Design, synthesis, and metal binding of novel Pseudo- oligopeptides containing two phosphinic acid groups

✍ Scribed by Yunpeng Ye; Min Liu; Jeff L.-F. Kao; Garland R. Marshall

• Publisher: Wiley (John Wiley & Sons)
• Year: 2008
• Tongue: English
• Weight: 515 KB
• Volume: 89
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/bip.20855

✦ Synopsis

Abstract

Phosphinic compounds have potential as amide‐bond mimetics in the development of novel peptidomimetics, enzyme inhibitors, and metal‐binding ligands. Novel pseudo‐oligopeptides with two phosphinic acid groups embedded in the peptide backbone serving as amide‐bond surrogates, Ψ[P(O,OH)CH~2~], were targeted. A series of linear and cyclic pseudo‐oligopeptides with two phosphinic acid groups arrayed at different positions in the peptide sequence were designed, including AcPhe{(R,S)AlaΨ[P(O,OH)CH~2~]Gly}~2~NH~2~ (P2), AcNH(R,S)AlaΨ[P(O,OH)CH~2~]GlyPhe(R,S)AlaΨ[P(O,OH)CH~2~]GlyNH~2~ (P3), AcNH(R,S)AlaΨ[P(O,OH)CH~2~]GlyPhePhe(R,S) AlaΨ[P(O,OH)CH~2~]GlyNH~2~ (P4), cyclo{NH(R,S)AlaΨ[P(O,OH)CH~2~]GlyPhe}~2~ (P5), and cyclo[NH(R,S)AlaΨ[P(O,OH)CH~2~]GlyPhePhe]~2~ (P6). They were synthesized via conventional Fmoc chemistry on solid support utilizing Fmoc‐protected phosphinic acid‐containing pseudo‐dipeptide fragment, i.e. Fmoc(R,S)AlaΨ[P(O,OCH~3~)CH~2~]GlyOH. The pseudo‐peptides containing two phosphinic acid groups exhibited the highest binding affinity and selectivity for Fe(III) among the 10‐metal ions screened by ESI‐MS analysis––Cu(II), Zn(II), Co(II), Ni(II), Mn(II), Fe(II), Fe(III), Al(III), Ga(III), and Gd(III). P4 and P6 with 11‐atom linkages between the two phosphinic acids preferred intramolecular metal binding to form 1:1 ligand/metal complexes. As revealed by competition experiments, P4 showed the highest relative binding affinity among the six compounds tested. Noteworthy, P4 also showed higher relative binding affinity than similar dihydroxamate‐containing pseudo‐peptides reported previously. The novel structural prototype and facile synthesis along with selective and potent Fe(III) binding strongly suggest that pseudo‐peptides containing the two or more phosphinic groups as amide‐bond surrogates deserve further exploration in medicinal chemistry. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 72–85, 2008.

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