title: Unanticipated differences between alpha- and gamma-diaminobutyric acid-linked hairpin polyamide-alkylator conjugates.
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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Tsai
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Farkas
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D000478:Alkylation; D000613:Aminobutyrates / Q000737:chemistry*; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D010957:Plasmids / Q000235:genetics; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000477:Alkylating Agents; D000613:Aminobutyrates; D009757:Nylons; D002699:Chlorambucil; C005959:2,4-diaminobutyric acid; D004247:DNA