Dicationic Bis(9-methylphenazine-1-carboxamides):  Relationships between Biological Activity and Linker Chain Structure for a Series of Potent Topoisomerase Targeted Anticancer Drugs

Dicationic Bis(9-methylphenazine-1-carboxamides):  Relationships between Biological Activity and Linker Chain Structure for a Series of Potent Topoisomerase Targeted Anticancer Drugs

Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH2) n NR(CH2) m NR(CH2) n linkers of varying length (carboxamide N−N distances from 11.0 to 18.4 Å) and rigidity were prepared by reaction of 9-methylphenazine-1-carboxylic acid imidazolide with the appropriate polyamines. The...

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Veröffentlicht in:Journal of medicinal chemistry 2001-04, Vol.44 (9), p.1407-1415
Hauptverfasser: Gamage, Swarna A, Spicer, Julie A, Finlay, Graeme J, Stewart, Alistair J, Charlton, Peter, Baguley, Bruce C, Denny, William A
Format: Artikel
Sprache:eng
Schlagworte:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cations, Divalent
DNA Topoisomerases, Type I - chemistry
DNA Topoisomerases, Type II - chemistry
DNA, Superhelical - chemistry
Drug Screening Assays, Antitumor
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General aspects
Humans
Inhibitory Concentration 50
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Nude
Pharmacology. Drug treatments
Phenazines - chemical synthesis
Phenazines - chemistry
Phenazines - pharmacology
Structure-Activity Relationship
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Transplantation, Heterologous
Tumor Cells, Cultured
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Zusammenfassung:Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH2) n NR(CH2) m NR(CH2) n linkers of varying length (carboxamide N−N distances from 11.0 to 18.4 Å) and rigidity were prepared by reaction of 9-methylphenazine-1-carboxylic acid imidazolide with the appropriate polyamines. The compounds were evaluated for growth inhibitory properties in P388 leukemia, Lewis lung carcinoma, and wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia with low levels of topoisomerase II (topo II). The compounds all had IC50 ratios of
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0003283