The reductive conversion of ribonucleotides to deoxyribonucleotides, catalyzed by ribonucleotide reductase is a crucial and rate-limiting reaction in the DNA biosynthetic pathway. This reaction, therefore, represents a logical target for cancer chemotherapy. In response to the need for an effective agent at this site, a series of ribonucleotide reductase inhibitors, based on a vicinal polyhydroxphenyl structure, have been developed. Amidox, second generation compound, and VF323, developed during the phrase I effort, exhibit marked antitumor activity in animal tumor models. It is proposed to study the effect of substituents on known active structures of 3 classes of polyhydroxphenyl compounds with the purpose of enhancing the binding on the enzyme and leading to improve antitumor activity. In order to accomplish this purpose, the degree of enzyme inhibition will be measured as well as the rate of free radical scavenging (mechanism of inhibition) and antitumor activity in the L1210 leukemia model. Additionally, drug combination studies will be conducted involving doxorubicin or cyclophosphamide and synthetic compounds to determine whether they enhance the effectiveness and/or reduce their toxicity. Furthermore, the effect of these compounds of deoxynucleotide pools will be ascertained to determine whether they might enhance deoxynucleosidelike anticancer and antiviral agents. After the first year a compound will be selected for pharmacological evaluation. Toxicity studies will be performed in mice and dogs dependent on that evaluation.
