This project was initiated to study the molecular basis of action of the benzophenenthridinum alkaloid of known antitumor activity, fagaronine. Analogues were synthesized to establish the active center and correlate the biological effect(s) with the molecular structure. At the time, 3- nitrobenzothiazolo [3,2-a] quinolinium (NBQ) was found the most active of the analogues with strong potential as antitumor agent. Fundamental investigation on its mode of action showed that NBQ intercalates to DNA. NBQ is able to trap Topo II on DNA as a cleavable complex. The cytotoxicity of NBQ is apparently associated with DNA strand breaks as a result of this cleavable complex. Moreover, NBQ significantly enhances lens regeneration of Notophtalmus viridescens, and induces HL-60 cells to differentiate to granulocytes. NBQ, at non-lethal doses that stimulate differentiation, is able to bind in vitro Topo II to pure DNA. These findings raise several questions: Why and how is the cleavable complex cytotoxic? By what mechanism(s) does NBQ induces tumor cell differentiation? What role has Topo II in the induction of differentiation? Knowledge of the mechanism(s) through which NBQ exerts its cytotoxic effect in contrast to differentiation induction will give us an important insight of a potentially new mode of cancer chemotherapy. Thus, we will study the molecular and biochemical basis of the interaction of NBQ with DNA Topo II in vivo and in vitro. In view of our success in the design and synthesis of NBQ, we will expand our research program to synthesize novel analogues of NBQ and fagaronine. Compounds with increased affinity for Topo II, lipid solubility and differentiation inducing ability will be the target for our synthetic effort. These analogues will be assayed in vitro for cytotoxic and/or differentiation induction ability. The mechanism of action of analogues that show potential as antitumor agents or differentiation inducers will be studied and compared with NBQ. This will provide the basis for the design of more effective anticancer drugs.
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