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Design, synthesis, and metal binding of novel Pseudo‐ oligopeptides containing two phosphinic acid groups
Author(s) -
Ye Yunpeng,
Liu Min,
Kao Jeff L.F.,
Marshall Garland R.
Publication year - 2008
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20855
Subject(s) - chemistry , dipeptide , amide , stereochemistry , peptide , oligopeptide , metal , peptidomimetic , amino acid , metal ions in aqueous solution , peptide bond , medicinal chemistry , organic chemistry , biochemistry
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 AcPhe{( R , S )AlaΨ[P(O,OH)CH 2 ]Gly} 2 NH 2 (P2), AcNH( R,S )AlaΨ[P(O,OH)CH 2 ]GlyPhe( R,S )AlaΨ[P(O,OH)CH 2 ]GlyNH 2 (P3), AcNH( R,S )AlaΨ[P(O,OH)CH 2 ]GlyPhePhe( R,S ) AlaΨ[P(O,OH)CH 2 ]GlyNH 2 (P4), cyclo{NH( R,S )AlaΨ[P(O,OH)CH 2 ]GlyPhe} 2 (P5), and cyclo[NH( R,S )AlaΨ[P(O,OH)CH 2 ]GlyPhePhe] 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 ]GlyOH. 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. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com