300-48-1Relevant articles and documents
Biocascade Synthesis of L-Tyrosine Derivatives by Coupling a Thermophilic Tyrosine Phenol-Lyase and L-Lactate Oxidase
Jiang, Yiqi,Ju, Shuyun,Li, Guosi,Lian, Jiazhang,Lin, Jianping,Wu, Mianbin,Xue, Hailong,Yang, Lirong
supporting information, (2020/02/25)
A one-pot biocascade of two enzymatic steps catalyzed by an l-lactate oxidase and a tyrosine phenol-lyase has been successfully developed in the present study. The reaction provides an efficient method for the synthesis of l-tyrosine derivatives, which exhibits readily available starting materials and excellent yields. In the first step, an in situ generation of pyruvate from readily available bio-based l-lactate catalyzed by a highly active l-lactate oxidase from Aerococcus viridans (AvLOX) was developed (using oxygen as oxidant and catalase as hydrogen peroxide removing reagent). Pyruvate thus produced underwent C–C coupling with phenol derivatives as acceptor substrate using specially designed thermophilic tyrosine phenol-lyase mutants from Symbiobacterium toebii (TTPL). Overall, this cascade avoids the high cost and easy decomposition of pyruvate and offered an efficient and environmentally friendly procedure for l-tyrosine derivatives synthesis.
Synthesis of a Photo-Caged DOPA Derivative by Selective Alkylation of 3,4-Dihydroxybenzaldehyde
Schneider, Tobias,Kubyshkin, Vladimir,Budisa, Nediljko
, p. 2053 - 2063 (2018/05/31)
Natural and synthetic polymers containing the catechol moiety of noncoded amino acid 3,4-dihydroxyphenylalanine (DOPA) are capable of metal-coordination and adhesion under wet conditions. Masking the catechol subunit with a photo-cleavable group would provide an opportunity to design tunable adhesion properties that are especially important for biomaterial and biomedicine applications. Herein, we report the regioselective synthesis of a photo-caged DOPA bearing an ortho-nitrobenzyl (oNB) group that is capable of undergoing cleavage upon irradiation with UV light. We developed a selective synthetic route towards a 3-O-oNB alkylated DOPA regioisomer that can be readily incorporated into proteins by using a previously developed bio-expression platform. The synthesis is based on a regioselectivity switch in 3,4-dihydrozybenzaldehyde alkylation upon application of different equivalents of deprotonating base. The enantiomerically pure 3-O-oNB-DOPA was prepared on a gram scale and proved to be generally compatible with the solid-phase peptide synthesis conditions. We also demonstrate the general applicability of the developed synthetic strategy by providing the synthesis of 3-O-methyl-DOPA.
Biocatalytic One-Pot Synthesis of l-Tyrosine Derivatives from Monosubstituted Benzenes, Pyruvate, and Ammonia
Dennig, Alexander,Busto, Eduardo,Kroutil, Wolfgang,Faber, Kurt
, p. 7503 - 7506 (2015/12/11)
l-Tyrosine derivatives were obtained in >97% ee via a biocatalytic one-pot two-step cascade using substituted benzenes, pyruvate, and NH3 as starting materials. In the first step, monosubstituted arenes were regioselectively hydroxylated in the o-position by monooxygenase P450 BM3 (using O2 as oxidant with NADPH-recycling) to yield the corresponding phenols, which subsequently underwent C-C coupling and simultaneous asymmetric amination with pyruvate and NH3 using tyrosine phenol lyase to furnish l-DOPA surrogates in up to 5.2 g L-1. Instead of analytically pure arenes, crude aromatic gasoline blends containing toluene were used to yield 3-methyl-l-tyrosine in excellent yield (2 g L-1) and >97% ee.
Cutting long syntheses short: Access to non-natural tyrosine derivatives employing an engineered tyrosine phenol lyase
Seisser, Birgit,Zinkl, Rene,Gruber, Karl,Kaufmann, Franz,Hafner, Andreas,Kroutil, Wolfgang
experimental part, p. 731 - 736 (2010/06/21)
The chemical synthesis of 3-substituted tyrosine derivatives requires a minimum of four steps to access optically enriched material starting from commercial precursors. Attempting to short-cut the cumbersome chemical synthesis of 3-substituted tyrosine derivatives, a single step biocatalytic approach was identified employing the tyrosine phenol lyase from Citrobacter freundii. The enzyme catalyses the hydrolysis of tyrosine to phenol, pyruvate and ammonium as well as the reverse reaction, thus the formation of tyrosine from phenol, pyruvate and ammonium. Since the wild-type enzyme possessed a very narrow substrate spectrum, structure-guided, site-directed mutagenesis was required to change the substrate specificity of this C-C bond forming enzyme. The best variant M379V transformed, for example, o-cresol, o-methoxyphenol and o-chlorophenol efficiently to the corresponding tyrosine derivatives without any detectable side-product. In contrast, all three phenol compounds were non-substrates for the wild-type enzyme. Employing the mutant, various Ltyrosine derivatives (3-Me, 3-OMe, 3-F, 3-Cl) were obtained with complete conversion and excellent enantiomeric excess (>97%) in just a single 'green' step starting from pyruvate and commercially available phenol derivatives.
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.
Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual α4β7/α4β1 integrin antagonist
Sircar, Ila,Gudmundsson, Kristjan S.,Martin, Richard,Liang, Jimmy,Nomura, Sumihiro,Jayakumar, Honnappa,Teegarden, Bradley R.,Nowlin, Dawn M.,Cardarelli, Pina M.,Mah, Jason R.,Connell, Samuel,Griffith, Ronald C.,Lazarides, Elias
, p. 2051 - 2066 (2007/10/03)
α4β1 and α4β7 integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of α4 integrins. The potency of the initial lead compound (1: IC50 α4β7/α4β1 =5/33 μM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual α4β1/α4β7 antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC50 α4β7/α4β1 =7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.
Process for the preparation of l-dopa
-
, (2008/06/13)
The present invention is directed to preparing L-Dopa, an agent effective in the treatment of Parkinson's Disease, from a D,L-N-benzoyl-3-(4-hydroxy-3-methoxyphenyl) alanine utilizing dehydroabietylamine as a resolving agent and intermediates in this proc
