Synthesis, DNA-cleaving properties and cytotoxicity of intercalating chelidamic acid derivatives.

M Searcey, S McClean, B Madden, A T McGown, L P Wakelin

文献索引：Anticancer Drug Des. 13(8) , 837-55, (1998)

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摘要

We have explored the potential antitumour activity of DNA-intercalating free radical generators based on compounds constructed from 9-anilinoacridine and chelidamic acid as an iron (II) binding centre. Here we describe their synthesis, DNA cleaving ability and activity against a panel of human tumour cell lines in culture. We also investigate their potential for use as DNA footprinting agents. Previous work has shown that the parent compound, FTP1, cleaves DNA in an essentially sequence neutral fashion and has modest cytotoxicity [Searcey, M., McClean, S., Madden, B. & Wakelin, L.P.G. (1997) Journal of the Chemical Society. Perkin Transactions, 2, 523]. Here we have equipped the acridine chromophore with an N,N-dimethylaminoethyl-4-carboxamide substituent, giving the threading agent FTP2, which confers selectivity for cleaving in GC-rich sequences, avoidance for binding to AT-tracts and 8-fold enhanced cytotoxicity compared with FTP1. Although this side chain bestows slow dissociation kinetics on DNA complexes of 9-anilinoacridines, it does not enhance the overall cutting efficiency of FTP2, implying that free-radical generation, DNA hydrogen abstraction and sugar fragmentation are fast compared with DNA-ligand complex lifetimes. FTP2 does not appear to be susceptible to resistance by the mdr phenotype in human ovarian carcinoma cells. We also report that FTP2 is an effective footprinting agent for GC-selective binding ligands and that it has some advantages over FTP1 in this regard.