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Relevant academic research and scientific papers

Tailored Approaches towards the Synthesis of l-S-(Trifluoromethyl)cysteine- and l-Trifluoromethionine-Containing Peptides

Among the fluorinated noncanonical amino acids, l-trifluoromethionine (TFM) and l-S-(trifluoromethyl)cysteine (TfmCys), fluorinated analogues of methionine and cysteine, are of particular interest because of their ability to locally increase the hydrophobicity of peptides. We report herein the synthesis of tert-butoxycarbonyl/benzyl-protected TFM and TfmCys by using a cheap and user-friendly radical trifluoromethylation approach. The benzyl protecting group of these fluorinated amino acids could be conveniently removed by hydrogenolysis, which circumvented troublesome saponification reactions. For the first time, TfmCys was inserted into a peptide sequence by liquid- or solid-phase peptide synthesis. Finally, a late trifluoromethylation strategy with the use of Togni's reagent on disulfide-bridged peptides was also efficient to incorporate TFM or TfmCys at both N-terminal and internal positions.

Thiirancarboxamides as inhibitors of papain

Derivatives of the thiirancarboxylic acid building-block containing a peptide bond were synthesised and screened against the model cysteine protease papain. The most active of the series showed a second-order rate constant of inactivation comparable to that of the parent compound. The insertion of a peptide moiety seems to compensate the lack of a free carboxylate interacting with the histidinium ion at the enzyme's active site.

Highly Cytotoxic Bioconjugated Gold(I) Complexes with Cysteine-Containing Dipeptides

Several gold(I) complexes with cysteine-containing dipeptides have been prepared starting from cystine by coupling different amino acids and using several orthogonal protections. The first step is the reaction of cystine, where the sulfur centre is protected as disulfide, with Boc2O in order to protect the amino group, followed by coupling of an amino acid ester; finally the disulfide bridge is broken with mercaptoethanol to afford the dipeptide derivative. Further reaction with [AuCl(PPh3)] gives the gold-dipeptide-phosphine species. Starting from these formally gold(I) thiolate-dipeptide phosphine complexes with the general formula [Au(SR)(PR3)] different structural modifications, such as change in the type of the amino protecting group, the type of phosphine, the number of gold(I) atoms per molecule, or the use of a non-proteinogenic conformationally restricted amino acid ester, were introduced in order to evaluate their influence in the biological activity of the final complexes. The cytotoxic activity, in vitro, of these complexes was evaluated against different tumour human cell lines (A549, MiaPaca2 and Jurkat). The complexes show an outstanding cytotoxic activity with IC50 values in the very low micromolar range. Structure-activity relationship studies from the complexes open the possibility of designing more potent and promising gold(I) anticancer agents. Striking with gold: Gold(I) complexes with cysteine-containing dipeptides were prepared starting from cystine by coupling different amino acids, and using several orthogonal protections. The complexes show excellent cytotoxic activity with IC50 values in the very low micromolar range. The structural changes in the parent compound led to the synthesis of the most effective compound in the cell lines tested, which is the complex with two AuPPh3+ fragments coordinated to the Boc-Cys-Gly-OMe peptide (see scheme).

Electrophilic S-trifluoromethylation of cysteine side chains in α- and β-peptides: Isolation of trifluoromethylated sandostatin (octreotide) derivatives

The new electrophilic trifluoromethylating 1-(trifluoromethyl)-benziodoxole reagents A and B (Scheme 1) have been used to selectively attach CF3 groups to the S-atom of cysteine side chains of α- and β-peptides (up to 13-residues-long; products 7-14). Other functional groups in the substrates (amino, amido, carbamate, carboxylate, hydroxy, phenyl) are not attacked by these soft reagents. Depending on the conditions, the indole ring of a Trp residue may also be trifluoromethylated (in the 2-position). The products are purified by chromatography, and identified by 1H-, 13C-, and 19F-NMR spectroscopy, by CD spectroscopy, and by high-resolution mass spectrometry. The CF3 groups, thus introduced, may be replaced by H (Na/NH3), an overall Cys/Ala conversion. The importance of trifluoromethylations in medicinal chemistry and possible applications of the method (spin-labelling, imaging, PET) are discussed.