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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Intercalating Agents / chemical synthesis
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Intercalating Agents / chemistry
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Intercalating Agents / pharmacology
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Mice
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Neoplasm Transplantation
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Phenazines / chemical synthesis*
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Phenazines / chemistry
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Phenazines / pharmacology
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Structure-Activity Relationship
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Topoisomerase II Inhibitors
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Amides
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Antineoplastic Agents
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Enzyme Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Intercalating Agents
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Phenazines
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Topoisomerase II Inhibitors