title: Solid-phase synthesis of amidine-substituted phenylbenzimidazoles and incorporation of this DNA binding and recognition motif into amino acid and peptide conjugates.
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).
authors.affiliation: Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), 402 N. Blackford St., Indianapolis, IN, 46202, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Garner
authors.forename: Taxiarchis M
authors.initials: TM
authors.lastname: Georgiadis
authors.forename: Jessica Bo
authors.initials: JB
authors.lastname: Li
authors.forename: Tianxiu
authors.initials: T
authors.lastname: Wang
authors.forename: Eric C
authors.initials: EC
authors.lastname: Long
mesh_terms: D000578:Amidines / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques / Q000295:instrumentation / Q000379:methods*
chemical_list: D000578:Amidines; D000596:Amino Acids; D016227:Benzoquinones; D010455:Peptides; C004532:quinone; D004247:DNA