Some chemical and biological studies pretaining to the mechanism of action of tetra-[mu]-carboxylatodirhodium(II) antitumor compounds



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The effect of tetra-[mu]-carboxylatodirhodium(II) complexes on the activity of 18 enzymes was evaluated. All enzymes that have essential sulfhydryl groups in or near their active site were found to be irreversibly inhibited. Those enzymes without essential sulfhydryl groups were not affected. In each case, the rate of inactivation closely paralleled the observed toxicity and antitumor activity of the tetra-[mu]-carboxylato-dirhodium(II) compounds tested. Proton magnetic resonance measurements made during the titration of rhodium(II) acetate with cysteine showed that breakdown of the carboxylate cage occurred as a result of reaction with this sulfhydryl-containing amino acid. In addition, the effect of these complexes on the proliferation and macromolecular synthesis of L1210 cells in suspension culture was evaluated. The cellular synthesis of DNA and protein were found to be strongly inhibited by tetra-[mu]-prcpionato-dirhodium(II) while no inhibition of RNA synthesis was observed. Flow microfluorometric analysis of the drug treated cells revealed the arrest of cell growth in the G[lowered 2] phase of the cell cycle. These results were interpreted as being consistent with the observed inhibition of protein synthesis.