title: ortho-Methoxyphenols as Convenient Oxidative Bioconjugation Reagents with Application to Site-Selective Heterobifunctional Cross-Linkers.
abstract: The synthesis of complex protein-based bioconjugates has been facilitated greatly by recent developments in chemoselective methods for biomolecular modification. The oxidative coupling of o-aminophenols or catechols with aniline functional groups is chemoselective, mild, and rapid; however, the oxidatively sensitive nature of the electron-rich aromatics and the paucity of commercial sources pose some obstacles to the general use of these reactive strategies. Herein, we identify o-methoxyphenols as air-stable, commercially available derivatives that undergo efficient oxidative couplings with anilines in the presence of periodate as oxidant. Mechanistic considerations informed the development of a preoxidation protocol that can greatly reduce the amount of periodate necessary for effective coupling. The stability and versatility of these reagents was demonstrated through the synthesis of complex protein-protein bioconjugates using a site-selective heterobifunctional cross-linker comprising both o-methoxyphenol and 2-pyridinecarboxaldehyde moieties. This compound was used to link epidermal growth factor to genome-free MS2 viral capsids, affording nanoscale delivery vectors that can target a variety of cancer cell types.
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720-1460, United States.
authors.forename: Adel M
authors.initials: AM
authors.lastname: ElSohly
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720-1460, United States.
authors.forename: James I
authors.initials: JI
authors.lastname: MacDonald
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720-1460, United States.|Laboratory of Organic Chemistry, D-CHAB, ETH Zurich , Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Nina B
authors.initials: NB
authors.lastname: Hentzen
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720-1460, United States.|Materials Sciences Division, Lawrence Berkeley National Laboratories , Berkeley, California 94720-1460, United States.
authors.forename: Ioana L
authors.initials: IL
authors.lastname: Aanei
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720-1460, United States.
authors.forename: Kareem M
authors.initials: KM
authors.lastname: El Muslemany
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720-1460, United States.|Materials Sciences Division, Lawrence Berkeley National Laboratories , Berkeley, California 94720-1460, United States.
authors.forename: Matthew B
authors.identifier: 0000-0003-2837-2538
authors.initials: MB
authors.lastname: Francis
mesh_terms: D000627:Aminophenols / Q000737:chemistry*; D000814:Aniline Compounds / Q000737:chemistry; D040761:Biomimetic Materials / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D010084:Oxidation-Reduction
chemical_list: D000627:Aminophenols; D000814:Aniline Compounds; D003432:Cross-Linking Reagents; C027667:2-aminophenol