Abstract
Thioether containing peptides were obtained following three synthetic routes. In route A, halo acids esterified on 2-chlorotrityl(Cltr) resin were reacted with N-fluorenylmethoxycarbonyl (Fmoc) aminothiols. These were either cleaved from the resin to the corresponding (Fmoc-aminothiol)carboxylic acids, which were used as key building blocks in solid phase peptide synthesis (SPPS), or the N-Fmoc group was deprotected and peptide chains were elongated by standard SPPS. The obtained N-Fmoc protected thioether containing peptides were then condensed either in solution, or on solid support, with the appropriate amino components of peptides. In route B, the thioether containing peptides were obtained by the reaction of N-Fmoc aminothiols with bromoacetylated peptides, which were synthesized on Cltr-resin, followed by removal of the N-Fmoc group and subsequent peptide elongation by standard SPPS. In route C, the thioether containing peptides were obtained by the condensation of a haloacylated peptide synthesized on Cltr-resin and a thiol-peptide synthesized either on 4-methoxytrityl(Mmt) or trityl(Trt) resin.
Highlights
IntroductionThe use of native peptides for clinical applications has been hampered mainly by their rapid degradation by proteases, poor oral bioavailability, difficult transportation through cell membranes and nonselective receptor binding [1]
Peptides are used as therapeutic agents for controlling diseases related to peptide functions.the use of native peptides for clinical applications has been hampered mainly by their rapid degradation by proteases, poor oral bioavailability, difficult transportation through cell membranes and nonselective receptor binding [1]
In route B, the thioether containing peptides were obtained by the reaction of N-Fmoc aminothiols with bromoacetylated peptides, which were synthesized on Cltr-resin, followed by removal of the N-Fmoc group and subsequent peptide elongation by standard solid phase peptide synthesis (SPPS)
Summary
The use of native peptides for clinical applications has been hampered mainly by their rapid degradation by proteases, poor oral bioavailability, difficult transportation through cell membranes and nonselective receptor binding [1]. These limitations of peptides have led to the synthesis of peptidomimetics through numerous modifications of peptide structures [2,3,4]. Such modifications alter the physical and chemical properties of the native peptide, reducing its peptide character and leading to peptide analogues with increased resistance to proteolytic enzymes, flexibility and lipophilicity, while they confer diverse electrostatic properties and new secondary conformations on the peptidomimetic chain, often resulting in improved pharmacokinetic properties [2,16,17]
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