Insulinomimetic vanadyl-hydroxythiazolethione complexes with VO(S 2O2) coordination mode: The correlation between the activity and Hammett's substituent constant

Article abstract of DOI:10.1246/cl.2004.1274

Four kinds of vanadyl-hydroxythiazolethione complexes with VO(S ₂O₂) coordination mode were newly synthesized, and demonstrated for the first time that the insulinomimetic activity apparently correlates to the Hammett's substituent c

Full text of DOI:10.1246/cl.2004.1274

1274
Chemistry Letters Vol.33, No.10 (2004)
Insulinomimetic Vanadyl–Hydroxythiazolethione Complexes
with VO(S2O2) Coordination Mode:
The Correlation between the Activity and Hammett’s Substituent Constant
Akira Katoh,ꢀ Mika Yamaguchi, Ryota Saito, Yusuke Adachi,y and Hiromu Sakuraiy
Department of Applied Chemistry, Faculty of Engineering, Seikei University, Musashino, Tokyo 180-8633
yDepartment of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8413
(Received June 30, 2004; CL-040767)
Four kinds of vanadyl–hydroxythiazolethione complexes
with VO(S2O2) coordination mode were newly synthesized,
and demonstrated for the first time that the insulinomimetic ac-
tivity apparently correlates to the Hammett’s substituent con-
stant of the ligands.
ture was adjusted to 5 (pKa þ 1) with 6 M HCl, and stirred for
another 10 h at room temperature. The resulting yellow precipi-
tate was collected by suction filtration, washed with small
amount of H2O, and then dried over anhydrous P2O5 to give va-
nadyl complex (4a), [2,3-dihydro-2-thioxo-4-(p-nitrophenyl)-3-
thiazololato]oxovanadium (IV), (240 mg, 71%): mp 225 ꢁC (de-
comp.); IR(KBr): 1063 (ꢁC=S), 1513 (ꢁNO ), 1348 (ꢁNO ), 997
2
2
(ꢁV=O), and 854 cmꢂ1 (ꢂC-H); Anal Found: C, 37.97; H, 1.60;
N, 9.63%. Calcd for C18H10N4O7S4V: C, 37.70; H, 1.76; N,
9.77%.10
The number of people suffering from diabetes mellitus
(DM) has been estimated over 16 million in Japan, including po-
tential patients. DM is generally classified into insulin-depend-
ent type 1 DM caused by destruction of pancreatic ꢀ cells, and
noninsulin-dependent type 2 DM caused by aging, obesity, spi-
ritual stress, or other environmental factors.1 Orally active che-
motherapeutic agents for type 2 DM have already been devel-
oped and are currently available.2 Patients with type 1 DM, how-
ever, can be only treated by daily injections of insulin several
times in a day, which are painful and elevate the levels of patient
stress, especially in young people. From these reasons, the crea-
tion and development of new orally active synthetic drugs in
place of insulin injections are extremely desirable.3 The estab-
lishment of a clear correlation between the structure and the in-
sulin-mimetic activity is quite important for the strategy in the
molecular design and development of new chemotherapeutic
agents. Only a few factors, for example, the hydrophilic/lipo-
philic balance,4,5 the stability constant,5,6 the redox potential,4
and the absolute configuration4 have been proposed owing to
an absolute lack of available data. We considered that the intro-
duction of the p-substituted phenyl group results in the change of
the electronic structure of a ligand, the stability and the insulino-
mimetic activity of a vanadyl complex.
As intensive studies on heterocycles7 for the application to
chemotherapeutic agents for DM, we describe here the synthesis
of insulinomimetic vanadyl complexes of 4-(p-substituted phen-
yl)-3-hydroxythiazole-2(3H)-thiones with VO (S2O2) coordina-
tion mode, and a proposal of a new factor, the correlation be-
tween the Hammett’s substituent constant and the insulinomi-
metic activity, in determining the structure-activity relationship.
4-(p-Substituted phenyl)-3-hydroxythiazole-2(3H)-thiones
(3) were synthesized from acetophenones (1) via 4 steps by
the modified literature method8 as shown in Scheme 1. The
pKa values of 3-hydroxythiazole-2(3H)-thiones in H2O were es-
timated by means of the pH titration method; pKa ¼ 3:9 for 3a,
4.9 for 3b, 4.0 for 3c, and 4.6 for 3d.9 A typical procedure for
synthesis of vanadyl complexes is as follows. A solution of 3a
(303 mg, 1.19 mmol) in H2O (50 mL) was adjusted to pH 10 with
10 M KOH to dissolve completely. To the solution was added
Br
Me
1) Br2
C
C
N
O
2) NH2OH
OH
R
R
2
1
S
S
S
N
1) KSCOEt
2) ZnCl2
VOSO4
OH
R
3
R
S
O
O
S
S
N
V
N
S
O
a: R = NO2
b: R = Cl
c: R = H
4
d: R = OMe
R
Scheme 1.
