BIS(DIALKYL)DITHIOCARBAMATO COBALT(III) COMPLEXES OF BIDENTATE NITROGEN MUSTARDS - SYNTHESIS, REDUCTION CHEMISTRY AND BIOLOGICAL EVALUATIONAS HYPOXIA-SELECTIVE CYTOTOXINS

Cobalt(III) complexes [Co(R(2)dtc)(2)(L)](+) containing two dithiocarb amate ligands (R = Me, Et, pyrrolidine) and a bidentate nitrogen musta rd ligand (L) prepared as potential hypoxia-selective cytotoxins. The complexes were synthesized by treatment of the binuclear precursor [Co -2(R(2)dtc)(5)](+) With the diamine N,N'-bis(2-chloroethyl)ethylenedia mine (BCE) and N,N-bis(2-chloroethyl)ethylenediamine (DCE), or their n on-alkylating analogues [N,N-diethylethylenediamine and N,N'-diethylet hylenediamine (BEE)]. Cyclic voltammetry of the complexes reveals quas i-reversible behaviour for the Co(III)/Co(II) couple, with E-1/2 incre asing order DCE < DEE approximate to: BCE < BEE. In MeCN/H2O electroch emical reduction irreversible, indicating rapid substitution of H2O in to the coordination sphere Co(II) intermediate. This fast ligand loss was confirmed by pulse radiolysis [Co(Me(2)dtc)(2)(DEE)](+), while ste ady-state radiolysis showed that the initial intermediate disproportio nates to [Co-II(H2O)(6)](2+) + 2[Co-II(Me(2)dtc)(3)](-). The latter sp ecies additional parent complex to give an overall stoichiometry of 3 mel parent complex/mol reductant. [Co(Me(2)dtc)(2)(DCE)](+) decays rap idly by an analogous mechanism culture medium. This reaction is not in hibited by O-2, indicating that reoxidation Co(II) intermediate by O-2 is not rapid enough to compete with ligand dissociation. resulting fr ee R(2)dtc(-) ligands, rather than the released mustards, are primaril y responsible for growth inhibition by [Co(R(2)dtc)(2)(L)](+) complexe s, although DCE release contribute to clonogenic cell killing. Clonoge nic cell killing is not appreciably under hypoxic conditions far any o f the dithiocarbamato complexes. This coupled with their instability i n culture medium, suggests that [Co(R(2)dtc)(2)(L)](+) complexes are p robably not suited for further development as bioreductive drugs.