Tyrosine Bioconjugation through Aqueous Ene-Like Reactions

摘要

A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an Ene-like reaction is reported. This mild aqueous tyrosine ligation reaction works over a broad pH range and expands the repertoire of aqueous chemistries available for small molecule, peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in buffered aqueous solution. This reaction provides a novel synthetic approach to bispecific antibodies. This reaction will find broad utility in peptide and protein chemistry and in the chemistry of phenol-containing compounds.;

主权项

1. A compound having Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each H whenis a single bond, and R1 and R2 are each absent whenis a double bond;
W is independently a direct bond or is O; R3 is independently hydrogen, halogen, carboxyl, cyano, nitro, amino, substituted or unsubstituted alkyl, substituted or unsubstituted thioalkyl, perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy; substituted or unsubstituted alkylaryl, or substituted or unsubstituted alkylheteroaryl, or two R3's form a cyclic or heterocyclic ring, wherein each R3 is optionally independently substituted with 1 to 3 groups selected from halogen, carboxyl, cyano, nitro, amino, alkyl, alkenyl, alkynyl, perfluoroalkyl, thioalkyl, alkoxy, aryloxy, aryl, alkylaryl, heteroaryl, and alkylheteroaryl; L is independently H, N3, CH3, C═CH, C═CHN3, CH═CHN3, CH2CH2N3, O(CH2)N3, C6H5, COCH3, OCH2C≡CH, OCH2COCH3, OCOCF3, or X—[CH2CH2—Y]n—(CH2)q—N3; X and Y are each independently CH2, O, NH, S, NHCO or CONH; and n and q are each independently an integer from 0 to 12.