Design, synthesis, and conformational analysis of a novel spiro-bicyclic system as a type II .beta.-turn peptidomimetic

Génin, Michaël; Johnson, Rodney L.

doi:10.1021/ja00049a005

Cited by 81 publications

(57 citation statements)

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“…The design of mimetics that constrain a peptide to adopt a reverse turn is an important aspect of modulating protein-protein interactions. The dipeptide lactam [114], the bicyclic dipeptide BTD [115], and similar proline derivatives [116], spirolactam-bicyclic and tricyclic systems based on proline [117][118][119][120], substitution by N-amino proline [121] and dehydro amino acids [122][123][124][125] and metal complexes of linear peptides [126] are all examples which partially constrain the four backbone torsion angles of residues i+1 and i+2 and enhance reverse-turn propensity (Figure 9). Other efforts have focused on stabilizing type-VI turn with a cisamide bond between residues i+1 and i+2 through using the 1,5-disubstituted tetrazole [127][128][129][130], 1,2,5-triazole [131], or 1,2,4-triazole [132] as Table 4.…”

Section: Mimics Of Turn Surface and Functionmentioning

confidence: 99%

Development of small molecules designed to modulate protein–protein interactions

Che

Brooks

Marshall

2006

J Comput Aided Mol Des

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Protein-protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein-protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the "privileged-structure hypothesis" [Che, Ph.D. Thesis, Washington University, 2003] - that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists--to address the challenges inherent in the discovery of small-molecule inhibitors of protein-protein interactions.

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Section: Mimics Of Turn Surface and Functionmentioning

confidence: 99%

Development of small molecules designed to modulate protein–protein interactions

Che

Brooks

Marshall

2006

J Comput Aided Mol Des

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“…An earlier report by the same authors described the generation of the corresponding 5.5.5-sized scaffold [72]. Structural analysis by X-ray and computational methods revealed these compounds to mimic a type II b-turn, and a strong dependence of torsion angles with ring size has been evidenced.…”

Section: D-amino Acids As Reverse Turn Mimeticsmentioning

confidence: 85%

“…Subsequent conversion of (72) into the corresponding g-amino acid (75) is achieved with a Krapcho decarboxylation reaction on the cyano ester (72), giving the corresponding nitrile (73), that is successively reduced to give (74). Finally, an oxidative cleavage of the alkene (74) affords the carboxylic acid (75).…”

Section: Alkene-derived G-amino Acidsmentioning

confidence: 99%

Synthesis of γ‐ and δ‐Amino Acids

Trabocchi

Menchi

Guarna

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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An area of significant importance that provides new dimensions to the field of molecular diversity and drug discovery is the area of peptidomimetics [1]. Biomedical research has reoriented towards the development of new drugs based on peptides and proteins, by introducing both structural and functional specific modifications, and maintaining the features responsible for biological activity. As a part of this research area, unnatural amino acids are of valuable interest in drug discovery and their use as new building blocks for the development of peptidomimetics with a high structural diversity level is of key interest. In particular, medicinal chemistry has taken advantage of the use of amino acid homologs to introduce elements of diversity for the generation of new molecules as drug candidates in the so-called peptidomimetic approach, where a peptide lead is processed into a new nonpeptidic molecule. The additional methylenic unit between the N-and C-termini in b-amino acids results in an increase of the molecular diversity in terms of the higher number of stereoisomers and functional group variety, and many synthetic approaches to the creation of b-amino acids have been published. There is great interest in these as a tool for medicinal chemistry [2] and in the field of b-peptides generally [3]. The g-and d-amino acids have garnered similar interest. In particular, the folding properties of g-[4] and d-peptides [5] have been investigated, as they have been proved to generate stable secondary structures. The homologation of a-amino acids into g-and d-units allows an enormous increase of the chemical diversity within the three and four atoms between the amino and carboxyl groups. Thus, additional substituents and stereocenters expand the number of compounds belonging to the class of g-and d-amino acids. g-Amino acids have been reported both in linear form, and with the amino and carboxyl groups separated or incorporated in a cyclic structure. In the case of d-amino acids, five-and six-membered rings have been mainly reported having two substituents variously tethered between the amino and carboxyl groups. Moreover, bicyclic and spiro compounds have been reported as constrained d-amino acids, especially in the field of peptidomimetics. The synthetic approaches for the preparation of

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“…More generally, the proposed approach could provide ready access to a range of α-quaternary proline derviatives. 3,4 Last year, we reported the complementary generation of α-quaternary proline-based amino amides based on SRS chemistry, where we found that the structure of the “temporary” substituent had a direct impact on the stereochemical outcome of enolate alkylations (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

An analysis of the complementary stereoselective alkylations of imidazolidinone derivatives toward α-quaternary proline-based amino amides

2015

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Alkylations of proline-based imidazolidinones are described based on the principle of self-regeneration of stereocenters (SRS), affording high levels of either the cis or trans configured products. Stereoselectivity is dictated solely on the nature of the “temporary” group, where isobutyraldehyde-derived imidazolidinones provide the cis configured products and 1-naphthaldehyde-derived imidazolidinones afford the complementary trans configured products. These stereodivergent products can be readily cleaved to afford both α-alkylated proline enantiomers from readily available L-proline. A series of imidazolidinones were alkylated to investigate the origin of the anti-selectivity. Potential contributions toward the observed anti-selectivity are discussed on the basis of these experiments, suggesting a refined hypothesis for selectivity may be in order.

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Design, synthesis, and conformational analysis of a novel spiro-bicyclic system as a type II .beta.-turn peptidomimetic

Cited by 81 publications

References 0 publications

Development of small molecules designed to modulate protein–protein interactions

Development of small molecules designed to modulate protein–protein interactions

Synthesis of γ‐ and δ‐Amino Acids

An analysis of the complementary stereoselective alkylations of imidazolidinone derivatives toward α-quaternary proline-based amino amides

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