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1 2009

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Indukowane hipoksją, selektywne działanie związków kompleksowych kobaltu(III) na komórki nowotworowe

Sobiesiak M., Budzisz E.

Wiadomości Chemiczne

2009

[Z] 63, 3-4

285-307

Metal-based therapeutics have played an important role in modifying the pharmacological properties of known/new drugs [2, 60]. Both cobalt(II) and cobalt(III) complexes have been investigated for their antiviral, antifungal, antibacterial and antitumor properties [13-24]. Cobalt(III) compounds have been explored for their biological activity since 50' of XX century and they are still being examined especially for their anticancer properties. Oncological diseases are still actual and very important problem. The new mechanism of drug action has been researched. Development of tumor-selective cytotoxic agents, which would strongly injure tumor cells but affect as little as possible the normal tissues and organs having no side effect on a patient's organism, plays a key role [25]. The search for selective anticancer drugs (tumor-activated prodrugs; TAP) led to compounds that can exploit the characteristic, unique microenvironment of tumor cells, such as selective enzyme expression, low extracellular pH and hypoxia. Tumor hypoxia provides a basis for the selective targeting of solid tumor [3]. This property has been explored for reduction by endogenous enzymes or radiation for quinones, N-oxides and nitroaromatics. Complexes of nitrogen-based ligands with many transition metals such as cobalt have been investigated as potential hypoxia activated prodrugs. Such complexes are very stable in the low-spin Co(III) oxidation state. They have reduction potentials in the appropriate range to undergo reduction by cellular reductases, but this is inhibited in oxygenated cells, apparently by competition for cellular reductants between the Co(III) complex and oxygen [4]. Cobalt(III) plays "passive" role in the complexes, but it chaperones and delivers cytotoxic ligand, which is deactivated when coordinated to the metal centre. In hypoxic regions of reduction to cobalt(II), the anticancer agent would be released from less stable Co(II) complex and thereby activated in their sites of action. Many studies have described developments and prospect for cobalt(III) - based pharmaceuticals for their red-ox properties as promising antitumor agents - hypoxia activated prodrugs [2]. Structure, enhanced reactivity with potential biological targets upon reduction, correlations between electrochemical parameters and anticancer activity in hypoxic tumor cells have been presented for cobalt complexes of nitrogen mustards or Schiff bases. Moreover Co(III) complexes of azahydroxy-CBI toxins show selective toxicity following irradiation under hypoxic but not aerobic conditions as potential hypoxia-selective cytotoxins.