Prolyl amide

Fig. 2. Comparison of prolyl amide and the corresponding olefin isostere.

Tertiary amides, such as those associated with prolyl amide bonds frequently influence turn architectures. The importance of the cis Xaa-Pro bond on activity was recognized and proposed to be the source of differentiation in biological activity [86] therefore, isomerization of the prolyl amide bond is central to regulation of protein folding, immunosuppression, and mitosis. These functions are not surprisingly associated with several disease states and thus substitution of the acyl-proline amide bond with the fluoroolefin isostere has received considerable attention. 

Fig. 9. C/s and trans isomers of prolyl amide olefin isosteres.

Solution-state NMR studies suggest that the catalysts containing l- and D-Pro adopt p-turns and p-hairpins in solution,respectively. Reactions exhibit first-order dependence on catalyst 24, consistent with a monomeric catalyst in the ratedetermining step of the reaction. These catalysts exhibit enantiospecific rate acceleration, in comparison to the reaction rate when NMI is employed as catalyst. An isosteric replacement of an alkene for a backbone amide in a tetrapeptide catalyst (catalysts 32 and 33, Fig. 4) has lent credence to a proposed mechanism of rate acceleration [31). While catalyst 32 exhibits a fcrei=28 with substrate 27, alkene-containing catalyst 33 is not selective in this kinetic resolution and also affords a reduced reaction rate. This suggests that the prolyl amide is kinetically significant in the stereochemistry-determining step of the reaction. 

L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-L-phenylalanine methyl ester trihydrochloride Angiotensin amide Atropic acid ethyl ester Tilidine HCI Atropine... 

CN 5-oxo-L-prolyl-L-glutaminyl-L-a-aspartyl-O-sulfo-L-tyrosyl-L-threonylglycyl-L-tryptophyl-L-methionyl-L-a-aspartyl-L-phenylalanin amide... 

This zinc-dependent enzyme [EC 3.4.11.1], also referred to as cytosol aminopeptidase, leucyl aminopeptidase, and peptidase S, catalyzes the hydrolysis of a terminal peptide bond such that there is a release of an N-terminal amino acid, Xaa-Xbb-, in which Xaa is preferably a leucyl residue, but may be other aminoacyl residues including prolyl (although not arginyl or lysyl). Xbb may be prolyl. In addition, amino acid amides and methyl esters are also readily hydrolyzed, but the rates with arylamides are exceedingly slow. The enzyme is activated by heavy metal ions. 

The preparation of the fluoroolefin amide isosteres is reviewed. The incorporation of the amide isosteres in peptidomimetics and the influence of that isosteric substitution on biological activity on inhibition of peptidyl prolyl isomerases cyclophilin (CyP) and Pini, dipeptidyl peptidase IV/CD26 (DPP IV) and thermolysin is described. In addition, select fiuoroolefination procedures which may have utility in the construction of fluoroolefin amide isosteres are illustrated. 

The potential utility of peptides as therapeutics with clinical applications is limited by its metabolic instability or poor transmembrane mobility. Consequently, the preparation of metabolically stable peptide analogs that can either mimic or block the function of natural peptides or enzymes is an important area of medicinal chemistry research. Synthesis of fluoroolefin amide isosteres, its incorporation in peptidomimetics, and the influence of that isosteric substitution on the inhibition of several enzymes such as peptidyl prolyl isomerases, dipeptidyl peptidase IV, and thermolysin is described. Moreover, protein folding and activity... 

Management of endometriosis, uterine leiomyomata (Fibroids) CAS Registry 53714-56-0 (leuprorelin) 74381-53-6 (leuprorelin acetate) 5-oxo-L-prolyl-L-his tidyl-L-tryptophyl-L- seryl-L-tyrosyl-D-le ucyl-L-leucyl-L-argi nyl-A-ethyl-L-prolin amide acetate NA... 

Intramolecular catalysis of amide bond isomerization is believed to play a key role in the folding of several proteins and this process has now been demonstrated experimentally including evidence for an H-bond between the side-chain and the prolyl Na in a cis-proline peptidomimetic.143 The amide (178) and the ester (179) have been used as substrates for these studies. Support for intramolecular nucleophilic attack... 

In this respect, Scheme 27, the ring opening of /V-sulfonyl p-lactam 80 with a dipeptide affords a-keto amide precursor 81. Subsequent elaboration of 81 and final hydrolysis of the ketal moiety affords poststatin 82, a naturally occurring pentapeptide which shows inhibitory activity against prolyl endopeptidase. 

The List group demonstrated that N-terminal prolyl peptides also can efficiently catalyze the aldol reaction [76d]. The best result was obtained by use of the dipeptide Pro-Ser, which enabled formation of the aldol adduct between acetone and p-nitrobenzaldehyde in 87% yield and with 77% ee (compared with 68% yield and 76% ee when using proline as a catalyst under the same conditions). These promising results with N-terminal prolyl peptides are particularly worthy of note when it is considered that use of proline amide itself resulted in low enantioselectivity (with only 20% ee for the aldol adduct between acetone and p-nitrobenzaldehyde). 

---