Bleomycin mimics. Design and synthesis of an acridine derivative which cleaves DNA in a sequence-neutral manner

Abstract

Bleomycin 1 is a clinically used anticancer drug that cleaves DNA at guanine–pyrimidine dinucleotides by a free-radical mechanism. The compound FTP1 2 was designed as a bleomycin mimic to cleave DNA in a non-sequence selective manner. Compound 2 may provide a route to novel, chemically simple, bleomycin analogues that also have potential as new DNA footprinting agents. FTP1 2 was synthesised from chelidamic acid, 1,3-phenylenediamine and 9-chloroacridine. An untargeted agent 8 was also made. Compound 2 cleaves DNA in a relatively non-sequence selective manner although a number of hotspots of similar sequence were found. It has a 20-fold higher cutting activity than the untargeted agent 8 and has been used to footprint two antibiotics, actinomycin D 9 and a minor groove binder, distamycin A 10. It gives clear, well-defined footprints which compare favourably with those reported by MPE–Fe^II, DNase I and iron–EDTA and is a useful addition to the range of footprinting agents. Its cytotoxicity against human colon carcinoma cells in culture is 20 times lower than that of bleomycin although its ability to cleave naked DNA is 10 000-fold less, suggesting that on a mole-for-mole basis FTP1-induced DNA damage is more biologically harmful.

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