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Synthesis of Unnatural Lipohilic N ‐(9 H ‐Fluoren‐9‐ylmethoxy)carbonyl‐Substituted α‐Amino Acids and Their Incorporation into Cyclic RGD‐Peptides: A structure‐activity study
Author(s) -
Koppitz Marcus,
Huenges Martin,
Gratias Rainer,
Kessler Horst,
Goodman Simon L.,
Jonczyk Alfred
Publication year - 1997
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19970800423
Subject(s) - chemistry , peptide , stereochemistry , amino acid , cyclic peptide , peptide synthesis , biochemistry
Abstract The α v /β 3 integrin is implicated in human tumor metastasis and angiogenesis. It has been shown that structures of the sequence cyclo(‐Arg 1 ‐Gly 2 ‐Asp 3 ‐ D ‐Phe 4 ‐Xaa 5 ‐) ( I ) and cyclo(‐Arg 1 ‐Gly 2 ‐Asp 3 ‐Phe 4 ‐ D ‐Xaa 5 ‐) ( II ) bind with high affinity and the latter with high selectivity to this receptor. The residues Xaa and D ‐Xaa accept a broad variety of amino acids. Here, we report on the synthesis, activities, and conformational analysis of cyclic Arg‐Gly‐Asp (RGD) peptides containing liophilic amino acids Xaa or D ‐Xaa in position 5. For I , these were (2 S )‐2‐aminohexadecanoic acid (Ahd) and N ′‐hexadecylglycine (Hd‐Gly) and in II , D ‐Ahd and Hd‐Gly, and, for control purposes, Ahd were incorporated ( Fig. 1 ). The enantiomerically pure a‐amino acids were obtained by non‐enantioselective synthesis and subsequent enzymatic separation of isomers using acylase I ( Scheme ). Hd‐Gly was prepared in a modified procedure according to Stewart from ethyl bromoacetate and hexadecylamine ( Scheme ). The synthesis and physicochemical properties of the corresponding (9 H ‐fluoren‐9‐ylmethoxy)carbonyl (Fmoc) derivatives, compatible with solid‐phase peptide synthesis, are described. Structure elucidation by NMR reveals that the lipid modification has no significant impact on the template structures when incorporated into them. For peptides I with Xaa = Ahd or Hd‐Gly ( 1 or 2 ), a βII′/γ‐turn‐like arrangement with D ‐Phe in i + 1 position of the β‐turn is found. Peptides II with D ‐Xaa = D ‐Ahd or Hd‐Gly ( 3 or 4 ) exhibit a βII′/γ‐turn conformation with Gly in i + 1 position of the β‐turn, whereas II with Ahd instead of D ‐Xaa, i.e., lacking a D ‐amino acid in position 4 or 5 ( 5 ). adopts no defined conformation. However, in assays of receptor specificity employing human α v v/β 3 integrin, the compounds exhibit IC 50 values ranging from nanomolar to less than millimolar. These results indicate that although the arrangement of the pharmacophoric groups is preserved in the target compounds, the biological activity is highly dependent on spatial requirements of the lipid anchor in the receptor binding pocket. Obviously, only certain positions do not affect the binding.