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

Yunpeng Ye, Min Liu, Jeff L.F. Kao, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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-NH2 (P2), Ac-NH-(R,S)-AlaΨ[P(O,OH)- CH2]Gly-Phe-(R,S)-AlaΨ[P(O,OH)-CH2]Gly-NH2 (P3), Ac-NH-(R,S)-AlaΨP[P(O,OH)-CH2]Gly-Phe-Phe-(R,S)- AlaΨ[P(O,OH)-CH2]Gly-NH2 (P4), cyclo{NH-(R,S)-AlaΨ [P(O,OH)-CH2]Gly-Phe}2 (P5), and cyclo[NH-(R,S)-AlaΨ [P(O,OH)-CH2]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,OCH3)-CH2]Gly-OH. The pseudopeptides 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.

Original languageEnglish
Pages (from-to)72-85
Number of pages14
JournalBiopolymers
Volume89
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Metal binding
  • Phosphinic acid
  • Pseudopeptide bond

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