Dimerization of lawsone occurs upon reaction with Co(BF(4))(2)·6H(2)O and N,N'-bis(pyridin-2-ylmethyl)ethylenediamine (py(2)en) to produce the mononuclear complex [Co(III)(bhnq)(py(2)en)]BF(4)·H(2)O (1). This complex has been investigated as a prototype of a bioreductive prodrug, where the bhnq(2-) ligand acts as a model for cytotoxic naphthoquinones. Cyclic voltammetry data in aqueous solution have shown a quasi-reversible Co(III)/Co(II) process at E(1/2) = -0.26 V vs Fc/Fc(+). Reactivity studies revealed the dissociation of bhnq(2-) from the complex upon reduction of 1 with ascorbic acid, and a dependence of the reaction rate on the oxygen concentration suggests the occurrence of redox cycling.
In 2005, cancer was responsible for 13% of the overall deaths in the World. Currently, the two main cancer treatments are chemo and radiotherapies, which are not entirely effective due to hypoxic cells. These cells form a microenvironment in the tumor characterized by poor vascularization and, consequently, low partial pressure of oxygen (5-10 mmHg), which limits drug concentration that reaches the area and generation of radicals by the radiotherapy. Although hypoxic cells represent a therapeutic obstacle, they also have a great potential to the development of new selective pro-drugs (the pro-drugs activated by hypoxia -PDAHs). As the hypoxic cells are characteristic of solid tumors, and usually do not occur in normal tissues, they are the target of new treatments. Low oxygen concentrations guarantee a reducing environment to these areas, and so reduction of the pro-drug is responsible for the generation of the cytotoxic species that kill the tumor from the inside to the outside. Three main properties are necessary for the success of a PDAH: (i) satisfactory solubility and diffusibility, (ii) reduction of the reactive species only in the hypoxic areas and (iii) activity only of the reduced species. Some classes of compounds have been studied as new PDAHs, such as nitroaromatics, nitroimidazoles, N-oxide-benzotriazines and coordination compounds of the first row metals employing polynitrogenated, aminonaphtoquinones and hydroxiquinolines ligands, in addition to ruthenium and platinum complexes. Cobalt complexes have been studied because they present an inert (+3) and a labile (+2) oxidation states. Co(III) complexes may be inactive, and used as carriers of anticancer agents. However, when reduced to Co(II) in the hypoxia environment they might selectively deliver the drug. This review covers mainly the advances in the Co(III) studies.
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