Synthesis of Polyhydroxybenzene Derivatives for Evaluation as Antitumor Agents

• Main Author: Brown, Douglas L.
• Format: Others
• Published: VCU Scholars Compass 1986
• Subjects: Medicine and Health Sciences
• Online Access: http://scholarscompass.vcu.edu/etd/4380; http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=5441&context=etd

In order to prepare more effective inhibitors of ribonucleotide reductase a series of 4-substituted and 4,5-disubstituted catechols were synthesized and tested. The derivatives synthesized were also examined for their antitumor activity against L1210 leukemia in mice. A free radical scavenging assay was performed to establish what electronic parameters may govern in vitro and/or in vivo activity. The molecular features of the most potent compounds were compared to the features of the natural substrate of reduction, CDP, UDP, GDP and ADP. The results obtained from the free radical assay did not show any correlation to the results observed either in vitro or in vivo. Enhanced activity, both in vitro andin vivo, was shown when the amide function of 3,4-dihydroxybenzamide was substituted with a hydroxyethyl or a dimethylaminoethyl side chain. Reversal of the amide bond, ex. N-(3,4-dihydroxyphenyl)acetamide, resulted in a log unit increase as an inhibitor of ribonucleotide reductase. Antitumor activity was also substantially increased. The most potent compounds found in this study appear to physically resemble the molecular features found in the natural substrates.