The attraction of H‐bonding: Proline derivatives with a C4‐endo ring pucker and a preference for the trans amide conformer are introduced as building blocks to tune the cis/trans amide conformer ratio in Xaa‐Pro bonds within peptides. Noncovalent interactions, such as hydrogen bonding between the substituent at C4 of the proline ring and the amide backbone are key for favoring or disfavoring the trans conformer (see picture).
The effect of preorganized versus undefined charge display on the cellular uptake of cationic cell-penetrating peptides (CPPs) was investigated by comparing conformationally well-defined guanidinylated oligoprolines with flexible oligoarginines. Flow cytometry and confocal microscopy studies with different cancer cell lines (HeLa, MCF-7, and HT-29) showed that preorganization of cationic charges in lateral distances of ≈9 Å enhanced the cellular uptake of CPPs. Binding affinity measurements revealed tighter binding of analogues of cell-surface glycans to the guanidinylated octaproline with localized charges compared to flexible octaarginine, a finding that was further correlated to the cellular uptake by studies with CHO cells deficient in glycans on the outer plasma membrane.
Attraktive H‐Brücken: Prolinderivate mit einem C4‐endo‐Ringpucker und einer Präferenz für trans‐Amidbindungen werden als Bausteine eingesetzt, um das cis/trans‐Verhältnis der Amidbindung in Xaa‐Pro‐Einheiten von Peptiden einzustellen. Nichtkovalente Wechselwirkungen wie H‐Brücken zwischen dem Substituenten am Prolinring‐C4 und dem Amidrückgrat sind ausschlaggebend für die Begünstigung oder Benachteiligung des trans‐Konformers (siehe Bild).
Different L-prolinamides 21, prepared from L-proline and chiral β-amino alcohols are active bifunctional catalysts for the direct nitro-Michael addition of ketones to β-nitrostyrenes. In particular, catalyst 21e prepared from L-proline and (1S,2R)-cis-1-amino-2-indanol exhibits the highest catalytic performance working in polar aprotic solvents such as NMP especially in the presence of 20 mol% of acid additives such as 4-nitrobenzoic acid or under microwave heating. High syn-diastereoselectivities (up to 94% de) and good enantioselectivities (up to 80% ee) are obtained at r.t. Moreover, [a] Transition state structures for the rate-limiting C-C bond-forming step are calculated.Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis and that the energy barrier for Re-face attack to form syn-(4S,5R) products is lower than that for the Si-face attack leading to syn-(4R,5S) products.
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