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–FeII, 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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