ARYL HYDRAZONES WITH ANTICANCER ACTIVITIES

取代二苯甲酮苯基腙已被确定具有

Substituted benzophenone phenylhydrazones have been identified that possess antiestrogen activities with absent estrogenicity. 4,4'- Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (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-071, and is twice as cytotoxic as the former. It is not antiestrogenic and x-ray crystallography 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.