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Nucleic Acids Research, 2003, Vol. 31, No. 17 5149-5156
© 2003 Oxford University Press

Clerocidin alkylates DNA through its epoxide function: evidence for a fine tuned mechanism of action

Sara Richter, Barbara Gatto, Daniele Fabris1, Ken-ichi Takao2, Susumu Kobayashi2 and Manlio Palumbo*

Department of Pharmaceutical Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy, 1 Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA and 2 Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

*To whom correspondence should be addressed. Tel: +39 049 827 5711/7; Fax: +39 049 827 5366; Email: manlio.palumbo{at}unipd.it

Clerocidin (CL) is an effective topoisomerase II-poison, which has been shown to produce DNA depurination and strand breaks per se at the guanine (G) level. To elucidate the roles played by the different functional groups of CL in the reactivity towards nucleic acids, we investigated CL derivatives with key structural modifications. The derivatives were reacted with plasmid, single-/double-stranded DNA and isolated 2'-deoxy-guanosines (dG). We show here that an intact oxirane ring is essential to achieve DNA modification and depurination. Through HPLC/MS and MS/MS techniques we were able to unambiguously characterize adducts obtained by reacting isolated dG and single-/double-stranded DNA with the drugs, indicating beyond reasonable doubt that the structure of a typical adduct is formed by epoxide alkylation at N7 of G with subsequent loss of the pentose unit. Further, we showed that reduction of vicinal carbonyl functions affect drug activity to a large extent. Our findings demonstrate that the characteristic DNA-alkylating properties of CL arise from mutual action of the functional groups present in this molecule. Its oxidation state seems crucial to modulate the rates of reactivity by finely tuning the strain applied on the oxirane ring.


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