Pseudoprolines (Pro) in Drug Design: Direct Insertion of Pro Systems into Cyclosporin C

Abstract

The insertion of acetals that exhibit variable structural features into complex peptides such as cyclosporin C (CsC) results in oxazolidine derivatives (pseudoprolines, psiPro) of tailored physico-chemical and biological properties. N,O-Acetalation of the 2-threonine hydroxyl group and the preceding amide nitrogen of CsC is achieved by treating the molecule with a number of both arylated and non-arylated dimethyl acetals. The psiPro-containing CsC derivatives exhibit enhanced conformational backbone rigidity, as suggested by analytical HPLC, NMR spectroscopy and by kinetic measurements on binding with their receptor protein cyclophilin A (CypA) that were not time-dependent. IC50 values for calf-thymus CypA were obtained by kinetic evaluation of its cis-->trans isomerase activity. The choice of the para-substituted aryl dimethyl acetals allows the inhibitory properties of the corresponding derivatives to be modulated to either prodrugs or moderately strongly binding cyclosporin C derivatives.

Thiazolidines to lock cis Xaa-Pro amide bond: new synthetic approach

“…Despite the efficiency of this method, the synthesis of the corresponding dipeptide unit in solution, FmocXaaCys(W R,R' pro), is mandatory that prevents the generalization of the approach. More recently, the insertion of thiazolidine systems into Ser-peptides has been investigated [10,11]. But the procedure has only been proved on a dipeptide and in the case of the cyclosporine A analog the yield remains very low.…”

Synthesis of sansalvamide A peptidomimetics: triazole, oxazole, thiazole, and pseudoproline containing compounds

“…The oxazole was then formed via cyclodehydration upon treatment with DAST and potassium carbonate, then subsequent oxidation using bromochloroform and DBU. 32,37,38 Coupling fragments 1 and 2, followed by peptide macrocyclization furnished the desired oxazole peptidomimetic derivatives.…”

“…27,32 Further, triazoles induce a rigid conformation by mimicking trans amide bonds. 27,30 Studies have shown that a single N -methyl, D-aa or N -methyl D-aa play a critical role in locking the San A-amide macrocyclic analogs into a single conformation.…”

Structure-Activity Relationship Studies: Methods and Ligand Design for G-Protein Coupled Peptide Receptors

“…If L-proline increases affinity this will indicate the important role of a turn segment. Proline and other N-alkylated amino acids (8), (9) prevent the formation of α-helices as they do not contribute to hydrogen bonds but induce turn structures [93,94].…”