Influence of ring substitution on the conformation and β-turn mimicry of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one peptide mimetics

Wachter, Rien De; Brans, Luc; Ballet, Steven; Eynde, Isabelle Van den; Feytens, Debby; Keresztes, Attila; Tóth, Géza; Urbańczyk‐Lipkowska, Zofia; Tourwé, Dirk

doi:10.1016/j.tet.2009.01.057

Cited by 14 publications

(26 citation statements)

References 59 publications

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“…[20] In contrast, the a-Me-substituted Aba analogue adopts a boat-like ring conformation, and was shown to be a strong b-turn inducer in this model. [21] This is an analogy to the finding that a-MePro is a stronger turn inducer than Pro. [22,23] Herein we compare the effects of S and R stereoisomers of Aba and a-MeAba incorporated into the dermorphin sequence on m-and d-opioid receptor affinity, functionality and on the conformation of the dermorphin analogues.…”

Section: Introductionmentioning

confidence: 69%

“…In order to assign the absolute configuration of these [aMeAba 3]-containing epimers, asymmetric synthesis of aMeAba-Gly was performed. Since (R,S)-a-Me-o-cyanophenylalanine was conveniently obtained by phase-transfer catalyzed (PTC) alkylation of N-benzylidene alanine ethyl ester with o-cyanobenzyl bromide, [21] and since we obtained o-cyanophenylalanine with high enantiomeric purity using a cinchonidiniumbased chiral phase-transfer catalyst, [20] this method was our first choice for the asymmetric synthesis of a-MeAba (Scheme 1).…”

Section: Synthesismentioning

confidence: 99%

“…[21] To investigate the persistence of these features in the novel dermorphin compounds 5 to 8, conformational studies by using NMR-based molecular modeling techniques were performed.…”

Section: Conformational Analysis Of 5 Tomentioning

confidence: 99%

“…Whereas asymmetric synthesis of Aba-Gly has been described, [18][19][20] only a racemic synthesis of a-MeAba-Gly was reported. [21] We now also describe the asymmetric variant of the latter.…”

Section: Introductionmentioning

confidence: 99%

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Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

et al. 2011

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Dermorphin analogues, containing a (S)- and (R)-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba) and the α-methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase-transfer catalysis was unable to provide the (S)-α-Me-o-cyanophenylalanine precursor for (S)-α-MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)-Aba 3-Gly 4]dermorphin retained μ-opioid affinity but displayed an increased δ-affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)-α-MeAba 3-Gly 4]dermorphin isomer was more potent than its S epimer. Tar-MD simulations of both non-methylated [Aba 3-Gly 4]dermorphin analogues showed a degree of folding at the C-terminal residues toward the N terminus of the peptide, without however, adopting a stabilized β-turn conformation. The α-methylated analogues, on the other hand, exhibited a type I/I' β-turn conformation over the α-MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5-HN and D-Ala 2-CO.

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Section: Introductionmentioning

confidence: 69%

Section: Synthesismentioning

confidence: 99%

“…[21] To investigate the persistence of these features in the novel dermorphin compounds 5 to 8, conformational studies by using NMR-based molecular modeling techniques were performed.…”

Section: Conformational Analysis Of 5 Tomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

et al. 2011

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“…However, the crystal structure exhibited a different folding model for this group of oligomer. An increasing number of novel turn mimics are being developed with a more specic purpose of targeting, such as benzazepin-3-one or benzodiazepinone derivatives as a new group of b-turn 74 or g-turn mimics, 75 respectively. More complicated motifs with turn structures as a b-hairpin motif have also been mimicked 76 and characterized.…”

Section: 57mentioning

confidence: 99%

Protein/peptide secondary structural mimics: design, characterization, and modulation of protein–protein interactions

et al. 2016

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Protein-protein interactions (PPIs) play a critical role in many essential biological processes, and numerous diseases result from malfunctioning PPIs. The modulation of undesirable PPIs via synthetic chemical molecules has long been considered of medical importance, but still remains challenging. Thanks to the development of synthetic chemistry, chemists can synthesize protein/peptide secondary structure mimics to modulate the specific PPIs. This review discusses general aspects of novel artificial peptide secondary structure mimics for the modulation of PPIs, their therapeutic applications and future prospects.

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Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

Fuse

Komuro

Otake

et al. 2021

Chemistry A European J

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Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventionall actamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope,m uch waste, and/orh igh cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein,amethods using highly electrophilic triphosgene in am icroflow reactor that accomplishesr apid (0.5-10s), mild, inexpensive, and less-wasteful lactamizationare described. Methods Aa nd B, which use N-methylmorpholine and Nmethylimidazole, respectively, were developed. Various lactams and ac yclic peptide containing acid-and/orh eat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimizedb yt he use of microflow technology.

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Influence of ring substitution on the conformation and β-turn mimicry of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one peptide mimetics

Cited by 14 publications

References 59 publications

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

Protein/peptide secondary structural mimics: design, characterization, and modulation of protein–protein interactions

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

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