Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics

“…While peptide 12 maintained a binding on-rate similar to the parent pTyr-containing congener, analogue 13 exhibited a greater than two orders of magnitude loss of binding affinity relative to the un-constrained parent. A similarly large loss of binding affinity was observed for compound 14 , which made an alternate use of a cyclohexyl moiety to constrain χ 1 and χ 2 angles (Oishi et al., 2004 ). To date, local conformational constraint of the pTyr mimicking residue has not proven to be a useful approach toward affinity enhancement of Grb2 SH2 domain-binding ligands.…”

Section: Use Of Conformational Constraintmentioning

confidence: 80%

Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents

Burke

2006

Int J Pept Res Ther

Self Cite

View full text Add to dashboard Cite

Aberrant signaling through protein-tyrosine kinase (PTK)-dependent pathways is associated with several proliferative diseases. Accordingly, PTK inhibitors are being developed as new approaches for the treatment of certain cancers. Growth factor receptor bound protein 2 (Grb2) is an important downstream mediator of PTK signaling that serves obligatory roles in many pathogenic processes. One of the primary functions of Grb2 is to bind to specific phosphotyrosyl (pTyr)-containing sequences through its Src homology 2 (SH2) domain. Agents that bind to the Grb2 SH2 domain and prevent its normal function could disrupt associated PTK signaling and serve as alternatives to kinase-directed inhibitors. Starting from the X-ray crystal structure of a lead peptide bound to the Grb2 SH2 domain, this review will summarize important contributions to these efforts. The presentation will be thematically arranged according to the region of peptide modified, proceeding from the N-terminus to the C-terminus, with a special section devoted to aspects of conformational constraint.

show abstract

“…In turn, these hydantoins can be hydrolyzed into the corresponding amino acids with resolution of the enantiomers, notably by lipase catalysis . This strategy afforded potent group II mGluR agonists, , phosphotyrosyl mimetics to induce a specific conformation in peptides, or cage-like amino acids that, once incorporated into drugs, would improve its transport through lipophilic membranes …”

Section: Spirohydantoinsmentioning

confidence: 99%

“…Usually, the hydantoins are prepared from the corresponding ketone following the Bucherer–Bergs conditions and are then hydrolyzed chemically or enzymatically. This approach is generally used to prepare quaternary , and constrained amino acids, ,,,− such as spiro structures, − which can then find applications as potent bioactive compounds, − as peptidomimetics for peptide modification, ,,− or as intermediates in the synthesis of natural products . In this section, we will present the different methods to prepare amino acids from hydantoins (Scheme ).…”

Section: Preparation Of Amino Acids From Hydantoinsmentioning

confidence: 99%

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

et al. 2017

View full text Add to dashboard Cite

The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates.

show abstract

Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics

Cited by 18 publications

References 24 publications

Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

Contact Info

Product

Resources

About