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J Org Chem. 2013 Jan 4;78(1):124-33. doi: 10.1021/jo302053v. Epub 2012 Nov 2.

Synthesis of cyclic Py-Im polyamide libraries.

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1
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

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.

PMID:
23106218
PMCID:
PMC3538502
DOI:
10.1021/jo302053v
[Indexed for MEDLINE]
Free PMC Article

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