110774-03-3Relevant articles and documents
Synthesis of new DOPA derivative from l-tyrosine for construction of bioactive compound
Sun, Dequn,Wan, Peihong,Zhang, Guoqing,Luo, Min
, p. 9407 - 9408 (2013/11/19)
A practical synthetic method of new DOPA derivative was developed with L-tyrosine as starting material. The new DOPA analogue could be used in building bioactive compounds.
Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3′-substituted tyrosine derivatives
Song, Yan-Li,Peach, Megan L.,Roller, Peter P.,Qiu, Su,Wang, Shaomeng,Long, Ya-Qiu
, p. 1585 - 1596 (2007/10/03)
The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. An impressive number of synthetic Grb2-SH2 domain inhibitors have been identified; however, clinical agents operating by this mechanism are lacking, due in part to the unique requirement of anionic phosphate-mimicking functionality for high SH2 domain-binding affinity or the extended peptide nature of most inhibitors. In the current study, a new binding motif was successfully developed by the incorporation of 3′-substituted tyrosine derivatives into a simplified nonphosphorylated cyclic pentapeptide scaffold (4), which resulted in high affinity Grb2-SH2 inhibitors without any phosphotyrosine or phosphotyrosine mimetics. The new L-amino acid analogues bearing an additional nitro, amino, hydroxy, methoxy or carboxy group at the 3′-position of the phenol ring of tyrosine were prepared in an orthogonally protected form suitable for solid-phase peptide synthesis using Fmoc protocols. The incorporation of these residues into cyclic peptides composed of a five-amino acid sequence motif, Xx′-Leu-(3′- substituted-Tyr)-Ac6c-Asn, provided a brand new class of nonphosphorylated Grb2 SH2 domain inhibitors with reduced size, charge and peptidic character. The highest binding affinity was exhibited by the 3′-aminotyrosine (3′-NH2-Tyr)-containing (R)-sulfoxide-cyclized pentapeptide (10b) with an IC50 = 58 nM, the first example with low-nanomolar affinity for a five-amino acid long sequence binding to Grb2-SH2 domain free of any phosphotyrosine or phosphotyrosine mimics. However, the incorporation of 3′-NO2-Tyr, 3′-OH-Tyr or 3′-OCH3-Tyr surrogates in the pentapeptide scaffold is detrimental to Grb2-SH2 binding. These observations were rationalized using molecular modeling. More significantly, the best Grb2-SH2 inhibitor 10b showed excellent activity in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with an IC50 value of 19 nM. This study is the first attempt to identify novel nonphosphorylated high affinity Grb2 SH2 inhibitors by the utilization of 3′-substituted tyrosine derivatives, providing a promising new strategy and template for the development of non-pTyr-containing Grb2-SH2 domain antagonists with potent cellular activity, which potentially may find value in chemical therapeutics for erbB2-related cancers.
Chemical approaches to protein engineering 20: The transformation of coded amino acid tyrosine to pro-templates having metal uptake potential in peptide/protein segments
Ranganathan,Tamilarasu
, p. 1081 - 1103 (2007/10/03)
From vantage of inorganic chemistry, the inability of any of the coded amino acid side chains to carry metal ions should appear as a grave omission in the genetic code, particularly since, metallo-enzymes play a pivotal role in diverse facets of life processes. The ready transformation of the coded amino acid tyrosine to metal uptake systems forms the core of the present work. 3-Acetyl-tyrosine [Tyr(3-Ac)]- readily derived from tyrosine is amenable to normal protocols in peptide synthesis and offers ideal ligand dispositions to craft protemplates. This aspect has been illustrated by three broad strategies. The reaction of Tyr(3-Ac) with AEH, the mono Schiff base of acetylacetone and ethylenediamine (EDA), yields the protemplates II [TYr(3-Ac)-AEH] which can also be conveniently assembled, in situ, from acetylacetone, EDA and Tyr(3-Ac). Tripeptide, where Tyr(3-Ac) is flanked by Ala and Ser has been prepared and protemplate formation demonstrated in a peptide environment. Thus, either by normal peptide synthesis or by insertion of peptides containing Tyr(3-Ac), active sites for metal uptake can be constructed, thereby, in principle, obviating the need for 50-70 residues normally required. Protemplates for metal uptake can be readily crafted by cross linking of Tyr(3-Ac) with EDA. This has also been illustrated with Ala-Tyr(3-Ac)-Ser-OMe. Thus, peptides where Tyr(3-Ac) is placed at appropriate locations, with EDA, can provide conformationally restrained metal uptake systems. Conversely, the oxime of Tyr(3-Ac) as well as the Schiff bases with β-ethanolamine and Gly-OMe can bring together proximate residues by metal complexation. This aspect has been experimentally realized. The protemplates from Tyr(3-Ac) [Schiff bases with AEH / EDA / β-ethanolamine / Gly-OMe / and oximes] readily take up Cu(II), Co(II), and Ni(II) to form stable, well defined templates. The EPR spectra of the Cu(II) templates are that for typical square planar complexes, although in few sterically crowded examples rhombohedral distortion was seen. The observed A and g parameters compared favorably with that reported for metalloproteins, with particular closeness to laccase. Cyclic voltammetric studies were complicated by incursion of ligand oxidation, although in two cases clear E° values of 340 mV and 305 mV were obtained, which lie in the range reported for metallo-proteins. The Ni(II) templates exhibited the expected 1H NMR profile; in one example, coordination with two water molecules was seen. The Co(II) templates exhibited typical d-d transition at ～600 nm in the visible spectrum.