The electrochemical behavior of vanadyl complexes in the
presence of 0.1 M tetrabutylammonium perchlorate in MeCN:
CHCl3 (1:1) mixture was evaluated by means of cyclic voltam-
metry: scan rate 100 mV sꢂ1; a working electrode Pt; an auxili-
ary electrode Pt wire; a reference electrode Ag/AgCl. The elec-
tron transfer processes of the complexes were irreversible, the
ipa/ipc ratio being 1.5 for 4a, 3.0 for 4b, and 2.2 for 4d. E1=2
vs Ag/AgCl values (880 for 4a; 840 for 4b, and 960 mV for
.
dropwise a solution of VOSO4 3H2O (140 mg, 0.64 mmol) in
H2O (10 mL). After stirring for 6 h, the pH of the reaction mix-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.10 (2004)
1275
4d) were higher than that of bis(maltolato)oxovanadium(IV),11
indicating that these complexes are more stable towards the ox-
idation. Further, ꢀꢁC=S (ꢁC=S for complex–ꢁC=S for ligand) was
calculated to be þ7 for 4a, þ10 for 4b, þ17 for 4c, and ꢂ22 for
4d, indicating that the single bond character of C=S double bond
increases with an increase of the electron-donating character of
the substituent R upon complexation, and 4d is most stable
owing to the ꢃ-delocalization of the thiazole-2(3H)-thione ring.
The insulinomimetic activity of vanadyl complexes was
evaluated by in vitro experiments, in which the inhibition of
the release of free fatty acid (FFA) from isolated rat adipocytes
treated with epinephrine was estimated by comparing the activ-
ity of vanadyl sulfate (VS).12 The effect of vanadyl complexes
was found to be dose-dependent in the concentration range from
1 ꢃ 10ꢂ5 to 5 ꢃ 10ꢂ4 M. The apparent IC50 value, which is a
50% inhibition concentration of FFA release in each complex,
was estimated, and the results are summarized in Table 1 togeth-
er with IC50 value of VS.
Vanadyl complex (4a) with 4-(p-nitrophenyl)-3-hydroxy-
thiazole-2(3H)-thione showed the highest insulinomimetic ac-
tivity among the complexes tested. Plots of IC50 values vs the
Hammett’s substituent constants (ꢄp) of the ligands are shown
in Figure 1. It is noteworthy that the IC50 value decreased with
increase of the electron-withdrawing property of the substituent
R. This is the first example showing the correlation between
the insulinomimetic activity and the Hammett’s substituent
constant.
complexes (4a–4c) are expected to be potent insulinomimetic
complexes for treating type 1 DM in animals.
This work was partially supported by the Science Research
Promotion Fund, the Promotion and Mutual Aid Corporation
for Private School of Japan.
References and Notes
1
2
3
WHO, Diabetes Mellitus, Reports of a WHO Study Group,
WHO Technical Report Series (1985), p 727, 876.
S. Patel, in ‘‘Diabetes in Focus,’’ 2nd ed., Pharmaceutical Press
(2003), p 79.
a) H. Sakurai and A. Tsuji, in ‘‘Vanadium in the Environment,
Part II,’’ ed. by J. O. Nriagu, John Wiley & Sons, New York
(1998), p 297. b) H. Sakurai, Chem. Rec., 2, 237 (2002); H.
Sakurai, Y. Kojima, Y. Yoshikawa, K. Kawabe, and H. Yasui,
Coord. Chem. Rev., 226, 187 (2002). c) K. H. Thompson and
C. Orvig, J. Chem. Soc., Dalton Trans., 2000, 2885. d) K. H.
Thompson and C. Orvig, Coord. Chem. Rev., 219–221, 1033
(2001).
4
5
K. Kawabe, M. Tadokoro, A. Ichimura, Y. Kojima, T. Takino,
and H. Sakurai, J. Am. Chem. Soc., 121, 7937 (1999).
Y. Yoshikawa, K. Kawabe, M. Tadokoro, Y. Suzuki, N.
Yanagihara, A. Nakayama, H. Sakurai, and Y. Kojima, Bull.
Chem. Soc. Jpn., 75, 2423 (2002).
