ARYL HYDRAZONES WITH ANTICANCER ACTIVITIES

SUBSTITUTED BENZOPHENONE PHENYLHYDRAZONES HAVE BEEN IDENTIFIED THAT POSSESS ANTIESTROGEN ACTIVITIES WITH ABSENT ESTROGENICITY. 4, 4'-DIHYDROXYBENZOPHENONE-2, 4-DINITROPHENYLHDRAZONE (A-007) HAS DEMONSTRATED ANTIESTROGENIC ACTIVITIES AT LOW CONCENTRATIONS AND CYTOTOXIC ACTIVITIES AT HIGHER CONCENTRATIONS IN ESTROGEN INDEPENDENT BREAST CANCERS. A-007 IS PRESENTLY BEING PREPARED FOR CLINICAL STUDIES. THE 2, 2'-DIHYDROXY ISOMER OF A-007 HAS RECENTLY BEEN PREPARED, A-701, AND IS TWICE AS CYTOTOXIC AS THE FORMER. IT IS NOT ANTIESTROGENIC AND X-RAY CRYSTALLOGRAPY STUDIES REVEAL TWO SETS OF INTRAMOLECULAR HYDROGEN BONDING. A-071 THUS, CONTAINS MORE POTENTIAL COPLANARITY THAN DOES A-007, WHICH MAY BE INFLUENCING BIOLOGICAL ACTIVITIES. THE SPECIFIC OBJECTIVES OF THIS PHASE I STUDY WILL BE TO MODIFY A-007'S HYDRAZONE AND BENZOPHENONE MOIETIES USING X-RAY CRYSTALLOGRAPHY MODELLING AND CHEMICAL REACTIVITY TO INTRODUCE PLANARITY AND FUNCTIONAL GROUPS THAT MAY POTENTIATE OR MODIFY BIOLOGICAL ACTIVITIES. ALL SYNTHESIZED HYDRAZONES WILL BE ASSAYED IN VITRO IN HUMAN/MOUSE CELL LINES, THE GRANULOCYTE/MACROPHAGE COLONY FORMING CELL ASSAY (GM-CFC), IN THE IMMATURE UTERINE RAT MODEL AND IN RAT/MOUSE ACUTE/CHRONIC TOXICITY STUDIES.