Synthesis and Antitumor Activity of Tropolone Derivatives. 6. Structure-Activity Relationships of Antitumor-Active Tropolone and 8-Hydroxyquinoline Derivatives

The bis derivative 6 of 8-hydroxyquinoline, which, like tropolones, readily forms a chelate, was synthesized and found to have high potency (dose = 12.5 mg/kg, T/C % = 164) against leukemia P388 in mice approximately equivalent to that of the bistropolone lb. 8-Hydroxyquinoline analogues with broad structural variation were synthesized and their structure-activity relationships followed the same pattern as in the tropolone series. In addition, the bistropolones la-e were tested for their ability to bind to tubulin and found to have no such property. The results of this study suggested that bistropolone and bis(8-hydroxyquinoline) derivatives must form a chelate with the metal necessary for the enzyme, such as ribonucleotide reductase, which catalyzes the DNA biosynthetic pathways.