This article describes the solid-phase combinatorial methods developed for the synthesis of polyhydroxamate-based siderophores. This strategy was applied to generate several libraries of structural DFO (1a) analogues that include DFO variants, non-amide analogues, C-terminal modified analogues, reverse-amide analogues, and hybrid analogues. To assess the relative iron-binding affinities of these compounds, a high-throughput spectrophotometric screening method based on competition with 8-hydroxyquinoline-5-sulfonic acid was developed. Some of the promising candidates containing various terminal functional groups were identified and prepared on large scale to enable future studies in animal models for iron-overload diseases.

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The syntheses and RNA cleavage efficiencies of a new series of oligonucleotide conjugates of Cu(II)-serinol-terpyridine and 1,3-propanediol are reported. These reagents, termed ribozyme mimics, were designed such that they would yield multiple unpaired RNA residues directly opposite the site of the RNA cleavage catalyst upon ribozyme mimic-RNA duplex formation. This design effect was implemented using the 1,3-propanediol linker 3, which mimics the three-carbon spacing between the 5'- and 3'-hydroxyls of a natural nucleotide. Incorporation of one or more of these 1,3-propanediol linkers at positions directly adjacent to the serinol-terpyridine modification in the ribozyme mimic DNA strand resulted in cleavage at multiple phosphates in a complementary 31-mer RNA target sequence. The linkers effectively created artificial mismatches in the RNA-DNA duplexes, rendering the opposing RNA residues much more susceptible to cleavage via the transesterification/hydrolysis pathway. The RNA cleavage products produced by the various mimics correlated directly with the number and locations of the linkers in their DNA strands, and the most active ribozyme mimic in the series exhibited multiple turnover in the presence of excess 31-mer RNA target.

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This paper investigates aspects of the fundamental mechanism of transesteriÐcation and hydrolysis. The ability of remote phosphates to coordinate and deliver metal catalysts to the active site (the 2@-OH) of an RNA residue is reported. Previous literature reports show that ApUp is cleaved much faster than ApU at the internal phosphodiester. This supports the accepted mechanism whereby remote phosphates coordinate and deliver metal catalysts to the active site to promote transesteriÐcation of RNA. We report that remote phosphates do not recruit metal catalysts from the bulk solution in a productive manner for transesteriÐcation. By using a polyanionic substrate, termed embedded RNA, and methyl phosphonates to mask the charge at single positions in the polyanionic backbone, we report rate increases in transesteriÐcation with methyl phosphonate substitution adjacent to the cleavage site with aqueous Ce(III) and a Ce(III) hexaaza macrocycle.