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Nucleic Acids Research Advance Access published online on December 14, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl1025
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© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemistry

Unanticipated differences between {alpha}- and {gamma}-diaminobutyric acid-linked hairpin polyamide-alkylator conjugates

Sherry M. Tsai, Michelle E. Farkas, C. James Chou1, Joel M. Gottesfeld1,* and Peter B. Dervan*

Division of Chemistry and Chemical Engineering, California Institute of Technology Pasadena CA 91125, USA 1 Department of Molecular Biology, The Scripps Research Institute La Jolla CA 92037, USA

*To whom correspondence should be addressed. Tel: +1 626 395 6002; Fax: +1 626 683 8753; Email: dervan{at}caltech.edu

Received September 16, 2006. Revised November 8, 2006. Accepted November 14, 2006.

Hairpin polyamide–chlorambucil conjugates containing an {alpha}-diaminobutyric acid ({alpha}-DABA) turn moiety are compared to their constitutional isomers containing the well-characterized {gamma}-DABA turn. Although the DNA-binding properties of unconjugated polyamides are similar, the {alpha}-DABA conjugates display increased alkylation specificity and decreased rate of reaction. Treatment of a human colon carcinoma cell line with {alpha}-DABA versus {gamma}-DABA hairpin conjugates shows only slight differences in toxicities while producing similar effects on cell morphology and G2/M stage cell cycle arrest. However, striking differences in animal toxicity between the two classes are observed. Although mice treated with an {alpha}-DABA hairpin polyamide do not differ significantly from control mice, the analogous {gamma}-DABA hairpin is lethal. This dramatic difference from a subtle structural change would not have been predicted.

*Correspondence may also be addressed to Joel M. Gottesfeld. Tel: +1 858 784 8913; Fax: +1 858 784 8965; Email: joelg{at}scripps.edu


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