348 JOURNAL OF CHEMICAL RESEARCH 2007
NH2
NH2
N
NH2
N
N
N
N
N
N
Na2CO3
DMF
N
BrCH
+
+
2
R
N
H
N
N
N
CH2
CH2
R
1a-c
9-BA
2a-c
a R= o-B(OH)2 b R= m-B(OH)2 c R= p-B(OH)2
Scheme 1
Table 3 In vitro antitumor activities to human tumor cell lines
of the compounds at the concentration of 10 μmol/l
Table 2 Effects of compounds on TNF production from mouse
peritoneal macrophages at the concentration of 1 × 10-5 mol/l
Compound
Suppression ratio
Group
Absorbance value
Inhibition/%
HL-60
BGC-823
Bel-7402
KB
Control
0.669 0.041
0.181 0.016
0.324 0.040**
0.197 0.003
0.360 0.005***
0.333 0.017***
LPS (2.5 mg/ml)
2a
2b
2c
9.25
19.96
17.42
–4.62
7.81
15.00
–24.12
–10.39
–5.93
–24.39
–20.23
–29.19
9-BA
2a
2b
2c
29.3
3.2
36.6
31.0
9-o-Boronobenzyladenine(2a): M.p. 279–280°C; 1H NMR (300 MHZ,
DMSO-d6): δ5.51 (s, 2H, N9–CH2), 7.35–7.44 (m, 4H, Ar–H), 7.75
(s, 1H, purin-8-H), 7.90 (s, 2H, D2O exchangeable, B(OH)2), 8.55
(s, 1H, purin-2-H); IR: υmax/cm-1 (KBr) 3324, 3104 and 1659 (NH2),
1619, 1568, 1512 and 1495 (purine and benzene), 1428 (Ar–B), 1373
(B–O), 1330 (CAr–N), 1270 (CH2–N); Anal. Calcd for C12H12BN5O2:
C, 53.56; H, 4.50; N, 26.03. Found: C, 53.37; H, 4.67; N, 25.96.
9-m-Boronobenzyladenine(2b): M.p. 240–242°C; 1H NMR
(300 MHZ, DMSO-d6): δ 5.28 (s, 2H, N9–CH2), 6.63–6.73 (m, 3H,
Ar–H), 7.11 (t, 1H, Ar–H), 7.24 (s, 2H, D2O exchangeable, NH2),
8.15 (s, 1H, purin-8-H), 8.23 (s, 1H, purin-2-H); IR: υmax/cm-1 (KBr)
3270, 3104, 1675 (NH2), 1603, 1570 and 1488 (purine and benzene),
1423 (Ar-B), 1366 (B-O), 1338 (CAr–NH2), 1250 (CH2-N); Anal.
Calcd for C12H12BN5O2: C, 53.56; H, 4.50; N, 26.03. Found: C,
53.48; H, 4.47; N, 26.08.
Mean s n = 3 *P < 0.05 **P < 0.01 ***P < 0.001 vs LPS.
9-BA, and were worthy of further study. The data in Table 3,
however, showed all three compounds have poor activities
against human tumor cell lines in vitro. Their properties as
antitumor agents for Boron Neutron Capture Therapy are
being in process.
Experimental
Microwave assisted syntheses were performed in a commercal
microwave reactor (XA-100, Beijing Xianghu Scence and
Technology Development Co. Ltd, Beijing, P. R. China) at 500 W. The
temperature of the reaction mixture was measured by an immersed
platinum resistance thermometer. All starting boronic acd and other
reagents employed are commercal available and were used without
further purification. TLC analyses and separations were performed
on silica gel GF254 plates using CH2Cl2 – MeOH (8: 1, v/v) as
eluent, and the plates were visualized with UV light. Melting points
9-p-Boronobenzyladenine(2c): M.p. 256–258°C; 1H NMR (300
MHZ, DMSO-d6): δ 5.36 (s, 2H, N9–CH2), 7.25 (d, 2H, Ar–H),
7.24 (s, 2H, D2O exchangeable, NH2), 7.73 (d, 2H, Ar–H), 8.07(s,
2H, D2O exchangeable, B(OH)2), 8.14 (s, 1H, purin-8-H), 8.27 (s,
1H, purin-2-H); IR: υmax/cm-1 (KBr) 3472, 3352, 1638 (NH2), 1610,
1579, 1511 and 1485 (purine and benzene), 1421 (Ar–B), 1351
(B–O), 1325 (CAr–N), 1250 (CH2–N); Anal. Calcd for C12H12BN5O2:
C, 53.56; H, 4.50; N, 26.03. Found: C, 53.21; H, 4.39; N, 26.24.
