d = 177.03, 176.76, 170.79, 169.20,
norbornane and cyclohexyl), 11.35 (s, 1 H, NH). 13C NMR
(100 MHz, DMSO-d6): d = 171.23, 121.79, 50.48, 48.21,
37.17, 35.69, 34.57, 31.82, 27.95, 25.87, 22.53.
LC-MS: m/z (%) = 308.1 (100) [M+ + 1]
(18) Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull,
K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-
Wolff, A. J. Nat. Cancer Inst. 1991, 757.
(19) Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 91.
(20) Monks, A.; Scudiero, D. A.; Johnson, G. S.; Paull, K. D.;
Sausville, E. A. Anti-Cancer Drug Des. 1997, 533.
(21) Compounds 2a, 3a, and 2b were evaluated with a 60 human
tumor cell lines panel at concentrations of 10–5 M and
showed the following mean growth percent values: 2a –
101.51%, 3a – 108.41%, 2b – 105.07%. However, decreases
in the growth percent values were detected following
treatment of selected cell lines with compounds: MOLT-4
(leukemia) – 62.73% (compound 2a); IGROV1 (ovarian
cancer) – 50.98% and UO-31 (renal cancer) – 49.34%
(compound 2b). Compounds 4a, 5a, and 6a were passed on
for evaluation in the full panel of 60 human tumor cell lines
at 10-fold dilutions ranging from 10–4 to 10–8 M. Compounds
were characterized by the following values of mean dose
response parameters: lgGI50 = –4.04, lgTGI = –4.01,
lgLC50 = –4.0 (compound 4a); lgGI50 = –4.00, lgTGI =
–4.00, lgLC50 = –4.00 (compound 5a); lgGI50 = –4.66,
lgTGI = –4.25, lgLC50 = –4.04 (compound 6a). Compound
4a showed the highest antitumor cytotoxicity against
leukemia cell lines: HL-60 (TB), (lgGI50 = –4.62), MOLT-4;
(lgGI50 = –4.48) and SR (lgGI50 = –5.13). Compound 6a
sensitized melanoma UACC-62 cell line (lgGI50 = –4.91)
as well as breast cancer MDA-MB-435 cell line (lgGI50
=
–4.87) but did not show a selective influence on any whole
cancer subtype cell line panel.
Synlett 2011, No. 10, 1385–1388 © Thieme Stuttgart · New York