Novel 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes to investigate structure/activity relationships

Abstract

A previous evaluation of the insulin-like activity of three 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes raised questions about structure/activity relationships, namely the influence of the hydrophilic/lipophilic balance of the complex and the capacity of the ligand to stabilize the +4 oxidation state of vanadium ion, on achieving an positive effect. To address these questions, we synthesized six new oxidovanadium(IV) complexes with variable hydrophilic/lipophilic balance, obtained by introducing different substituents on the nitrogen atom, and used two 3-hydroxy-4-pyrones as starting reagents to provide methyl and ethyl groups in the ortho position of the ring. For the new and previously reported complexes, we studied the oxidation-reduction properties and insulin-like activity in terms of inhibitory effect on Free fatty acid (FFA) release in isolated rat adipocytes. The results obtained show that only one of the complexes, Bis(3-hydroxy-1(H)-2-methyl-4-pyridonato)oxidovanadium(IV), VO(mpp)(2), exhibits a significantly greater capacity to inhibit FFA release than VOSO(4) and consequently is worthy to be considered for further studies. The establishment of structure activity relationships was not attainable but this study brings new information about the influence of some properties of the compounds on the achievement of an insulin-like effect. The results reveal that: (i) the oxidation-reduction cycles of the complexes are identical; (ii) the presence of more lipophilic substituents on the nitrogen atom does not enhance insulin-like properties; (iii) a high solubility in water proved to be not sufficient for a positive activity in inhibiting FFA release; (iv) a small molecular size may be an important property for reaching the right targets.

Synthesis of 3-Hydroxy-1-(p-methoxyphenyl)-2-methylpyridine-4-one and Spectrophotometric Extraction Studies on its Complexation of Vanadium(V)

“…p-TsOH and HCl were used as the acid catalysts giving HM in 65 % and 52 %, respectively after 2 days of heating. A slight increase in the yield of the product only in the case of p-TsOH (65 %) compared to the synthesis without the catalyst (56 %) 15 was detected. After that, an influence of the duration of the reaction catalysed by p-TsOH on the yield was tested.…”

“…It can be concluded that the optimal reaction time for the preparation of HM in the above mentioned conditions is 24 h and that the reaction time extension does not affect the yield of the product significantly. Compared with the known data for HM synthesis, 10,15 the most important benefit of the described procedure is a significant reduction of the reaction time (1 day compared to 2 15 or 3 10 days). The isolation and the purification of HM was performed only by filtration and recrystallization.…”

“…The preparation of the pyridinone derivatives, as well as HM, by heating the aqueous reaction mixtures without the addition of a catalyst in a sealed thick-walled glass tube for a shorter time (2 days) is also a well established literature procedure. 15 Bearing all this in mind, we carried out the synthesis of HM by heating aqueous solution of the reactants (in an equimolar ratio) and the acid catalyst (0.1 equiv.) in a sealed thickwalled glass tube at 150 °C.…”

“…13 It plays an important role in physiological systems including normalization of sugar levels and it has been reported that some vanadium complexes with pyran-4-one and pyridin-4-one derivatives are suitable compounds for treatment of type 2 diabetes. 14,15 In trace amounts vanadium represents an essential element for normal cell growth, but can be toxic when present in higher concentrations. The toxic action is largely confined to the respiratory tract 16 but it can also cause anaemia, reproductive toxicity in males and affect vision.…”

Oxidovanadium(IV) Complexes of 3-Hydroxy-4-pyrone and 3-Hydroxy-4-pyridinone Ligands: A New Generation of Homogeneous Catalysts for the Epoxidation of Geraniol

“…In particular, the bis(maltolato)oxidovanadium(IV) complex has been extensively studied from the chemical and pharmaceutical point of view and the oxidovanadium(IV) complex of ethylmaltol has passed Phase I clinical trials in 2000 and recently Phase II clinical trials [33][34][35]. A series of oxidovanadium(IV) complexes of 3-hydroxy-4-pyridinones has been synthesized and characterized, the evaluation of its insulin-like effect in vitro showed promising results [36][37][38][39] and their potential activity in an animal model is currently under study. These complexes present a central vanadium atom (V=O) coordinated to two O 2 -type bidentate ligands and their chemical properties indicate that they may also find application in other fields such as catalysis.…”