Synthesis and <i>C</i><sub>2</sub>‐symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine

Akazome, Motohiro; Enzu, Masashi; Takagi, Koji; Matsumoto, Shoji

doi:10.1002/chir.20972

Cited by 3 publications

(2 citation statements)

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“…[25][26][27][28][29][30][31][32][33][34][35][36][37][38] There are also numerous examples of similar hexapeptides and higher homologs incorporating anthranilic acid, 25,[39][40][41][42][43][44][45] a few 10-membered tripeptide derivatives [46][47][48] and several cyclic systems containing the "Anth" residue and another non-encoded amino acid. [49][50][51] However, 13-membered ring systems containing this ubiquitous residue have been under-explored. Only one natural tetrapeptide H that features Anth in a 13-membered ring has been discovered, 52 and the only 13-membered cyclic peptide containing Anth that has been synthesized is compound I, prepared as part of a medicinal chemistry project.…”

Section: Introductionmentioning

confidence: 99%

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Xin

Burgess

2016

Org. Biomol. Chem.

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Each amino acid in a peptide contributes three atom units to main-chains, hence natural cyclic peptides can be 9, 12, 15, …. ie 3n membered-rings, where n is the number of amino acids. Cyclic peptides that are 9 or 12-membered ring compounds tend to be hard to prepare because of strain, while their one amino acid homologs (15-membered cyclic pentapeptides) are not conformationally homogeneous unless constrained by strategically placed proline or D-amino acid residues. We hypothesized that replacing one genetically encoded amino acid in a cyclic tetrapeptide with a rigid β-amino acid would render peptidomimetic designs that rest at a useful crossroads between synthetic accessibility and conformational rigidity. Thus this research explored non-proline containing 13-membered ring peptides 1 featuring one anthranilic acid (Anth) residue. Twelve cyclic peptides of this type were prepared, and in doing so the viability of both solution- and solid-phase methods was demonstrated. The library produced contained a complete set of four diastereoisomers of the sequence 1aaf (ie cyclo-AlaAlaPheAnth). Without exception, these four diastereoisomers each adopted one predominant conformation in solution; basically these conformations feature amide N-H vectors puckering above and below the equatorial plane, and approximately oriented their N-H atoms towards the polar axis. Moreover, the shapes of these conformers varied in a logical and predictable way (NOE, temperature coefficient, D/H exchange, circular dichroism). Comparisons were made of the side-chain orientations presented by compounds 1aaa in solution with ideal secondary structures and protein-protein interaction interfaces. Various 1aaa stereoisomers in solution present side-chains in similar orientations to regular and inverse γ-turns, and to the most common β-turns (types I and II). Consistent with this, compounds 1aaa have a tendency to mimic various turns and bends at protein-protein interfaces. Finally, proteolytic- and hydrolytic stabilities of the compounds at different pHs indicate they are robust relative to related linear peptides, and rates of permeability through an artificial membrane indicate their structures are conducive to cell permeability.

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Section: Introductionmentioning

confidence: 99%

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Xin

Burgess

2016

Org. Biomol. Chem.

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“…The addition of a catalytic amount of DMAP to the carbodiimide-mediated reactions improved the conversions, but resulted in severe racemization. The best result was obtained by employing N -ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) as coupling reagent, which gave the optically active tripeptide 7 in 51% yield [16–17]. Intermediate 7 was converted into amine 8 under acidic conditions, and coupled directly to N , N -dimethylanthranilic acid ( 9 ).…”

Section: Resultsmentioning

confidence: 99%

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

Filho¹,

Stark²,

Westermann³

et al. 2012

Beilstein J. Org. Chem.

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SummaryTwo syntheses of natural viridic acid, an unusual triply N-methylated peptide with two anthranilate units, are presented. The first one is based on peptide-coupling strategies and affords the optically active natural product in 20% overall yield over six steps. A more economical approach with only four steps leads to the similarly active racemate by utilizing a Ugi four-component reaction (Ugi-4CR) as the key transformation. A small library of viridic acid analogues is readily available to provide first SAR insight. The biological activities of the natural product and its derivatives against the Gram-negative bacterium Aliivibrio fischeri were evaluated.

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Heterogeneous Foldamers from Aliphatic–Aromatic Amino Acid Building Blocks: Current Trends and Future Prospects

et al. 2014

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Chemists' constant pursuit of understanding of the underlying principles of nature's most intricate phenomenon such as protein folding has led to the development of the field of “foldamers”. The emergence of diverse classes of unnatural amino acid building blocks has unleashed countless opportunities to design, develop and explore the structural and functional aspects of synthetic peptides. One current trend in foldamer chemistry is the heterofoldamer approach, which involves systematic stoichiometric variation of various natural/unnatural amino acid residues, leading to conformational ordering with intriguing structural architectures. In this regard, the incorporation of aromatic amino acids provides efficient structural rigidification and tunability to the molecular scaffolds, which can exhibit a range of secondary structural features. Recent times have witnessed an upsurge of foldamers featuring aliphatic‐aromatic residues with diverse structural propensities. This review is an effort to cover this rapidly developing field of foldamer science and also to envisage its future perspectives.

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Synthesis and C₂‐symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine

Cited by 3 publications

References 33 publications

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

Heterogeneous Foldamers from Aliphatic–Aromatic Amino Acid Building Blocks: Current Trends and Future Prospects

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Synthesis and C2‐symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine

Cited by 3 publications

References 33 publications

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

Heterogeneous Foldamers from Aliphatic–Aromatic Amino Acid Building Blocks: Current Trends and Future Prospects

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Synthesis and C₂‐symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine