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Unanticipated differences between α- and γ-diaminobutyric acid-linked hairpin polyamide-alkylator conjugates

Tsai, Sherry M. and Farkas, Michelle E. and Chou, C. James and Gottesfeld, Joel M. and Dervan, Peter B. (2007) Unanticipated differences between α- and γ-diaminobutyric acid-linked hairpin polyamide-alkylator conjugates. Nucleic Acids Research, 35 (1). pp. 307-316. ISSN 0305-1048. PMCID PMC1802559. http://resolver.caltech.edu/CaltechAUTHORS:TSAnar07

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802559/PubMed CentralArticle
http://nar.oxfordjournals.org/content/35/1/307/suppl/DC1PublisherSupplementary Data
Additional Information:© 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. Received September 16, 2006. Revised November 8, 2006. Accepted November 14, 2006. The authors thank David Alvarez for helpful discussions; David M. Chenoweth for molecular modeling; Kathy Klingensmith, Pastorcito Nieto and Antonio Reyes from TSRI ICND Vivarium; and Dr Kent Osborn DMV and Leslie Nielsen from TSRI Pathology lab for helpful discussions and assistance on animal care and protocols. The authors are grateful to the National Institutes of Health for research support (CA107311) and for a predoctoral NRSA training grant to M.E.F. Funding to pay the Open Access publication charges for this article was provided by the National Institutes of Health (CA107311). Conflict of interest statement. None declared. Supplementary Data are available at NAR Online.
Funders:
Funding AgencyGrant Number
NIHCA-107311
NIH Predoctoral FellowshipUNSPECIFIED
Subject Keywords:DNA CROSS-LINKING; SEQUENCE-SPECIFIC RECOGNITION; MINOR-GROOVE; NUCLEAR-LOCALIZATION; AMINO-ACIDS; IMIDAZOLE; CHLORAMBUCIL; SPECIFICITY; DISTAMYCIN; PROLIFERATION
Issue or Number:1
PubMed Central ID:PMC1802559
Record Number:CaltechAUTHORS:TSAnar07
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:TSAnar07
Alternative URL:http://dx.doi.org/10.1093/nar/gkl1025
Official Citation:Sherry M. Tsai, Michelle E. Farkas, C. James Chou, Joel M. Gottesfeld, and Peter B. Dervan Unanticipated differences between α- and γ-diaminobutyric acid-linked hairpin polyamide-alkylator conjugates Nucl. Acids Res. (2007) 35 (1): 307-316 first published online December 14, 2006 doi:10.1093/nar/gkl1025
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7483
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:26 Feb 2007
Last Modified:09 May 2016 21:34

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