title: Antitumor agents. 2. Synthesis, structure-activity relationships, and biological evaluation of substituted 5H-pyridophenoxazin-5-ones with potent antiproliferative activity.
abstract: New antiproliferative compounds, 5H-pyrido[3,2-a]phenoxazin-5-ones (1-10), 5H-benzophenoxazin-5-one (11), 5H-pyrido[2,3-a]phenoxazin-5-one (12), 5H-pyrido[3,4-a]phenoxazin-5-one (13), and 5H-pyrido[4,3-a]phenoxazin-5-one (14), were synthesized and evaluated against representative human neoplastic cell lines. The excellent cytotoxic activity of these polycyclic phenoxazinones, structurally related to the actinomycin chromophore, is discussed in terms of structural changes made to rings A and D (Chart 1). Electron-withdrawing or electron-donating substituents were introduced at different positions of ring A to probe the electronic and positional effects of the substitution. A nitro group in R(2) or in R(1) increases the cytotoxic activity, whereas electron-donating methyl groups in any position lead to 10- to 100-fold decreasing of the activity. The low antiproliferative activity of benzophenoxazinone 11 and pyridophenoxazinones 13 and 14 confirms the crucial role of pyridine nitrogen in the W position of ring D in DNA binding. The unexpected high activity exhibited by 12, which has the nitrogen in the X position, could be ascribed to a different mechanism of action, which needs further investigation.
authors.affiliation: Dipartimento di Chimica Organica e Biochimica and Dipartimento di Chimica, Università di Napoli "Federico II", Via Cynthia 6, Monte Sant'Angelo, I-80126 Napoli, Italy. bologne@unina.it
authors.forename: Adele
authors.initials: A
authors.lastname: Bolognese
authors.forename: Gaetano
authors.initials: G
authors.lastname: Correale
authors.forename: Michele
authors.initials: M
authors.lastname: Manfra
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Orazio
authors.initials: O
authors.lastname: Mazzoni
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barone
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010078:Oxazines