Nitrogen mustards coordinated to Co(III) are potential hypoxia-selective cytotoxins, since one-electron reduction to the Co(II) complexes greatly labilizes the Co-N bonds, causing the release of activated aliphatic mustards which can act as diffusible cytotoxins. Two series of Co(III) complexes of the bidentate bisalkylating nitrogen mustard ligands N,N'-bis(2-chloroethyl)-ethylenediamine (BCE) and N,N-bis(2-chloroethyl)ethylenediamine (DCE) have been synthesized and evaluated for their hypoxia-selective cytotoxicity against AA8 cells in vitro. The complexes also bear two 3-alkylpentane-2,4-dionato (acac) auxiliary ligands; cyclic voltammetry studies show that variation of the alkyl group in the auxiliary ligands alters the reduction potentials of the complexes (within a series) over a range of about 150 mV. In both series, the patterns of cytotoxicities of the cobalt complexes were broadly similar to those of the respective free ligands, suggesting that the cytotoxicity of these compounds is due to release of the free ligands. The nonsymmetrical ligand DCE and its cobalt complexes were 1 order of magnitude more cytotoxic than the corresponding BCE compounds. Although the unsubstituted acac/DCE complex showed no hypoxic selectivity against repair-deficient UV4 cells in a stirred suspension culture assay, the methyl and ethyl analogues showed substantial selectivity. The results may indicate a narrow range of acceptable reduction potential, with an optimum close to that for the methyl analogue (E1/2 = -305 mV). The methyl analogue also shows hypoxic selectivity against repair-proficient cell lines (e.g., AA8 and EMT6) and has high activity against EMT6 cells in intact spheroids, suggesting that the released DCE is capable of back-diffusion from the hypoxic core of the spheroid. This work shows that metal complexes of nitrogen mustards have significant hypoxia-selective cytotoxicity toward mammalian cells in cell culture and are a new general class of hypoxia-selective cytotoxins.

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The complexes tris(3,5-di-iert-butyl-o-benzoquinone)chromium(0) and potassium tris(3,5-dwerr-butylcatecholato)chromate(III) have been isolated. Electrochemical techniques have demonstrated these complexes to be members of a reversible three-electron redox series with formal reduction potentials of +0.03, -0.47, and -0.89 V vs. SCE in acetonitrile. The four members of this series have been characterized by visible, infrared, and EPR spectroscopies as well as by cyclic voltammetry and magnetic susceptibility. From 4.3 to 298 K the neutral complex is diamagnetic. The mono-, di-, and trianion have, respectively, 1, 2, and 3 unpaired electrons. The EPR spectrum of the monoanion consists of a signal centered at g = 1.98 with 8-G line width and coupling to the metal of 24.3 G. The neutral complex has spontaneously resolved upon crystallization to the A-cis isomer in space group R3 with a = 16.385 (3) Á, c = 13.874 (4) Á, rf(exptl) = 1.08 g cm"3, and d(calcd) = 1.11 g cm"3 for Z = 3. The crystallographic symmetry of the molecule is C3 while the symmetry of the coordination polyhedron is Z)3. The ligand structure in the neutral complex retains significant quinone character; the C-0 bond length is 1.285 (8) Á and there is an alternation in the C-C bond lengths of the ring which range from 1.370 (10) to 1.433 (9) Á. The Cr-0 bond length is 1.933 (5) Á. The structural results are compared to those of the trianion, tris(catecholato)chromate(III), in which the ligand retains an undistorted catechol geometry.

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