9-Benzyladenine(9-BA): M.p. 230–232°C (lit.,17 230°C); 1H NMR
(300MHZ, DMSO-d6): δ5.37 (s, 2H, N9–CH2), 7.27 (s, 2H, D2O
exchangeable, NH2), 7.31(m, 5H, Ar–H), 8.14(s, 1H, purin-8-H),
8.27(s, 1H, purin-2-H), IR, υmax/cm-1 (KBr) 3432, 3299, 1646 (NH2),
1597, 1572 and 1485(purine and benzene), 1325 (CAr–N), 1246
(CH2–N).
1
uncorrected were measured on a XT-5 apparatus. H NMR spectra
were determined on a Bruker-300 MHz spectrometer with TMS
as internal standard. IR spectra were recorded on a Bruker IFS25
Infrared Spectrometer. Element analyses were performed on a Carlo
Erba 1106 Element Analyser. The in vitro anti-inflammatory activity
of the compounds was evaluated by testing their inhibitory effect on
TNFα production from cultured mouse peritoneal macrophages.22
Suppression ratio of the compounds to cell proliferation of human
promyelocytic leukaemia HL-60 was determined with MTT assay.23
Inhibitory effect of the compounds to cell proliferation of human
gastric carcnoma BGC-823, human hepatocarcnoma Bel-7402
and human nasopharyngeal carcnoma KB was measured by SRB
staining.24
Received 26 April 2007; accepted 25 June 2007
Paper 07/4621 doi: 10.3184/030823407X225491
Conventional thermal iynthetic procedure
A mixture of 2 mmol adenine, 2.4 mmol appropriate borono-
methylphenylboric acd, 300 mg anhydrous K2CO3, and 34 mg TBAI
in 10 ml dry DMF was stirred and heated at 120°C overnight, The
mixture was filtered while it was still hot, and the cake was washed
with DMF. DMF was removed from the filtrate under reduced
pressure. The residue was dissolved in a minor amount of methanol
and purified on TLC to yield the product.
References
1
A.D. Pivazyan, D.S. Matteson, Asztalos-L. Fabry, R.P. Singh, P.F. Lin,
W. Blair, K. Guo, B. Robinson and W.H. Prusoff, Biochem. Pharmacol.,
2000, 60, 927.
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U. Bacha, J. Barrila, A.Velazquez-Campoy, S.A. Leavitt and E. Freire,
Biochemiitry, 2004, 43, 4906.
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J. Adams and M. Kauffman, Cancer inveitigation, 2004, 22, 304.
K.C. Park, K. Yoshino and H. Tomiyasu, Syntheiii, 1999, 2041.
Y. Yamamoto, T. Seko, F.G. Rong and H. Nemoto, Tetrahedron Lett.,
1989, 30, 7191.
A. Matsumura, Y. Shibata, T. Yamamoto, F. Yoshida, T. Isobe, K. Nakai,
Y. Hayakawa, M. Kiriya, N. Shimojo, K. Ono, I. Sakata, S. Nakajima,
M. Okumura and T. Nose, Cancer Lett., 1999, 141, 203.
G. Springsteen and B. Wang, Tetrahedron, 2002, 58, 5291.
Microwave aiiiited iynthetic procedure
A dried round-bottom flask (25 ml) equipped with a condenser was
charged with a solution of 2 mmol adenine, 2.4 mmol appropriate
boronomethylphenylboric acd and 300 mg anhydrous K2CO3 in
10 ml dry DMF. The solution was stirred and irradiated under
microwave at 120°C for 10 min. The reaction mixture was worked up
similarly as that in the conventional procedure to give the product.
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PAPER: 07/4621