Chemistry Letters 2002
115
dependent in the concentration range from 5 ꢂ 10ꢃ5 to 1ꢂ
10ꢃ3 M (Figure 1), and the apparent IC50 value, which is a 50%
inhibition concentration of FFA release in each complex, was
estimated from these data, in which the IC50 values for VS are
normalized to 1.0 mM to compare with other complexes. The
obtained IC50 values for two vanadyl complexes (11.2 mM for 4a
and 2.45 mM for 4b) were shown to be higher than that of VOSO4
(IC50 ¼ 1:0 mM) as a positive control. On the other hand, zinc(II)
complex (5b) (IC50 ¼ 0:04 mM) exhibited an extremely high
insulin-mimetic activity than VOSO4 (IC50 ¼ 1:0 mM). The
partition coefficient (Coctanol/Cbuffer) of zinc(II) complex (5b) was
measured to be 1.62 by means of UV-vis spectroscopy, indicating
the importance of some degree of the hydrophobicity.3;8
Unfortunately, the activity of zinc(II) complex (5a) could not
be measured accurately owing to its low solubility under the
employed condition.
reported previously in terms of IC50 value, 2) zinc(II) complex
(5b) showed activity about 10 times higher than the first insulin-
mimetic zinc(II) complexes, bis(maltolato)zinc(II) and bis(2-
hydroxypyridine-N-oxide)zinc(II),7 and 3) zinc(II) complex (5b)
exhibited insulin-mimetic activity higher than the corresponding
vanadyl complex (4b). The result 3) is the first report concerning
the direct comparison of the activities between vanadyl and
zinc(II) complexes. On the basis of the results, we propose here
that zinc(II) complex (5b) is a potent insulin-mimetic complex.
Further investigation on in vivo activity as well as action
mechanism of the complex in relation to the insulin receptor
and glucose transporter is under way.
References and Notes
1
L. C. Y. Woo, V. G. Yuen, K. H. Thompson, J. H. McNeill, and C.
Orvig, J. Inorg. Biochem., 76, 251 (1999).
2
3
S. M. Brichard and J.-C. Henquin, TiPS, 16, 265 (1995).
H. Sakurai and A. Tsuji, in ‘‘Vanadium in the Environment, Part 2,’’ ed.
by J. O. Nriagu, John Wiley & Sons, New York (1998), p 297; H.
Sakurai, K. Fujii, S. Fujimoto, Y. Fujisawa, K. Takechi, and H. Yasui, in
‘‘Vanadium Compounds: Chemistry, Biochemistry, and Therapeutic
Applications,’’ ed. by A. S. Tracey and D. C. Crans, American
Chemical Society, Washington, D.C. (1998), p 344.
4
5
K. H. Thompson and C. Orvig, J. Chem. Soc., Dalton Trans., 2000,
2885.
H. Sakurai, H. Sano, T. Takino, and H. Yasui, Chem. Lett., 1999, 913; H.
Sakurai, H. Sano, T. Takino, and H. Yasui, J. Inorg. Biochem., 80, 99
(2000); S. Takeshita, I. Kawamura, T. Yasuno, C. Kimura, T.
Yamamoto, J. Seki, A. Tamura, H. Sakurai, and T. Goto, J. Inorg.
Biochem., 85, 179 (2001).
6
7
8
K. T. Smith and F. H. Nielsen, in ‘‘Trace Minerals in Foods,’’ ed. by
K. T. Smith, Marcel Dakker, New York (1988), p 209 and p 257.
Y. Yoshikawa, E. Ueda, K. Kawabe, H. Miyake, H. Sakurai, and Y.
Kojima, Chem. Lett., 2000, 874.
J. Ohkanda and A. Katoh, Rev. Heteroatom Chem., 18, 87 (1998) and
references cited therein; A. Katoh, K. Taguchi, H. Okada, M. Harata, Y.
Fujisawa, T. Takino, and H. Sakurai, Chem. Lett., 2000, 866.
B. L. Rai, L. S. Dekhordi, H. Khodr, Y. Jin, Z. Liu, and R. C. Hider, J.
Med. Chem., 41, 3347 (1998).
