Issue in Honor of Prof. Heinz Heimgartner ARKIVOC 2011 (vi) 130-136
Synthesis and application of photoproline - a photoactivatable derivative of proline
Benjamin Van der Meijden and John A. Robinson*
Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland E-mail:
[email protected]
This paper is dedicated to Professor Heinz Heimgartner
Abstract
A convenient synthesis is described of a derivative of L-proline called photoproline, containing a diazirine group at position-4 of the pyrrolidine ring, starting from L-4-hydroxyproline. The use of Fmoc-L-photoproline in the synthesis of a cyclic peptidomimetic antibiotic demonstrates that this photoprobe can be incorporated into synthetic peptides using solid-phase Fmoc chemistry. Photoproline may be of wide value in the preparation of diverse peptide-based photoaffinity probes.
Keywords: photoaffinity probe, peptide, receptor, peptidomimetic antibiotic, photolabel
Introduction
Photoaffinity labelling is a powerful tool for identifying targets of biologically active small molecules.1 A key requisite is that a photolabile group can be incorporated into the small molecule, along with a probe to allow later detection of photo-crosslinked receptors, without appreciable loss of biological activity and specificity. One of the most versatile photolabile groups for this purpose is the diazirine, due to its small size, and efficient and irreversible formation of a reactive carbene upon excitation at 350 nm.2, 3 Amino acid-based photoaffinity probes, including the phenylalanine analogues p-benzoylphenylalanine, p-azidophenylalanine and 4-[3-trifluoromethyl]-3H-diazirin-3-yl]-phenylalanine have been known for some time,4-6 and more recently the alkyldiazirine amino acid analogs photoleucine, and photomethionine have been described.7, 8 Here we describe the synthesis and application of a related alkyldiazirine derivative of proline (photoproline), containing a diazirine group at position-4 of the pyrrolidine ring. A photolabile derivative of proline may be of special interest, since proline can have an important influence on peptide backbone conformation, and it frequently occurs within the energetically important epitopes in many biologically active peptides and proteins.9
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