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)(4−)

Abstract

We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate(IV)(4À), [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]oxovanadium(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 administration 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.

A DFT quantum mechanical study of 3-hydroxy-4-pyrone and 3-hydroxy-4-pyridinone based oxidovanadium(IV) complexes

“…In fact, ligands can be classified into three different groups: acac ligand, to which corresponds complex (1), 3-hydroxy-4-pyrone based ligands (maltol, bromomaltol, kojato, and chlorokojato) to which correspond complexes (2) to (5), and 3-hydroxy-4-pyridinone-based ligands (dmpp, mepp, hempp, heepp, Hb1, depp, empp, epp, etpp, mpp, pbp, and ppp) to which correspond complexes (6) to (17). The O1-O2-O1 0 -O2 0 dihedral angle values, for instance, shows that the square plane of the pyramid defined by these four oxygen atoms is more distorted in the complexes with the 3-hydroxy-4-pyrone-based ligands, less with the 3-hydroxy-4-pyridinone-based ligands, and it is perfectly planar in (1).…”

“…Vanadium is known for being used as supplement for oral diabetes therapy [1], and it was found that its efficiency as a drug is improved when complexed with organic ligands rather than in the form of its inorganic salts [2]. Oxidovanadium(IV) complexes have shown interesting pharmacological properties like high-hypoglycemic efficacy and non-toxic nature, which make them promising as insulin enhancing agents [3][4][5]. The investigation on the pharmacological potential of oxidovanadium(IV) complexes formed with new ligands has attracted the attention of both experimentalists and theoreticians.…”

“…The investigation on the pharmacological potential of oxidovanadium(IV) complexes formed with new ligands has attracted the attention of both experimentalists and theoreticians. For example, complexes with the deprotonated hydroxyl-pyrones maltol (3-hydroxy-2-methyl-4H-pyran-4-one) and kojic acid (5-hydroxy-2[hydroxymethyl]-4H-pyran-4-one) have been analyzed at the density functional theory (DFT) level [6], and the insulin-like activity of complexes with porphyrinbased ligands has been studied in vitro and in vivo as well [5]. Very recently, a series of oxidovanadium(IV) complexes of 3-hydroxy-4-pyridinones were synthesized and characterized, and their insulin-like activity was evaluated [7].…”

In vitro insulin-mimetic activity and in vivo metallokinetic feature of oxovanadium(IV)porphyrin complexes in healthy rats

“…Recently, we found that [mesotetrakis(4-sulfonatophenyl)porphyrinato]oxovanadate (IV)(4-), [VO(tpps)], (Fig. 1), in which the equatorial coordination sphere of oxovanadium(IV) is VO(N 4 ), is a potential insulin-mimetic oxovanadium(IV)porphyrin complex for the treatment of not only STZ-mice but also type 2 diabetic KKA y mice when the complex was introduced by oral gavage [24][25][26].…”

“…We and other researchers have developed several types of oxovanadium(IV) complexes with different equatorial coordination spheres, such as VO(N 2 S 2 ), VO(N 2 O 2 ), VO(S 2 O 2 ), VO(O 4 ), VO(S 4 ) and VO(N 4 ) [13][14][15][16][17][18][19][20][21][22][23][24][25][26]. These complexes showed normoglycemic activity in type 1 and type 2 DM animals.…”