J. Med. Chem. 2001, 44, 1407-1415
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Dicationic Bis(9-methylphenazine-1-carboxamides): Relationships between Biological Activity and Linker Chain Structure for a Series of Potent Topoisomerase Targeted Anticancer Drugs Swarna A. Gamage,† Julie A. Spicer,† Graeme J. Finlay,† Alistair J. Stewart,# Peter Charlton,# Bruce C. Baguley,† and William A. Denny*,† Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1000, New Zealand, and Xenova Ltd., 240 Bath Road, Slough SL1 4EP, Berkshire, England Received August 1, 2000
Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH2)nNR(CH2)mNR(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
