Synthesis and evaluation of unsymmetrical bis(arylcarboxamides) designed as topoisomerase-targeted anticancer drugs.
Symmetrical dimers of lipophilic intercalating chromophores linked by cation-containing chains have recently been shown to have broad-spectrum in vivo anticancer activity. We report the preparation and evaluation of a series of both symmetric and unsymmetric dimers of a variety of intercalating chromophores of varied DNA binding strength, including naphthalimides, acridines, phenazines, oxanthrenes and 2-phenylquinolines. The unsymmetrical dimers were prepared by sequential coupling of the chromophores to linkers with selectively protected primary terminal amines to ensure high yields and unequivocal product. Protection of the internal (secondary) amines as BOC derivatives was used to ensure complete structural specificity, and was also an aid to the purification of these very polar compounds. The growth inhibitory abilities (as IC(50) values) of the compounds in a range of cell lines showed that the nature of the linker chain was important, and independent of the nature of the chromophore, with compounds containing the dicationic linker [-(CH2)2NH(CH2)2NH(CH2)2-] being on average 30-fold more potent than the corresponding compounds containing the monocationic linker [-(CH2)3NMe(CH2)3-]. However, the chromophores also play a role in determining biological activity, with the cytotoxicities of symmetric and unsymmetric dicationic dimers correlating with the overall DNA binding abilities of the chromophores.
Spicer
Julie A
JA
Auckland Cancer Society Research Centre, Faculty of Medical & Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1000, New Zealand. j.spicer@auckland.ac.nz
Gamage
Swarna A
SA
Finlay
Graeme J
GJ
Denny
William A
WA
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D014407:Tumor Cells, Cultured
D000577:Amides; D000970:Antineoplastic Agents; D004264:DNA Topoisomerases, Type I