Structure-Activity Relationship of Insulin-Mimetic Vanadyl Complexes

Chapter 27

Structure-Activity Relationship of Insulin-Mimetic Vanadyl Complexes with VO(N O ) Coordination Mode Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: December 10, 1998 | doi: 10.1021/bk-1998-0711.ch027

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H. Sakurai, K. Fujii, S. Fujimoto, Y. Fujisawa, K. Takechi, and H. Yasui Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Nakauchi-cho 5, Misasagi, Yamashina-ku, Kyoto 607, Japan

Insulin-dependent diabetes mellitus (IDDM), characterized by hyper glycemia due to an absolute deficiency of insulin, has been demonstrated to be improved by administration of vanadium complexes in place of insulin injections. Recently, we have found that vanadyl ion as well as vanadyl complexes are relevant to both onset and treatment of IDDM. Therefore, we synthesized vanadyl complexes with different coordination modes such as VO(O ), VO(N ), VO(S ), VO(N O ), VO(S O ) and VO(S O ) and evaluated their insulin-mimetic activities in vitro and in vivo. From the recent investigations on the relationship between structure and insulin-mimetic activity for vanadyl complexes of nitrogenous ligands, vanadyl-picolinate and vanadyl-methylpicolonate complexes with moderate partition coefficient and inhibitory effect of free fatty acid-release from rat adipocytes have been proposed to be long-acting insulin-replacements when they are given orally to streptozotocin-induced IDDM rats. The vanadium distribution and metallokinetic analysis in rats administered the vanadyl complexes were also examined to discuss the action of the complexes. 4

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Diabetes mellitus is one of the most widespread diseases of the world. The number of the patients suffering from the diabetes are increasing day by day. According to the definition of W H O (1), diabetes mellitus (DM) is mainly classified into insulin-dependent D M (IDDM) and non-insulin-dependent D M (NIDDM). To treat NEDDM, several therapeutics have already been developed and clinically used involving sulfonylureas, sulfonamides, biguanides and triglydazone (Noscal). However, I D D M can be yet controlled only by daily subcutaneous injections of insulin.

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©1998 American Chemical Society In Vanadium Compounds; Tracey, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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Vanadium, which was found by Seftrom in 1831 and named by him after the goddes, Vanadis, of Scandinavian legend has been proposed to improve the hepatic and peripheral insulin sensitivities in patients with both IDDM and N I D D M by giving simple vanadium compounds such as V O S 0 and N a V 0 around 100 years ago in France (2) and in recent years 1995-1996 in the U S A (3-7). These results indicate the need for investigations to establish the safest and long-term effectiveness of vanadyl compounds to treat diabetes mellitus (8, 9). For the purpose, several synthetic vanadyl coordination complexes, that are active on oral administration in place of insulin as well as simple compounds such as V O S 0 and N a V 0 , have been investigated on the basis of the results of experimental animals. We found first dose-dependent hypogycemic effects of bis(methycysteinato)oxovanadium(IV) (VO-CYSM) and bis(malonato)- oxovanadium(iV)(VO-MAL) complexes with VO(S N ) and VO(0 ) coordination mode, respectively, that were given by oral administration (10) (Table I, 1 and 9). Against the principle of Pearson's HSAB (11), which proposed the direction for the formation of stable complexes due to the combination such as hard acid-hard base or soft acid-soft base, the V O - C Y S M complex has been found to forms a strong coordination bond between V 0 and the thiolate of the C Y S M ligand (12). Encouraged with the results, we have proposed that bis(pyrrolidine-N-carbodithiolato)oxovanadium(IV) complex (VO(P)) (Table I (12)) is the most insulin-mimetic active compound among 6 prepared complexes with VO(S ) coordination mode when they are administered orally (13). On the other hand, we have prepared complexes with V O ( N 0 ) coordination mode to know the structure-activity relationship of antidiabetic vanadyl complexes, in which bis(picolinato)oxovanadium(IV) complex (VO(PA)) (Table I (5)) has been demonstrated to have orally active and long-term acting insulin-like properties (14).

Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: December 10, 1998 | doi: 10.1021/bk-1998-0711.ch027

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Structure-Activity Relationship of VO(N202) Coordination Mode

Antidiabetic Vanadyl

2

Complexes with

The orally active insulin-mimetic vanadyl complexes proposed so far are summarized in Table I. However, establishment of a clear correlation between structure of the complex and insulin-mimetic activity is yet very difficult due to absolute lack of available data, in which many important factors such as physico-chemical properties and electronic charges of the complex under physiological conditions, hydrophilicity or lipophilicity, availability for gastrointestinal absorption, organ and subcellular distributions of vanadium and its complex, and toxicity and safety of the complex are involved. Preparation of Vanadyl Complexes. Since we have found that the VO(PA) complex with the V O ( N 0 ) coordination mode is effective for normalizing the serum glucose levels of streptozotocin (STZ)-induced diabetic rats (STZ-rats) when given intraperitoneally (i.p.) or orally, we have examined the structure-insulin mimetic activity relationship of the vanadyl complexes with a VO(N 0 ) coordination mode by using VO(PA) as a leading complex as well as other 5 complexes such as (dipicolinato)-, 2

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In Vanadium Compounds; Tracey, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.


2

N 0

4

4

0

s

2

2

N S

2

mode

ν

2

2

S

*

I

CH CH/

2

v

8

12

S

2

N 2

I

ν

2

9

^ Χ CH2CH2 I

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CH CH

/

^ b

CH

}.C-N

0 ^ S - J / S ^

H

> '

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Bis(picolinato)oxovanadium VO (PA)

COOH



4

c

a

VO(PA) VO(MPA) VO(PAM) VO(DPA) VO(QA) VO(HIS)

V0S0

complex

a

PA=picolinic acid MPA=6-methlpicolinic acid PAM=picolinamide DPA=dipicolinic acid QA=quinaldinic acid HIS=histidine

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VO(N 0 ) VO(N 0 ) VO(N 0 ) VO(N 0 ) VO(N 0 ) VO(N 0 )

5 5 5 5 5 5

4

coordination mode VO(0 )

coordination number around V(IV) 5

c

b

2

0.46 0.45 0.30 0.29 0.28 2.00

6.0 ++ ++ ++ ++ ++ +

+

)

+ + (Ap- ) + + (/-Ρ- )

b

+ + (Lp. & p.o. )

+ + (/.p. & p.o.

+ + (/-Ρ- )

insulin-mimetic action in vitro in vivo

essentially no effect by p.o. administration 3 dimensional structure was analysed.

0.33 0.60 -

partition coefficient 0.03

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Table II. Vanadyl Complexes with VO(N 0 ) Coordination Mode and Their Insulin-mimetic Activities


350 VO(MPA) complex, which has been found to have a similar I C value to that of VO(PA) and moderate partition coefficient, was then administered to STZ-rats by daily i.p. injections at the doses of 3mg/kg body weight for 2 days, then 2mg/kg for 2 days and finally lmg/kg for 10 days or daily oral administrations at the doses of 10mg/kg body weight for 10 days and then 5mg/kg for 10 days. This complex has been revealed to have a good insulin-mimetic activity similarly to that of VO(PA) complex not ony by i.p. injection but by oral adiminstration without body weight loss of STZ-rats (22). It is interesting to note that the serum glucose normalizing effect of the VO(MPA) complex continued for at least 80 days after withdrawing the complex administration and the insulin-mimetic effect by the complex was observed at lower doses than those for VO(PA) administration (Sakurai, H . et al., manuscript in preparation) From the results, the vanadyl complexes with moderate partition coefficient and relatively good I C value around 0.4mM is expected to be a potent insulin-mimetic compound for experimental animals with IDDM. In addition, we observed preliminary that VO(MPA) is also effective for normalizing the serum glucose levels of rats with NIDDM.


