Abstract
Amidine-substituted phenylbenzimidazoles are well-established DNA-binding structural motifs that have contributed to the development of diverse classes of DNA-targeted agents; this ring system not only assists in increasing the overall DNA affinity of an agent, but can also influence its site selectivity. Seeking a means to conveniently exploit these attributes, a protocol for the on-resin synthesis of amino acid- and peptide-phenylbenzimidazole-amidine conjugates was developed to facilitate installation of phenylbenzimidazole-amidines into peptide chains during the course of standard solid-phase syntheses. Building from a resin-bound amino acid or peptide on Rink amide resin, 4-formyl benzoic acid was coupled to the resin-bound free amine followed by introduction of 3,4-diamino-N′-hydroxybenzimidamide (in the presence of 1,4-benzoquinone) to construct the benzimidazole heterocycle. Finally, the resin-bound N′-hydroxybenzimidamide functionality was reduced to an amidine via 1 M SnCl2·2H2O in DMF prior to resin cleavage to release final product. This procedure permits the straightforward synthesis of amino acids or peptides that are N-terminally capped by a phenylbenzimidazole-amidine ring system. Employing this protocol, a series of amino acid–phenylbenzimidazole-amidine (Xaa-R) conjugates was synthesized as well as dipeptide conjugates of the general form Xaa-Gly-R (where R is the phenylbenzimidazole-amidine and Xaa is any amino acid).
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Notes
While the model compounds synthesized during the course of this work (2, 3, and 4) were not intended or designed purposefully with the targeting of DNA in mind, we nonetheless carried out preliminary tests of their DNA binding—these studies indicated that systems possessing the phenylbenzimidazole-amidine moiety exhibited significantly enhanced DNA binding. A full account of these activities within rationally designed peptide sequences will be reported in due course.
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Acknowledgments
We gratefully acknowledge financial support from an IUPUI Research Support Funds Grant (to ECL). The authors would also like to thank Prof. Marty O’Donnell (IUPUI) for comments on the manuscript during its preparation.
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The authors declare that they have no conflict of interest.
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Garner, M.L., Georgiadis, T.M., Li, J.B. et al. Solid-phase synthesis of amidine-substituted phenylbenzimidazoles and incorporation of this DNA binding and recognition motif into amino acid and peptide conjugates. Amino Acids 46, 1297–1303 (2014). https://doi.org/10.1007/s00726-014-1691-5
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DOI: https://doi.org/10.1007/s00726-014-1691-5