9
10 Z. Zhang, S. J. Rettig, and C. Orvig, Inorg. Chem., 30, 509 (1991).
11 Bis(1,4-dihydro-1,2-dimethyl-4-thioxo-3-pyridinolato)oxovanadium-
(IV)(4a): IR(KBr):962 cmꢃ1 (ꢀV=O); UV-vis:ꢁmax (c ¼ 5 ꢂ 10ꢃ3 M in
DMSO)/nm649("/dm3 molꢃ1 cmꢃ1 92) and 541(146). Anal. Found: C,
44.70; H, 4.11; N, 7.34%. Calcd for C14H16N2O3S2V: C, 44.80; H, 4.30;
N, 7.46%. Bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridinola-
to)-oxovanadium(IV) (4b): IR(KBr): 972 cmꢃ1 (ꢀV=O); UV-vis: ꢁmax
(c ¼ 5 ꢂ 10ꢃ3 M in DMSO)/nm 716 ("/dm3 molꢃ1 cmꢃ1 38) and 551
(160). Anal. Found: C, 57.33; H, 3.95; N, 5.39%. Calcd for
C24H20N2O3S2V: C, 57.71; H, 4.04; N, 5.61%.
12 Bis(1,4-dihydro-1,2-dimethyl-4-thioxo-3-pyridinolato)zinc(II) (5a):
IR(KBr): 1585, 1454, 1313, and 1199 cmꢃ1; UV-vis: ꢁmax (c ¼
2 ꢂ 10ꢃ5 M in DMSO)/nm 357 ("/dm3 molꢃ1 cmꢃ1 35800), 290
(8400), and 263 (38500); 1H NMR (400 MHz, DMSO-d6) ꢂ 2.47 (3H,
s), 3.91 (3H, s), 7.42 (1H,d, J ¼ 6:2 Hz), and 7.53 ppm (1H, d,
J ¼ 6:2 Hz); Anal. Found: C, 45.15; H, 4.27; N, 7.27%. Calcd for
C14H16N2O2S2Zn: C, 44.99; H, 4.31; N, 7.49%. Bis(1,4-dihydro-2-
methyl-1-phenyl-4-thioxo-3-pyridinolato)zinc(II) (5b): IR(KBr): 1610,
Figure 1. Inhibitory effects of vanadul (upper) and zinc(II) complexes
(bottom) on FFA release from rat adipocytes treated with epinephrine in
the presence of 0.1% glucose.13 B is blank without epinephrine and
complex, and C is control without complex. In the case of VS1-3, 4a-1-3,
1571, 1490, 1459, 1321, 1222, and 1170 cmꢃ1
; UV-vis: ꢁmax
and 4b-1-3, 1-3 stand for concentrations of the complexes: 1 ¼ 1 ꢂ 10ꢃ4
;
(c ¼ 2 ꢂ 10ꢃ5 M in DMSO)/nm 363 ("/dm3 molꢃ1 cmꢃ1 48500), 289
(9400), and 269 (37700); 1H NMR (400 MHz, DMSO-d6) ꢂ2.17 (3H, s),
7.51 (1H,d, J ¼ 6:3 Hz), 7.56 (1H, d, J ¼ 6:3 Hz), and 7.50-7.65 (5H,
m); Anal. Found: C, 57.89; H, 3.88; N, 5.51%. Calcd for
C24H20N2O2S2Zn: C, 57.89; H, 4.05; N, 5.63%.
2 ¼ 5 ꢂ 10ꢃ4
,
3 ¼ 1 ꢂ 10ꢃ3 M. 5a-1-4 and 5b-1-4 also stand for
concentrations: 1 ¼ 5 ꢂ 10ꢃ5; 2 ¼ 1 ꢂ 10ꢃ4; 3 ¼ 5 ꢂ 10ꢃ4; 4 ¼ 1ꢂ
10ꢃ3 M. In each system, adipocytes (2:3 ꢄ 0:6 ꢂ 106 cells/mL) were
treated with complexes for 30 min, and then incubated with epinephrine
(1 ꢂ 10ꢃ5 M) for 3 h at 37 ꢅC. Each column is expressed as the mean ꢄ SD
for three repeated experiments.
13 H. Sakurai, K. Fujii, H. Watanabe, and H. Tamura, Biochem. Biophys.
Res. Commun., 214, 1095 (1995); S. Fujimoto, K. Fujii, H. Yasui, R.
Matsushita, J. Takeda, and H. Sakurai, J. Clin. Biochem. Nutr., 23, 113
(1997); M. Nakai, H. Watanabe, C. Fujiwara, H. Kakegawa, T. Satoh, J.
Takada, R. Matsushita, and H. Sakurai, Biol. Pharm. Bull., 18, 719
(1995).
It was concluded that 1) bis(1,4-dihydro-2-methyl-1-phenyl-
4-thioxo-3-pyridinolato)zinc(II) (5b) exhibited the highest in-
sulin-mimetic activity among vanadyl and zinc(II) complexes