Oxovanadium(IV)–Porphyrin Complex as a Potent Insulin-Mimetic. Treatment of Experimental Type 1 Diabetic Mice by the Complex [meso-Tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4À) Tapan Kumar Saha, Yutaka Yoshikawa, Hiroyuki Yasui, and Hiromu Sakurai  Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414 Received February 24, 2006; E-mail: sakurai@mb.kyoto-phu.ac.jp We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4), [VO(tpps)], and its in vitro insulin-mimetic activity, metallokinetic features in the blood of healthy rats, and in vivo hypoglycemic effect in streptozotocin (STZ)-induced diabetic mice (STZ mice) were investigated. The results were compared with those of previously proposed insulin-mimetic [meso-tetrakis(1-methylpyridinium-4-yl)porphyrinato]oxovana- dium(IV)(4+), [VO(tmpyp)], and vanadium(IV) oxide sulfate. The in vitro insulin-mimetic activity, the retention time and bioavailability of [VO(tpps)] in blood were considerably better than those of [VO(tmpyp)] and vanadium(IV) oxide sulfate. [VO(tpps)] caused a significant hypoglycemic effect in STZ mice within 8 h following a single oral administra- tion of the complex at 15 mg V/kg of body mass without ascorbate; this effect was sustained for at least 60 h. [VO(tpps)] normalized the hyperglycemia of STZ mice within 2 days when administered orally at 4–10 mg V/kg of body mass for 18 days. Vanadium, as determined by instrumental neutron activation analysis, was distributed in the tissues examined in the following decreasing order: bones, kidneys, liver, lungs, spleen, heart, pancreas, muscles, fatty pads, and brain. The improvement in diabetes was supported by oral glucose tolerance test, HbA 1c level and blood pressure. Based on the above results, [VO(tpps)] is an orally active oxovanadium(IV)–porphyrin complex for treating type 1 diabetic animals. Diabetes mellitus (DM) is a group of important metabolic syndromes that results from an absolute, or relative, deficiency of insulin secretion and/or its action, and it is widely accepted as one of the leading causes of death and disability worldwide. It can affect nearly every organ system in the body and lead to blindness, end-stage renal disease, lower extremity amputa- tions, increased risk of stroke, ischaemic heart disease, periph- eral vascular disease and neuropathy. Based on its type, the treatment for DM involves either daily injections of exogenous insulin (most common for type 1, i.e., insulin-dependent DM) or oral administration of hypoglycemic drugs, such as sulfo- nylureas, 1 metformin, 2 alpha-glucosidase inhibitors, thiazoli- dinediones, and meglitinides, 3 and in a combination therapy for type 2 (non-insulin-dependent) DM. 4 However, this ap- proach is not satisfactory for a large proportion of patients; hence, there have been continued efforts towards developing new hypoglycemic drugs with high potency, but little or no side effects. It has been established that vanadium compounds exert an insulin-mimetic action in both in vitro and in vivo sys- tems, including their ability to improve glucose homeostasis and insulin resistance in animal models of DM. 5–7 In recent years, several reports have documented vanadium therapy- induced improvements in insulin sensitivity in the liver and muscles of many type 2 diabetic human subjects. 8–10 Since the discovery of the orally active insulin-mimetic oxovanadium(IV)–cysteine methyl ester complex for the treat- ment of streptozotocin (STZ)-induced diabetic rats in 1990, 11 the therapeutic potential of oxovanadium(IV) complexes has been of great interest to us. We and other researchers have developed several types of oxovanadium(IV) complexes with different vanadium coordination spheres, such as VO(N 2 S 2 ), VO(N 2 O 2 ), VO(S 2 O 2 ), VO(O 4 ), and VO(S 4 ). 12–20 These com- plexes showed normoglycemic activity in type 1 and type 2 DM animals. However, only a few complexes, such as bis(bi- guanidato)oxovanadium(IV), [VO(big) 2 ], bis(N 0 ,N 0 -dimethyl- biguanidato)oxovanadium(IV), [VO(metf) 2 ], and bis(-phen- ethylbiguanidato)oxovanadium(IV), [VO(phenf) 2 ], with a VO(N 4 ) vanadium coordination sphere, have been examined. 21 Among these, [VO(metf) 2 ] was found to significantly lower the blood glucose levels in STZ-induced diabetic rats—a type 1 diabetic model—by oral gavage. However, hypoglycemic activity was sustained for 24 h. Recently, we found that [meso-tetrakis(1-methylpyridinium-4-yl)porphyrinato]oxovana- dium(IV)(4+), [VO(tmpyp)], (Fig. 1a), in which the vanadium coordination sphere is VO(N 4 ), is a potential insulin-mimetic oxovanadium(IV)–porphyrin complex for the treatment of STZ rats by intraperitoneal (i.p.) injection together with so- dium ascorbate. 22 This important finding prompted us to devel- Ó 2006 The Chemical Society of Japan Bull. Chem. Soc. Jpn. Vol. 79, No. 8, 1191–1200 (2006) 1191 BCSJ Award Article Published on the web August 7, 2006; doi:10.1246/bcsj.79.1191