Configurationally driven folding of model tetrapeptides containing L‐ or D‐morpholine‐3‐carboxylic acids as β‐turn nucleators

Abstract

The conformational analysis by NMR, IR, and molecular modeling of tetrapeptides containing morpholine-3-carboxylic acid (Mor) as a proline surrogate is presented. The relationship between the chirality of the cyclic amino acid at position i+1 and the turn propensity is maintained with respect to the reference proline-containing peptides, although marked differences in the type of folded structures were observed. The conformational profile of morpholine-containing turn peptides as a function of the chirality of the cyclic amino acid indicated that the heterochiral tetrapeptide containing the D-isomer of the cyclic amino acid is more prone to nucleate compact folded structures, although with no resemblance to the beta-turn structures of D-proline-containing peptides. Also, the solvation system proved to influence the organization of folded structures, as in the more interactive CD(3)CN the model peptides showed more compact conformations. The L-Mor-containing peptide displayed two rotamers at the Val-Mor amide bond. The trans isomer did not experience any turn structures, nor any intramolecular hydrogen-bonds, whereas the cis isomer showed a strong preference for a type VI beta-turn structure, thus providing a different conformational asset with respect to the beta-turn structure as reported for the reference L-proline model peptide.

Evaluation of stereochemically dense morpholine-based scaffolds as proline surrogates in β-turn peptides

“…See DOI: 10.1039/b913444a of peptides containing morpholine-3-carboxylic acid (Mor) as an unexplored proline surrogate. 22 The relevance of such a secondary amino acid in medicinal chemistry is remarkable, as morpholine-3-carboxylic acid is present in several bioactive molecules, such as TACE (TNF-a converting enzyme), 23 MMP (matrix metalloproteinase), and TNF (tumour necrosis factor) inhibitors, 24 and a potent orally active VLA-4 antagonist. 25 With the aim of gaining information for the design of turn peptides containing the morpholine nucleus, we decided to study the conformational role of more complex morpholines.…”

Chemical genetics approach to drug discovery by diversity-oriented synthesis (DOS) of peptidomimetics

“…6) [25]. Also, the conformational analysis of peptides containing morpholine-3-carboxylic acid (Mor) suggested this molecule acts as an unexplored proline surrogate [26]. We applied the reactivity of some morpholine acetals to give access to a library of morpholinederived molecules, some of which also contained the 2,5-diketopiperazine nucleus, which in turn is considered a privileged scaffold in medicinal chemistry owing to the wide number of bioactive natural products and drugs containing such chemical entity [9].…”

Two-step one-pot synthesis of dihydropyrazinones as Xaa-Ser dipeptide isosteres through morpholine acetal rearrangement

“…During the last few years we turned our attention to the chemistry of morpholines, [20][21][22][23][24] as this heterocycle represents a common motif in medicinal chemistry. A previous contribution reported the successful generation of bicyclic scaffolds starting from threonine-derived morpholines according to a sequential addition of reactants in one-pot.…”