Hypoxic selective agents

It is well established that hypoxic cells exist in solid tumors and that these cells are resistant to the cytotoxic effects of ionizing radiation.92,93 The non-cycling status of many hypoxic cells94 and the difficulty of achieving adequate drug concentrations in regions distant from blood vessels95 indicate that hypoxic cells may also be resistant to conventional chemotherapeutic agents. Therefore, there is a great interest in the design of drugs that are selectively cytotoxic under hypoxic conditions.96,97 The basic approach is to utilize net one-electron bio-reduction at a transition intermediate as the activation step. The properties of the Co(II)/Co(III) redox couple offer distinct advantages in this quest.

Ware etal. reported the interesting hypoxia-selective cytotoxic behaviors of cobalt(III) complexes containing coordinated nitrogen mustards.11,98 Two series of cobalt(III) complexes of the bidentate mustard ligands N,N-bis(2-chloroethyl)ethylenediamine (BCE) and N,N-bis(2-chloroethyl)ethyle-nediamine (DCE) have been synthesized (Figure 11.9).99 The complexes exhibited hypoxia-selective cytotoxicity against Chinese hamster ovary (CHO) fibroblasts and UV4 cells in vitro. In both of the BCE and DCE series, the pattern of cytotoxicity of the cobalt complexes paralleled that of the free ligands, suggesting that the cytotoxicity of the complexes is due to the release of the free ligands. The unsymmetrical DCE-cobalt complexes were an order of magnitude more cytotoxic than the corresponding free DCE compounds. The most effective complex was [Co(Meacac)2(DCE)]+, which was approximately 30-fold selective toward hypoxic EMT6 cell in culture, and which showed enhanced activity against EMT6 cells in multicellular spheroids.100 This work showed that metal complexes of nitrogen mustards have significant selectivity toward hypoxic mammalian cells and that they represent a promising new class of hypoxia-selective cytotoxins.

The kinetic basis for the in vitro sensitizing activity of [Co(Meacac)2(DCE)]+ has also been investigated by pulse radiolysis.100 The rate constants for the

Figure 11.9 [Co(Racac)2(DCE)]+ (left) and [Co(Reacac)2(BCE)]+ (right)

one-electron reduction of [Co(Meacac)2(DCE)]+ by model reductants exhibited a marked dependency on the reduction potential of the reductant, with values up to several orders of magnitude lower than those reported for misonidazole. To clarify the mechanism of hypoxic selectivity, other series of potentially radio-sensitizing cobalt(III) complexes, derived from the lead complex [Co(Meacac)2(DCE)]+ by replacing the Racac~ ligand with monoanionic, biden-tate dithiocarbamato or tropolonato (2-hydroxy-2,4,6-cycloheptatrien-1-one) ligands, were prepared (Figure 11.10).101 These results imply that the dithiocar-bamato and tropolonato complexes are not suitable as bioreductive anti-cancer drugs. Ware etal. recently synthesized cobalt(III) complexes containing the tri-dentate nitrogen mustard ligand N,N-bis(2-chloroethyl)diethylenetriamine (DCD)

a: X = H, R2 = Me2 b: X = Cl, R2 = Me2 c: X = Cl, R2= (CH2)4

a: X = H, R2 = Me2 b: X = Cl, R2 = Me2 c: X = Cl, R2= (CH2)4

c: X = H, R2 = (CH2)4 d: X = Cl, R2 = Me2 e: X = Cl, R2 = Et2

Figure 11.10 [Co(R2dtc)2(BCE)]+ (left) and [Co(R2dtc)2(DCE)]+ (right)

H2N H

Cl mer-[Co(DED)(acac)(NO2)]ClO4 Figure 11.11 Cobalt(III) complexes containing tridentate ligands DCD and DED

(Figure 11.11).102 Two DCD complexes were characterized by X-ray crystal structure determinations, which confirm the tridentate coordination with a long cobalt-tertiary nitrogen bond distance in the former, and bidentate coordination with the mustard nitrogen as a pendant arm in the latter. The bidentate complex, which contains a free nitrogen mustard, had cytotoxicity similar to that of the free ligand, but cytotoxicity was successfully masked in the tridentate complex, which showed modest hypoxic selectivity (fivefold) in a clonogenic assay.

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