Design and Synthetic Development of New Multifunctional Anti-cancer Agents

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1) We designed a guideline for the development of new multifunctional anti-cancer agents based on much information on the thiol chemistry, DNA-binding drugs, the relationship between chemical structure and toxicity, and radiosencitizing chemistry of DNA.2) According to our own guideline, we synthesized various thiazolidine-2-thiones, nitrofurazanes, 3-nitrotriazoles, and 2-nitroimidazoles, respectively. These new compounds and a Rabdosia diterpenoid, oridonin, were subjected to biological screening tests in vitro and in vivo system. From the results, the following facts were disclosed. Some thiazolidine-2-thione carboxylic acids having a weak immuno activity, exhibited fairly strong aldose reductase inhibition being concerned with the therapeutic agents for the chronic complications of diabetes. Nitrofurazanes, 3-nitrotriazoles, and 2-nitroimidazoles would be hopeful radiosencitizers in cancer radiotherapy. A tumor-inhibitor, oridonin showed an additive effect on the radiosencitizing activities of misonidazole to hypoxic cells. Thus, oridonin may be available for cancer radiotherapy.3) In order to clarify active mechanism of a clinically useful anti-cancer drugs: camptotecin derivatives and bleomycin A2, polyamine-containing radiosencitizers, and benzo[C]-phenanthridine alkaloids, interaction between drugs and DNA was investigated utilizing the Tm measurement, UV difference spectum, and <^1H> - and <^(13)C> -NMR spectrum. It was revealed that benzo[C]-phenanthridine alkaloids clearly form strong charge-transfer complexes with the nucleic bases in double and and single strand DNA.