title: Bis-naphthalimides 3: synthesis and antitumor activity of N,N'-bis[2-(1,8-naphthalimido)-ethyl] alkanediamines.
abstract: The bis-naphthalimides are a new class of antitumor agent. Previously, we have described initial synthetic series which established that two naphthalimide chromophores joined by polyamine linkers can produce agents with antitumor activity. We now extend these studies to describe the synthesis of a N,N'-bis[1,8-naphthalimido)-ethyl]alkanediamine series and examine the alkyl linker and chromophore substitution requirements for optimal antitumor activity. As a result, a bis-naphthal-imidoethyl derivative with no chromophore substitution and a NH-(CH2)3-NH bridge was identified. This agent (LU 79553) had both potent cellular cytotoxicity (IC50 = 0.014 microM) and was curative against MX-1 tumors grown in athymic mice. It has now been selected for clinical development.
authors.affiliation: Universidad San Pablo-CEU, Departamento de Química Orgánica y Farmacéutica, Madrid, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Braña
authors.forename: J M
authors.initials: JM
authors.lastname: Castellano
authors.forename: M
authors.initials: M
authors.lastname: Morán
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez de Vega
authors.forename: D
authors.initials: D
authors.lastname: Perron
authors.forename: D
authors.initials: D
authors.lastname: Conlon
authors.forename: P F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: C A
authors.initials: CA
authors.lastname: Romerdahl
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D013055:Spectrophotometry, Infrared; D014407:Tumor Cells, Cultured
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D009281:Naphthalenes