3
lymphoma (B cell non-Hodgkin's lymphoma)), Raji (human
Burkitt's lymphoma), DG-75 (metastatic Burkitt's lymphoma),
and HepG2 (hepatocellular carcinoma). Using the NIH 3T3
(mouse fibroblast) cell line, we determined the borderline
concentration, which is relevant to the highest tolerated dose, for
each compound. The basal cytotoxicity is expected to be used to
predict the starting doses for in vivo acute oral LD50 values in
rodents (Table 2).
molecule. A new simple synthetic procedure was used to
prepare selenopheno[2,3-c] and [3,2-c]dihydropyridines. As a
result, a convenient protocol to synthesize the (S)-clopidogrel
selenium analogue 10 and its isomer 18 was developed. The
introduction of a selenium atom into the clopidogrel molecule
increased its antiproliferative activity toward non-Hodgkin’s
lymphoma Mino cells. The obtained data results open a route to
further modifications of a series of analogues of selenopheno[2,3-
c]- and [3,2-c]dihydropyridines which may lead to a compound
with extended activity against tumours.
TMS
Br
Br
O
OTf
Se
b
c
a
Supporting Information
N
N
N
N
Supporting information contains full experimental data, copies
of the 1H and 13C NMR spectra of all compounds.
Bn
11
Bn
12
Bn
13
Bn
14
Acknowledgments
d
H
We are grateful for financial support provided by Latvian
Council of Science (447/2012).
g
N
e, f
Cl
N
N
Bn
R
Se
O
Se
Se
OMe
References and notes
18
16 [R=C(O)OMe]
17 [R=H]
15
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Scheme 2. Synthetic procedure used to prepare 18. Reaction conditions: (a):
0.8 M LHMDS (1.2 equiv.), PhN(Tf)2 (1.2 equiv.), THF, -78 °C to -20 °C, -
78 °C to r.t., 82%; (b): trimethylsilylacetylene (1.5 equiv.), 10% Pd(PPh3)4,
12% CuI, DMF/DIPEA, r.t., 65%; (c): SeO2/HBr (1.2 equiv.), dioxane, 0 °C
to r.t., 44%; (d):10% Pd/C (5 equiv.), H2, EtOH/THF/HCOOH = 5/1/0.1, r.t.,
72%; (e): MeOC(O)Cl (7 equiv.), 0 °C to r.t., 83%; (f): 2 M NaOH, MeOH,
reflux, 95%; (g): (R)-4-nitrobenzenesulfonyloxy-2-(2-chlorophenyl)acetate
(1.7 equiv.), 30% aq. solution of K2CO3, CH2Cl2, reflux (83%).
Table 2. In vitro cytotoxicity (IC50, µM) in monolayer tumour cell lines
and normal cell line NIH3T3 (mouse fibroblasts).
Cell line
HL-60
Jurkat
Clopidogrel
81 7
7
10
15
18
102 26
43 12
86 15
134 32
131 51
195 19
61 12
1313
81 19
27 10
60 10
24 8
153 22
56 6
71 22
26 8
54 11
43 18
114 32
92 16
79 8
811
33 7
U937
45 9
32 12
125 9
291 41
70 22
224 16
1438
Mino
76 18
88 9
Raji
81 11
144 16
54 13
848
DG-75
HepG2
LD50, (mg/kg)
88 19
74 14
546
By inspecting the cytotoxic profile of clopidogrel, we
concluded that this drug exhibited a medium cytotoxic effect on
the studied tumour cell lines (IC50 varied from 33 to 88 µM).
Jurkat and histiocytic lymphoma U937 cells were more sensitive
to clopidogrel and the basal toxicity was detected at LD50 = 546
mg/kg. Surprisingly, its selenium analogue 10 exhibited an
extended cell type selectivity. Compared to clopidogrel,
derivative 10 exhibits a good antiproliferative effect against non-
Hodgkin’s lymphoma Mino cells (IC50 = 24 µM). Moreover, the
basal toxicity data confirmed that 10 exhibited a substantially
lower toxicity than clopidogrel. In a similar manner to derivative
10, selenium isoster 18 showed better cytotoxicity using the
Mino cell line (IC50 = 43 µM) than clopidogrel (IC50 = 76 µM)
and a moderate projected LD50 value of 811 mg/kg. Notably, the
simple N-benzyl analogue 15 exhibited a slight better effect on
U937 than clopidogrel.
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981-992; c) Wu, B.; Yoshikai, N. Angew. Chem. Int. Ed. Engl.
2013, 52, 10496–10499; d) Kesherwani, T.; Worlikar, S. A.;
In summary, we have developed a simple approach to
construct the selenophene ring on a non-aromatic cyclohexene