POLYHYDROXYPHENYL DERIVATIVES DESIGNED FOR ANTITUMOR ACTIVITY

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 POLYHYDROXYPHENYL STRUCTURE, HAS BEEN DEVELOPED. THE COMPOUND OF THE INITIAL SERIES WITH THE BEST ANTITUMOR ACTIVITY IN ANIMAL TUMOR MODELS, DIDOX, HAS ENTERED HUMAN CLINICAL TRIALS. THE PURPOSE OF THIS PROPOSAL IS TO DEVELOP AN EVEN MORE EFFECTIVE AGENT OF THIS TYPE. SPECIFICALLY, MOLECULES FOR HEALTH, INC. WILL ADD SUBSTITUENTS TO KNOWN ACTIVE STRUCTURES IN SEVEN CLASSES OF POLYHYDROXYPHENYL COMPOUNDS TO ENHANCE BINDING ON THE ENZYME. STRUCTURAL REQUIREMENTS FOR OPTIMUM ACTIVITY WILL BE EVALUATED. TO OCCOMPLISH THIS,MOLECULES FOR HEALTH, INC. WILL MEASURE THE DEGREE OF ENZYMEINHIBITION, THE RATE OF FREE RADICAL SCAVENGING (MECHANISM OF INHIBITION), AND THE ANTITUMOR ACTIVITY IN THE L1210 LEUKEMIA MODEL. ADDITIONALLY, THE NATIONAL CANCER INSTITUTEWILL BE PROVIDED WITH ADEQUATE QUANTITIES OF THE MOST PROMISING COMPOUNDS FOR FURTHER ANTITUMOR TESTING. AN IMPROVED UNDERSTANDING OF STRUCTURAL FEATURES WILL GIVE DIRECTION TO FURTHER DEVELOPMENT. SUCCESSFUL COMPOUNDS RESULTING FROM PHASE I WILL UNDERGO PHARMACOKINETICS AND TOXICOLOGICAL EVALUATION IN PHASE II.