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://
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