Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity

Abstract

The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl 0-atoms and/or the hydroxy 0-atom of the MeBmt residue are replaced by an S-atom. The position of the S-atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X-ray crystallography. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for CsA in CDCl,, two conformers A and B, in a ratio 58:42 are found for ['yl',CS-NH]CsA, Extensive NMR studies including new 2D and 3D heteronuclear techniques and restrained MD calculations using ROE effects demonstrate that the major conformer

Electrophilic S‐Trifluoromethylation of Cysteine Side Chains in α‐ and β‐Peptides: Isolation of Trifluoro‐methylated Sandostatin® (Octreotide) Derivatives

“…-In one of our groups, there is a long-standing interest in the modification of peptides: naphthylselenation [1], dehydration of serine moieties [2], C¼O ! C¼S thionylation [3], electrochemical decarboxylation [4], Li-enolate formation and reactions with electrophiles [5], and homologation of amino-acid residues [6] [7]. In continuation of this tradition, we have now investigated the conversion of CH 2 ÀSÀH groups of cysteine side chains in peptides to CH 2 ÀSÀCF 3 groups, by using a method [8] [9] that has been recently introduced by another group of co-authors of the present article 5 ).…”

“…The products are purified by chromatography, and identified by 1 H-, 13 C-, and 19 F-NMR spectroscopy, by CD spectroscopy, and by high-resolution mass spectrometry. The CF 3 groups, thus introduced, may be replaced by H (Na/NH 3 ), an overall Cys/Ala conversion. The importance of trifluoromethylations in medicinal chemistry and possible applications of the method (spin-labelling, imaging, PET) are discussed.…”

“…by Stefania Capone a ) 1 ), Iris Kieltsch b ) 2 ), Oliver Flçgel a ) 3 ), Gerald Lelais a ) 4 The new electrophilic trifluoromethylating 1-(trifluoromethyl)-benziodoxole reagents A and B (Scheme 1) have been used to selectively attach CF 3 groups to the S-atom of cysteine side chains of aand b-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.…”

“…The method uses the hypervalent iodine reagents A and B with a CF 3 group attached to the I-atom. They are capable of transferring CF 3 to nucleophilic centers of substrate molecules. This electrophilic trifluoromethylation reaction is remarkably mild and selective.…”

Influence on proline‐specific enzymes of a substrate containing the thioxoaminoacyl–prolyl peptide bond

“…Thioxo amides are stronger acids [lo] but weaker bases than amides [ll]. Nevertheless, the introduction of a thioxo amide bond is a nearly isosteric substitution for an amide bond [12] often accompanied with surprising effects on the conforma-tion of peptides [13,141 and on the proteolytic stability [ 15 -…”