title: Design, synthesis, and anticancer properties of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and analogues.
abstract: 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a phase I clinical trial in advanced cancer with minimal toxicity, and impressive objective responses were noted. A-007 possesses three moieties that appear to have an influence on its anticancer activities: diphenylmethane, hydrazone, and dinitrophenyl. The goals of this study were to modify A-007's chemical moieties with the ultimate goal of maximizing its anticancer activity through increased planarity and introduction of functional groups. Thirty-five phenylhydrazone analogues of A-007 were synthesized and evaluated in vitro in a human primary cancer explant assay. Anticancer activities for selected analogues were also assayed for activity vs established human/murine cell lines. One-hundred-eighty-six fresh human solid tumors were used to screen for anticancer activity. Selected analogues were assayed for therapeutic indices (vs GM-CFC from bone marrow) in preparation for preclinical studies. Several polyaryl phenylhydrazones demonstrated improved cytotoxic activities by factors of 10(2)-10(3) when compared with A-007. However, the polyaryl quinone moieties of the latter analogues introduced potential toxic properties (cardiac, hematological) that do not exist with A-007.
authors.affiliation: DEKK-TEC, Inc., 4200 Canal Street, Suite A, New Orleans, LA 70119, USA. lrm1579@aol.com
authors.forename: Lee Roy
authors.initials: LR
authors.lastname: Morgan
authors.forename: Kanappan
authors.initials: K
authors.lastname: Thangaraj
authors.forename: Blaise
authors.initials: B
authors.lastname: LeBlanc
authors.forename: Andrew
authors.initials: A
authors.lastname: Rodgers
authors.forename: Lionel T
authors.initials: LT
authors.lastname: Wolford
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Hooper
authors.forename: Dominic
authors.initials: D
authors.lastname: Fan
authors.forename: Branko S
authors.initials: BS
authors.lastname: Jursic
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D046508:Culture Techniques; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D051379:Mice; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C097674:4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone; D000970:Antineoplastic Agents; D006835:Hydrazones; D007202:Indicators and Reagents; D010636:Phenols