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

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.