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Organ Distribution of Vanadium, in vivo Coordination Structure around Vanadyl, and ESR-Metallokinetic Analysis of Vanadyl State in Rats Administered Vanadyl-Picolinate Complex Vanadium Distribution. Previously, we observed that no significant differences in vanadium uptake between normal- and STZ-rats as estimated by neutron activation analysis method for total vanadium as well as by ESR method for vanadyl state (19). When VS was given to rats, total vanadium in terms of mg V/g wet weight of organ was found to be incorporated into the organs in the following order: kidney>bone>liver>pancreas>spleen as well as in the supernatant of the kidney and mitochondria of the liver. While, in rats given VO(PA) by oral administration the following order for vanadium accumulation was observed: bone>kidney>spleen>liver >pancreas. Vanadium has thus been assumed to act in part on the islet of the pancreas, mineralization of bone, electron transport or induction of metallothionein in the kidney and liver (Sakurai, H . et al. unpublished data). In Vivo Coordination Structure. Following to our conventional X-band ESR analysis on in vivo coordination structure of vanadyl state in the organs of rats given vanadyl complexes (19), E S E E M (electron spin echo envelope modulation) spectroscopy at 77 Κ has been applied to examine a more detailed in vivo coordination structure of vanadyl state in rats treated with VS. E S E E M analysis revealed the occurrence of nitrogen-vanadyl bonds suggesting the presence of in vivo coordination of Lys ε-amine or N-terminal α-amine of proteins to vanadyl ion (23). Recently, E S E E M analysis at 4 Κ on the organs of rats given VO(PA) complex has demonstrated that the complex is partially incorporated in the liver as a ternary complex such as (PA)-V0 -N(amino acid residues of proteins) (Fukui, K . et al., manuscript in preparation). +

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Metallokinetic Analysis. To develop a therapeutic compound, pharmacokinetic analysis of the compound in blood is essential. We have recently proposed a new pharmacokinetic analysis method combined with ESR spectrometer and named as BCM (blood circulation monitoring)-ESR method, in which the behaviours of several stable spin probes in the blood of rats were successfuly analysed (24). By using the BCM-ESR method, we performed the metallokinetic analysis of VS and VO(PA) complex in rats (25). VS or VO(PA) complex was given by single i.v. injection to rats under anesthesia with pentobarbital and ESR spectra were collected at room temperature every 30 second. The real-time ESR analysis of vanadyl state revealed that clearance rate of vanadyl from the blood of rats given VS was found to be higher than that given VO(PA) complex in terms of half-life (t ), being 10 min in VS-treated rats and 16 min in VO(PA)-treated rats. The slow clearance rate of vanady state in rats given VO(PA) complex suggests the high accumulation of vanadium in organs of rats. The metallo kinetic analysis by the BCM-ESR method is now under way in more detail. 1/2

Conclusion. The relationship between structure and insulin mimetic activity for vanadyl complexes of nitrogenous ligands was examined. In vitro results such as IC value for the inhibition of FF A release from the isolated rat adipocytes stimulated with EP and partition coefficient suggested the importance for predicting in vivo blood glucose normalizing effect of the complex in STZ-induced IDDM rats. Among 6 vanadyl complexes examined, both VO(PA) and VO(MPA) complexes with around 0.45 mM of IC value and higher partition coefficient than that of VS have been proposed to be potent reagents to treat STZ-rats with IDDM. 50

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Acknowledgments This research was in part supported by grants from the Ministry of Education, Science and Culture of Japan. HS thanks Drs. J. Takada and R. Matsushita of Research Reactor Institute of Kyoto University, and Drs. K. Fukui, H. Ohya-Nishiguchi and H. Kamada of the Institute for Life Support Technology of Yamagata Technopolis Foundation for their investigations and helpful discussions in the research project. References 1. WHO; Diabetes mellitus; Reports of a WHO study group. WHO Technical Report Series 1985, 727, 876-877. 2. Lyonnet, B.; Martz, X.; Martin, Ε. Presse Med. 1889, 1, 191-192. 3. Cohen, N; Halberstam, M.; Shilimovich, P.; Chang, C. J.; Shamoon, H . ; Rosseti, L. J. Clin. invest. 1995, 95, 2501-2509. 4. Goldfine, A. B.; Simonson, D. C.; Folli, F.; Patti, M. E.; Kahn, C. R. J. Clin. Endocrinol. Metab. 1995, 80, 3311-3320. 5. Goldfine, A. B.; Simonson, D. C.; Folli, F.; Patti, M. E.; Kahn, C. R. Mol. Cell. Biochem. 1995, 153, 217- 231.



