title: 2-substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent.
abstract: A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.
authors.affiliation: Department of Pharmaceutical Sciences and Cancer Center, University of Arizona, Tucson 85721.
authors.forename: S M
authors.initials: SM
authors.lastname: Sami
authors.forename: R T
authors.initials: RT
authors.lastname: Dorr
authors.forename: D S
authors.initials: DS
authors.lastname: Alberts
authors.forename: W A
authors.initials: WA
authors.lastname: Remers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines