title: Synthesis of cyclic Py-Im polyamide libraries.
abstract: Cyclic Py-Im polyamides containing two GABA turn units exhibit enhanced DNA binding affinity, but extensive studies of their biological properties have been hindered due to synthetic inaccessibility. A facile modular approach toward cyclic polyamides has been developed via microwave-assisted solid-phase synthesis of hairpin amino acid oligomer intermediates followed by macrocyclization. A focused library of cyclic polyamides 1-7 targeted to the androgen response element (ARE) and the estrogen response element (ERE) were synthesized in 12-17% overall yield. The Fmoc protection strategy also allows for selective modifications on the GABA turn units that have been shown to improve cellular uptake properties. The DNA binding affinities of a library of cyclic polyamides were measured by DNA thermal denaturation assays and compared to the corresponding hairpin polyamides. Fluorescein-labeled cyclic polyamides have been synthesized and imaged via confocal microscopy in A549 and T47D cell lines. The IC(50) values of compounds 1-7 and 9-11 were determined, revealing remarkably varying levels of cytotoxicity.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Li
authors.forename: David C
authors.initials: DC
authors.lastname: Montgomery
authors.forename: James W
authors.initials: JW
authors.lastname: Puckett
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002460:Cell Line; D003500:Cyclization; D019793:Fluorescein / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008872:Microwaves; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation; D009757:Nylons / Q000138:chemical synthesis* / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques; D005680:gamma-Aminobutyric Acid / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D005680:gamma-Aminobutyric Acid; D019793:Fluorescein