Parallel Synthesis of H-pin Polyamides by Alkene Metathesis on Solid Phase

Abstract

A small library of H-pin polyamides with variable aliphatic bridge lengths (CH(2))(n)(), where n = 4-8, connecting a central Py/Py pair was prepared via parallel synthesis with Ru-catalyzed alkene metathesis on solid phase as a complexity-generating cross-linking reaction. DNA binding affinities and sequence specificities were analyzed for each member of the library to determine the optimum linker length. An H-pin polyamide with a six-methylene bridge was found to have the highest affinity to its match site with high selectivity over a 1-bp mismatch site. The relationship between the number of methylenes in the linker (CH(2))(n)() and affinity is n = 6 > 4 > 7 > 5 > 8. These results indicate that 6 followed by 4 methylene-bridged polyamides represent the optimum spacer length for the H-pin motif in the DNA minor groove. Importantly, the H-pin is competitive with hairpin polyamides with respect to affinity and specificity. The metathesis-based convergent synthetic route to H-pin polyamides expands the scope of readily available DNA recognition motifs for small molecule-based gene regulation studies.

Biological Applications of Foldamers

“…Oligoamides can be synthesized through solid phase methods employing Bocor Fmoc-protected monomers [109][110][111]. The first residue attached to the resin determines the oligoamide C-terminal residue, which can dictate the DNAbinding specificity.…”

“…H-pin [111,194] oligoamides have also been designed, whereby an alkyl chain projecting from the minor groove is used to link oligoamide strands at the central position ( Fig. 8.16).…”

Artificial (Pseudo)peptides for Molecular Recognition and Catalysis

“…1.4c) or terminus (U-pin, Fig. 1.4d) have recently been prepared [13,14]. The Upins resulted in a loss in affinity, because of the removal of two hydrogen bond donors, but were insensitive to the base pair adjacent to the turn.…”

Design of a Sequence‐Specific DNA Bisintercalator

“…[11] Based on this sequence-specific intercalator lead [12] we explored the synthesis and binding properties of sequencespecific bisintercalators (Figure 2). Our design is a symmetric molecule which contains a minor-groove-binding polyamide based on the H-pin motif [13] with an acridine moiety at each C terminus. According to the pairing rules [14] the H-pin core should target the sequence 5'-TGACA-3' and, based on earlier precedent, the two acridine moieties should unwind DNA by !…”

“…Cross-linked resin 1 was synthesized by loading b-Ala-PAM (PAM = phenylacetamido methyl) resin with activated pyrrole amino acid, [15] subsequent tert-butoxycarbonyl (Boc) deprotection and addition of the ring-linked dimeric building block to couple the C termini of the growing polyamide chain on the resin, [13] and final capping by using activated imidazole carboxylate (Scheme 1). Resin-bound H-pin 1 was then subjected to aminolytic cleavage with 2,2'-(ethylenedioxy)-bis(ethylamine) to form H-pin diamine 2.…”