ANTITUMOR ACTIVITY OF FAGARONINE AND ANALOGUES

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This project has been designed to study the molecular basis of action of the benzophenanthridinum alkaloid of known antitumor activity, fagaronine and nitidine. A series of analogues has been synthesized to determine the active centre of these molecules in order to correlate the biological effect with the molecular structure. In view of our success in the design and synthesis of a potentially useful antitumor agent, based on the structural features present in known drugs displaying this property, we plan to continue and expand our research program directed towards the synthesis of new NBQ, fagaronine, and nitidine analogues. This will provide the basis for the design of more effective antitumor drugs. In our studies we have found that fagaronine and related analogues interfere with the DNA template function as a direct consequence of the intercalation process to double-stranded DNA. NBQ, the most active of these analogues, has been shown to induce differentiation of HL-60 promyelocytic leukemia at lower-than-chemotherapeutic doses. Our findings with NBQ as differentiation inducer raises the question: By what mechanism(s) does this drug expresses its differentiation effect? The understanding of how much of the biologic activity of these drugs can be attributed to cytocydal effect in contrast to differentiation induction will give us an insight of a potentially new mode of cancer chemotherapy.