fakultet 13

DZIAŁANIU ZWIĄZKÓW KOMPLEKSOWYCH KOBALTU!III) NA KOMÓRKI NOWOTWOROWE 3

ABSTRACT

Metal-bascd therapeutics havc playcd an important role in modifying the pharma-cological properties ofknown/new drugs [2.60]. Both cobalt(II) and cobalt(lll) com-plexes have been inyestigated for their antiviral, antifimgal, antibacterial and antitu-mor properties [13-24]. Cobalt(III) compounds have been explored for their biolo-gical activity sińce 50' of XX century and they are still being cxamined especially for their anticaneer properties. Oneological diseascs are still aetual and verv important problem. The new mechanism of drug action has been researehed. Develop-ment of tumor-selective cytotoxic agents, which would strongly injure tumor cells bul affect as little as possible the nonnal tissues and organs haying no side effect on a patienTs organism, plays a key role [25]. The search for selective anticaneer drugs (tumor-activatcd prodrugs; TAP) led to compounds that ean exploit the eharacte-ristic. uniąue microenvironment of tumor cells, such as selective enzyme expre-ssion, Iow extracellular pH and hypoxia. Tumor hvpoxia provides a basis for the selective targeting of solid tumor [3]. This property has been explored for reduction by endogenous enzym es or radiation for quinones, /V-oxides and nitroaromatics. Complexes of nitrogen-based ligands with many transition mctals such as cobalt have been investigated as potential hypoxia acliyated prodrugs. Such complexes are very stabłe in the low-spin Co(lll) oxidation State. They have reduction potentials in the appropriate rangę to undergo reduction by cellular reductases, but this is inhi-bited in oxygenated cells, apparently by competition for cellular reductants between the Co(III) complex and oxygen [4].

Cobalt(III) plays '^cpassive” role in the complexes, but it chaperones and deli-vers cytotoxic ligand. which is deactivated when coordinated to the metal centre. In hypoxic regions of reduction to cobalt(il), the anticaneer agent would be released from less stable Co(TT) complex and thereby activated in their sites of action. Many studics havc described devclopmcnts and prospcct for cobalt(III) - bascd pharma-ceuticals for their red-ox properties as promising antitumor agents - hypoxia activa-ted prodrugs [2J. Structure, enhanced reactiwity with potential biological targets upon reduction. correlations between electrochemical parameters and anticaneer actiyity in hypoxic tumor cells have been presented for cobalt complexes of nitrogen mustards or Schiff bases. Moreocer Co(III) complexcs of azahydroxy-CBI toxins show selectiye toxicity following irradiation under hypoxic but not aerobic condi-tions as potential hypoxia-selective cytotoxins.

Kcywords: cobalt(ITI) complexes, antitumor cffcct, hypoxia drug activation

Słowa kluczowe: związki kompleksowe kobaltu(III), właściwości przeciwno w otworowe. aktywacja leku pod wpływem niedotlenienia