352 6. Halberstam, M.; Cohen, Ν.; Shilimovich, P.; Rosseti, L.; Shamoon, H. Diabetes 1996, 45, 659-666. 7. Boden, G.; Chen, X.; Ruiz, J.; van Rossum, G. D. V.: Salvatore, T. Metabolism 1996, 45, 1130-1135. 8. Orvig, C.; Thompson, K. H.; Battell, H.; McNeil, J. H. In Metal Ions in Biological Systems, Editors, Siegel, H.; Sigel, A.;Vanadium and Its Roles in Life, Marcel Dekker, New York, 1995, Vol 31, pp. 575-594. 9. Sakurai, H. Chemistry Today 1996, No.304 (7), 14-20. (in Japanese) 10. Sakurai, H.; Tsuchya, K.; Nukatsuka, M.; Kawada, J.; Ishikawa, S.; Komatsu,M.J.Clin. Biochem. Nutr. 1990, 8, 193-200. 11. Pearson, R.G. J. Am. Chem. Soc. 1963, 85, 3533-3539. Inorg. Chim. Acta. 1980, 46, L119-L120. 13. Watanabe, H.; Nakai, M.; Komazawa, K.; Sakurai, H. J. Med. Chem. 1994, 37, 876-877. 14. Sakurai, H.; Fujii, K.; Watanabe, H.; Tamura, H. Biochem. Biophys. Res. Commun. 1995, 214, 1095-1101. 15. Nakai, M.; Watanabe, H.; Fujiwara, C.; Kakegawa, H.; Satoh. T.; Takada, J.; Matsushita, R.; Sakurai, H. Biol. Pharm. Bull. 1995, 18, 719-725. 16. Fujisawa, Y.; Fujimoto, S.; Sakurai, H. J. Inorg. Biochem. 1997, 67, 396. 17. Pederson, R.A.; Ramanadham, S.; Bucher, A. M. J.; McNeil, J. H. Diabetes 1989, 38, 1390-1395. 18. Ramanadham, S.; Mongold, J. J.; Brownsey, R.W.; Cros, G. H.; McNeil, J. H. Am. J. Physiol. 1989, 257, H904-H911. 19. Sakurai, H.; Tsuchiya, K.; Nukatsuka, M.; Sofue, M.; Kawada, J. J.Endocrinol.1990, 126, 451-459. 20. Cam, M. C.; Pederson, R. Α.; Brownsey, R. W.; McNeil, J. H. Diabetologia 1993, 36, 218-224. 21. Thompson, Κ. H.; Leichter, J.; McNeil, J. H. Biochem. Biophys. Res. Commun., 1993, 197, 1549-1555. 22. Fujimoto, S.; Tamura, H.; Sakurai, H. 31th Intern. Conf. Coord. Chem.; Vancouver, Canada, 1996, Abs. p.21. 23 Fukui, K.; Ohya-Nishiguchi, H.; Nakai, M.; Sakurai, H.; Kamada, H. FEBS Lett. 1995, 368, 31-35. 24. Takechi, K., Tamura, H.; Yamaoka, K.; Sakurai, H. Free Rad. Res. 1997, 26, 483-496. 25. Takechi, K.; Sakurai, H. 2nd Intern. Conf. Bioradicals; Yamagata, Japan, 1997, Abs. 355.


Structure-Activity Relationship of Insulin-Mimetic Vanadyl Complexes

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