title: Critical evaluation and rate constants of chemoselective ligation reactions for stoichiometric conjugations in water.
abstract: Chemoselective ligation reactions have contributed immensely to the development of organic synthesis and chemical biology. However, the ligation of stoichiometric amounts of large molecules for applications such as protein-protein conjugates is still challenging. Conjugation reactions need to be fast enough to proceed under dilute conditions and chemoselective in the presence of unprotected functional groups; the starting materials and products must be stable under the reaction conditions. To compare known ligation reactions for their suitability under these conditions, we determined the second-order rate constants of ligation reactions using peptide substrates with unprotected functional groups. The reaction conditions, the chemoselectivity of the reactions, and the stability of the starting materials and products were carefully evaluated. In some cases, the stability could be improved by modifying the substrate structure. These data obtained under the ligation conditions provide a useful guide to choose an appropriate ligation reaction for synthesis of large molecules by covalent ligation reactions of unprotected substrates in water.
authors.affiliation: †Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland.
authors.forename: Fumito
authors.initials: F
authors.lastname: Saito
authors.affiliation: †Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Noda
authors.affiliation: †Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland.|‡Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8602, Japan.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Bode
mesh_terms: D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D003300:Copper / Q000737:chemistry; D061565:Cycloaddition Reaction; D007700:Kinetics; D008301:Maleimides / Q000737:chemistry; D010091:Oximes / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D000480:Alkynes; D001386:Azides; D008301:Maleimides; D010091:Oximes; D010455:Peptides; D011506:Proteins; D013438:Sulfhydryl Compounds; D014867:Water; C043592:maleimide; D003300:Copper