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Current results in the development of cobalt complexes as sources of active radical species and their application as bioactive compounds are outlined.
A. Scope of the template synthesis of organocobalt chelates with Schiff bases was broadened. Namely, such complexes with either a tri- or tetra-dentate Schiff ligand derived from a mixed aliphatic-aromatic ß-diketone were prepared first and thoroughly characterized. Several mutually complementary analytical techniques to assay organocobalt complexes including labile ones in solid samples, solutions and living tissues were developed. In particular, cleavage of these compounds with iodine and electrophoretic behaviour of both organometallic and "inorganic" cationic cobalt(III) complexes with Schiff bases were explored in this connection. Kinetics and mechanism of homolytic decomposition of alkylcobalt chelates with aliphatic tridentate Schiff bases were studied in solution and microheterogeneous systems in relation to their biological activities as pH-dependent sources of active radical species. Effective stabilization of these rather labile complexes by certain Lewis bases and microheterogeneous systems of biological or artificial origin, namely blood plasma and milk emulsion, or a blood substituent was proved.
Conclusive evidence for a pH-dependent principle of anticancer activity of the alkylcobalt chelates with tridentate Schiff bases was provided. Their rather high modifying effects on (that means synergism with) certain well-known antitumour drugs and means, namely cis-DDP and taxol, and local microwave heating and high-energy radiation were established in vivo using various cancer models. A strong direct antimetastatic action of the complexes exceeding that of cis-DDP was revealed in the important case of Lewis lung carcinoma in mice.
Certain evidence indicating that DNA is a cellular target hit by these complexes was obtained. First, in vivo experiments have shown that they cause DNA cleavage on the same scale as the platinum preparation does. Second and more important, they substantially suppress the reparation of DNA strand breaks caused by cis-DDP.
Further, we have found that biological activity of the organocobalt complexes in question is not restricted to antitumour effects. Namely, they strongly suppress proliferation of microorganisms causing serious diseases in humans, animals and agricultural plants, or damaging microbiological production. Interestingly, this bactericide and fungicide effect, by contrast with the antitumour one, is not dependent on pH. Therefore another mechanism of cleaving the Co-C bond can be assumed in this case, namely an enzymatic one, probably involving oxidazes.
B. Catalytic activity of cobalt complexes of the B12 series in the auto-oxidation of ascorbic acid and generation of active oxygen species in the course of this process were examined as a chemical model of their potential biological effects including antitumour ones. Nuclease action of the complexes under conditions of the auto-oxidation of ascorbic acid was also studied in this connection. A nucleotide derivative of cobinamide, which had been previously synthesized by us, was proved to behave as targeted (that is site-specific) nuclease under the same conditions.
On the basis of these studies as well as preliminary biomedical trials, hydroxocobalamin was selected for a thorough examination for antitumour activity. Its cytotoxic effect is essentially enhanced if ascorbic acid is also introduced. A specific antitumour action of the combination was established with a number of cancer models both in vitro and in vivo.
Curable schemes for both the types of antitumour agents are under development.
The main result of this work is development of the approach to the creation of bioactive compounds and their combinations, in particular antitumour, fungicide and bactericide agents based on the use of chemical sources of active radical species.
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