RSP Amino Acids Note No. 2, L-para-acetylphenylalanine - RSP Amino Acid notes - RSP Amino Acids, LLC

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RSP Amino Acids Note No. 2, L-para-acetylphenylalanine

Published by in Tyrosine ·
1756, 1756-b, and 1756-f; L-Phe(4-acetyl)-OH, L-Ph(4-C(O)CH3)-OH, p-acetylphenylalanine, pAF, and AcF

RSP introduced 1756 in its N-Boc and N-Fmoc forms in 1999.  In 2002, Tirrell (4) used an expanded genetic code to site direct the incorporation of nonproteinogenic amino acids in mammalian cells creating antibody drug conjugates with improved stability relative to normal antibody drug conjugates.  Later in August of 2002, Schultz (5) evolved an orthogonal tRNA-synthetase pair and made possible the efficient incorporation of a L-para-acetylphenylalanine,  into  proteins  with E.  coli translation relative to an the amber nonsense codon.  In 2014, Dolino,et. al. (3) incorporated p-acetylphenylalanine into the glycine binding domain of NMDA receptor to examine the degree of agonist protein conformational change via smFRET assay.  In 2014 (4), Sakmar's lab at The Rockefeller compared AcF with AzF with their improved amber suppression tRNA biotinylating the AcF with an oxime bridge and utilized AzF, an azide– alkyne cycloaddition (SpAAC) reaction of dibenzocyclooctyne to the GPCR rhodopsin.  They compared them to the wild type.  In 2014, Feng Tian, et. al. used the ketone-hydroxylamine, oxime formation to create antibody drug conjugates in mammalian cells with site specialized, medicinal protein, chemical control.  They found the process superior when compared to heterogeneous conjugates formed by nonspecific chemical modifications.  All of this work from traditional medicinal chemistry to bio-incorporation of amino acids in proteins underscores the critical importance of amino acids in sculpting new medicine.  Open a PDR and count how many drugs contain amino acids, amino acid metabolites and/or synthetically derived cores.  We are very close to seeing the first genetically produced, site directed drugs containing nonproteinogenic amino acids.

We offer 1756 unprotected or protected for biosynthesis and synthesis.  As with any ketone containing molecules, synthetically they are subject to addition by amines.  Depending  on your purpose, we recommend solubilization in acid to break up any ketone hydrates in a standard solution.  A small percentage of a dipolar solvent will increase the concentration of the amino acid.  The acetophenone functionality is easily protected to full ketals.  Imine formation does not take place to a significant extent when you are a few pH units below the pKa of the protonated amine whether it's aliphatic or aromatic.

We have reduced the ketone to the alcohol, aminated with both aliphatic and aromatic amines, it can be fluorinated and also used to form heterocycles.  In proteins at physiological pH, p-acetylphenylalanine can be considered an analogue of tyrosine with a strong, aprotic, dipole.  

The products 1756-f and 1756-b are available at from grams to kilograms or larger at guaranteed specifications: 97+%, 99+% ee 2S.  There is a special offer of a 25% discount through 6/30/16.   We are open for requests for higher purities, racemates, different protection and the D-isomer.

1. "Addition of the keto functional group to the genetic code of Escherichia coli," Lei Wang, Zhiwen Zhang, Ansgar Brock, and Peter G. Schultz; 56–61, PNAS, January 7, 2003, vol. 100, no. 1.
2. "Site-specific Incorporation of Keto Amino Acids into Functional G Protein-coupled Receptors Using, Unnatural Amino Acid Mutagenesis," Shixin Ye, Caroline Ko ̈hrer, Thomas Huber, Manija Kazmi, Pallavi Sachdev, Elsa C.Y. Yan, Aditi Bhagat, Uttam L. RajBhandary, and Thomas P. Sakmar.  THE JOURNAL OF BIOLOGICAL CHEMISTRY, VOL. 283, NO. 3, pp. 1525–1533, January 18, 2008.
3. "Structural Dynamics of the Glycine-binding Domain of the N-Methyl-D-Aspartate Receptor"  Drew M. Dolino, David Cooper, Swarna Ramaswamy, Henriette Jaurich, Christy F. Landes, and Vasanthi Jayaraman. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 290, NO. 2, pp. 797–804, January 9, 2015.
4. "Bioorthogonal Fluorescent Labeling of Functional G Protein-Coupled Receptors," He Tian, Saranga Naganathan, Manija A. Kazmi, Thue W. Schwartz, Thomas P. Sakmar, corresponding author and Thomas Huber.  Chembiochem 2014 August 18; 15(12): 1820–1829.
5. "A Designed Phenylalanyl-tRNA Synthetase Variant Allows Efficient in Vivo Incorporation of Aryl Ketone Functionality into Proteins," Deepshikha Datta , Pin Wang , Isaac S. Carrico , Stephen L. Mayo ,
and David A. Tirrell.  J. Am. Chem. Soc., 2002, 124 (20), pp 5652–5653.
6. "A general approach to site-specific antibody drug conjugates," Feng Tian et. al. Proc Natl Acad Sci U S A. 2014 Feb 4; 111(5): 1766–1771.

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