title: Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents.
abstract: Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines. A 4-methoxypyrido[4,3-a]phenazine (IC(50)s 2.5-26 nM) gave modest (ca. 5 day) growth delays in H69/P xenografts with oral dosing.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Swarna A
authors.initials: SA
authors.lastname: Gamage
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: John
authors.initials: J
authors.lastname: Milton
authors.forename: Sukhjit
authors.initials: S
authors.lastname: Sohal
authors.forename: Wendy
authors.initials: W
authors.lastname: Dangerfield
authors.forename: Prakash
authors.initials: P
authors.lastname: Mistry
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Peter A
authors.initials: PA
authors.lastname: Charlton
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D010619:Phenazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; D010619:Phenazines; D059005:Topoisomerase II Inhibitors