95498-43-4Relevant academic research and scientific papers
Facile and stabile linkages through tyrosine: Bioconjugation strategies with the tyrosine-click reaction
Ban, Hitoshi,Nagano, Masanobu,Gavrilyuk, Julia,Hakamata, Wataru,Inokuma, Tsubasa,Barbas, Carlos F.
, p. 520 - 532 (2013/06/05)
The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivatives in peptide and protein chemistry, we synthesized PTAD derivatives possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivatives and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decomposition resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addition of a small amount of 2-amino-2-hydroxymethyl-propane- 1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD derivative linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small molecules. The tyrosine click linkage demonstrated stability to extremes of pH, temperature, and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies support the broad utility of this reaction in the chemoselective modification of small molecules, peptides, and proteins under mild aqueous conditions over a broad pH range using a wide variety of biologically acceptable buffers such as phosphate buffered saline (PBS) and 2-amino-2-hydroxymethyl- propane-1,3-diol (Tris) buffers as well as others and mixed buffered compositions.
α-Sulfonyl succinimides: Versatile sulfinate donors in Fe-catalyzed, salt-free, neutral allylic substitution
Jegelka, Markus,Plietker, Bernd
experimental part, p. 10417 - 10430 (2011/10/31)
Allyl sulfones are versatile intermediates in organic chemistry. The presence of two distinct functional groups sets the stage for a plethora of subsequent transformations. However, despite these advantages the preparation of regioisomerically enriched sulfones is not easy. The use of sulfinate salts as nucleophiles in substitutions is frequently accompanied by side reactions such as π-bond migration, β-elimination, and so on. Herein we present a preparatively simple way to synthesize a variety of different aryl or alkyl allyl sulfones starting from readily accessible allylic carbonates. By employing aryl or alkyl α-sulfonyl succinimides as sulfinate synthons, mild and regioselective ipso substitution of diverse allylic carbonates was realized.