6
7
Y. Yoshikawa, E. Ueda, Y. Suzuki, N. Yanagihara, H. Sakurai,
and Y. Kojima, Chem. Pharm. Bull., 49, 652 (2001).
a) A. Katoh, K. Taguchi, H. Okada, M. Harata, Y. Fujisawa,
T. Takino, and H. Sakurai, Chem. Lett., 29, 866 (2000). b) A.
Katoh, T. Tsukahara, R. Saito, K. K. Ghosh, Y. Yoshikawa,
Y. Kojima, A. Tamura, and H. Sakurai, Chem. Lett., 31, 114
(2002). c) A. Katoh, K. Taguchi, R. Saito, Y. Fujisawa, T.
Takino, and H. Sakurai, Heterocycles, 60, 1147 (2003).
a) D. H. R. Barton, D. Crich, and G. Kretzschmar, J. Chem. Soc.,
Perkin Trans. 1, 1986, 39. b) J. Hartung and M. Schwarz, in
‘‘Organic Synthses,’’ ed. by L. S. Hegedus, Organic Syntheses,
Inc., USA (2002), Vol. 79, p 228.
Further investigation on in vivo experiment of vanadyl com-
plex (4a) with STZ-rats (streptozotocin-induced diabetic rats) is
currently under way. On the basis of in vitro results, vanadyl
Table 1. Estimated IC50 values for the epinephrine-stimulated
FFA release from isolated rat adipocytes
8
9
Coordination
Mode
Compound
IC50 Value/mMa
Owing to low solubility in H2O, these pKa values were estimat-
ed from the extrapolation of pKa values in various ratio of
THF:H2O mixture.
4a
4b
4c
4d
S2O2
S2O2
S2O2
S2O2
ionic
0:08 ꢄ 0:01
0:15 ꢄ 0:02
0:35 ꢄ 0:07
1:49 ꢄ 0:37
0:67 ꢄ 0:03
10 [2,3-Dihydro-2-thioxo-4-(p-chlorophenyl)-3-thiazololato]oxo-
vanadium(IV) (4b): IR(KBr): 1061 (ꢁC=S), 995 (ꢁV=O), and
829 cmꢂ1 (ꢂC-H); Anal Found: C, 37.96; H, 1.82; N, 4.77%.
VOSO4
aEach value is expressed as the mean ꢄ SD for 3 experi-
.
Calcd for C18H10Cl2N2O3S4V H2O: C, 37.90; H, 2.12; N,
4.91%. (2,3-Dihydro-2-thioxo-4-phenyl-3-thiazololato)oxova-
nadium(IV) (4c): IR(KBr): 1069 (ꢁC=S), 988 (ꢁV=O), 752, and
700 cmꢂ1 (ꢂC-H); Anal Found: C, 44.76; H, 2.66; N, 5.64%.
Calcd for C18H12N2O3S4V: C, 44.71; H, 2.50; N, 5.79%. [2,3-
Dihydro-2-thioxo-4-(p-methoxyphenyl)-3-thiazololato]oxova-
nadium(IV) (4d): IR(KBr): 1030 (ꢁC=S), 984 (ꢁV=O), and
832 cmꢂ1 (ꢂC-H); Anal Found: C, 45.66; H, 3.36; N, 5.12%.
ments.
1.4
OMe
1.0
.
Calcd for C20H16N2O5S4V 0.5THF: C, 45.59; H, 3.48; N,
4.93%.
0.6
11 P. Caravan, L. Gelmini, N. Glover, F. G. Herring, H. Li, J. H.
McNeil, S. J. Retting, I. A. Setyawati, E. Shuter, Y. Sun, A. S.
Tracy, V. G. Yuen, and C. Orvig, J. Am. Chem. Soc., 117,
12759 (1995).
H
Cl
0.2
NO2
12 a) H. Sakurai, K. Fujii, H. Watanabe, and H. Tamura, Biochem.
Biophys. Res. Commun., 214, 1095 (1995). b) S. Fujimoto, K.
Fujii, H. Yasui, R. Matsushita, J. Takeda, and H. Sakurai, J.
Clin. Biochem. Nutr., 23, 113 (1997). c) M. Nakai, H. Watanabe,
C. Fujiwara, H. Kakegawa, T. Satoh, J. Takeda, R. Matsushita,
and H. Sakurai, Biol. Pharm. Bull., 18, 719 (1995).
-0.2
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
σp
Figure 1. The relationship between IC50 values and the
Hammett’s substituent constants.
Published on the web (Advance View) September 4, 2004; DOI 10.1246/cl.2004.1274