Water-soluble phosphinothiol reagents
AssigneeWisconsin Alumni Research Foundation
InventorsRonald T. Raines, Annie Tam, Matthew B. Soellner
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Abstract
Water soluble reagents and methods for the formation of an amide bond between a phosphinothioester and an azide in an aqueous medium. The phosphinothioester is generated using a water-soluble phosphinothiol reagent. This reaction allows formation of an amide bond between a wide variety of chemical species including amino acids, peptides or protein fragments in an aqueous solution. Of particular interest, this reaction allows for the formation of an amide bond in a physiological setting. In a specific embodiment, this invention provides reagents and methods for peptide ligation in an aqueous medium. The reaction eliminates the need for a cysteine residue and is traceless leaving no residual atoms in the ligated peptide product.
Claims21
A method for forming an amide bond in an aqueous solution which comprises forming a phosphinothioester from a corresponding water soluble phosphinothiol, and thereafter reacting the phosphinothioester with an azide in an aqueous solution to form the amide bond,
- wherein the water soluble phosphinothiol has formula:
- or protonated ions, quaternary ammonium ions or salts thereof wherein:
- n and m are 0, 1, or 2 and n+m is 1 or more;
- R1 and R2 are linkers that are organic biradicals which are selected from optionally substituted arylenes, optionally substituted heteroarylenes, optionally substituted alkylenes, or optionally substituted cycloalkylenes or combinations thereof;
- n and m are 0, 1, or 2 and n+m is 1 or more;
- and
- each R3-R6, independently, is selected from guanidine, alkyl, alkenyl, alkynyl, aryl, or heteroaryl all of which are optionally substituted and wherein R3 and R4 or R5 and R6 or both combinations of groups are optionally linked to form a 5-8 member ring which contains N and optionally contains one or more additional heteroatoms;
- wherein substitution, when present, is substitution with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycyl, —OH, —OR, —COH, —COR, —COOH, —COOR, or —N(R)2, where each R is independently selected from optionally substituted alkyl, alkenyl, alkynyl, heterocyclic, aryl or heteroaryl groups.
A water soluble phosphinothiol having formula:
- or protonated ions, quaternary ammonium ions or salts thereof wherein:
- n and m are 0, 1, or 2 and n+m is 1 or more;
- R1 and R2 are linkers that are organic biradicals which are selected from optionally substituted arylenes, optionally substituted heteroarylenes, optionally substituted alkylenes, or optionally substituted cycloalkylenes or combinations thereof;
- n and m are 0, 1, or 2 and n+m is 1 or more;
- and
- each R3-R6, independently, is selected from guanidine, alkyl, alkenyl, alkynyl, aryl, or heteroaryl all of which are optionally substituted and wherein R3 and R4 or R5 and R6 or both combinations of groups are optionally linked to form a 5-8 member ring which contains N and optionally contains one or more additional heteroatoms;
- wherein substitution, when present, is substitution with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycyl, —OH, —OR, —COH, —COR, —COON, —COOR, or —N(R)2, where each R is independently selected from optionally substituted alkyl, alkenyl, alkynyl, heterocyclic, aryl or heteroaryl groups.
Dependencies are inferred from the claim text.