Chemical synthesis of the organoarsenical antibiotic arsinothricin
The subject invention provides methods for the chemical synthesis of racemic arsinothricin (D,L-AST), the novel organoarsenical antibiotic. One is by condensation of the 2-chloroethyl(methyl)arsinic acid with acetamidomalonate, and the second involves reduction of the N-acetyl-protected derivative of hydroxyarsinothricin (AST-OH) and subsequent methylation of the resulting sodium salt of trivalent arsenic intermediate with methyl iodide. The enzyme AST N-acetyltransferase (ArsNl) was utilized to purify L-AST from racemic AST. This expedient chemical synthesis of AST provides a source of this novel antibiotic for future drug development.
1. A method for chemically synthesizing racemic arsinothricin (D,L-AST) comprising mixing a pentavalent N-acetyl protected analogue of AST-OH with a reducing agent to reduce the pentavalent N-acetyl protected analogue of AST-OH to form a trivalent arsine compound; and
mixing the trivalent arsine compound with alkylation reagent.
2. The method of claim 1 , the method further comprising mixing the synthesized D,L-AST with an ArsNl and AcCoA to produce a mixture of D-AST and L-N-Ac-AST; separating D-AST and L-N-Ac-AST; deacetylating L-N-Ac-AST and purifying L-AST.
3. The method of claim 1 , the N-acetyl protected analogue of AST-OH being ethyl-2-acetamido-2-ethoxycarbonyl-4-(hydroxymethylarsinoyl)butanoate.
4. The method of claim 1 , the reducing agent being SO 2 .
5. The method of claim 1 , the alkylation reagent being methyl iodide.
6. The method of claim 1 , the reducing agent being combined with a catalytic agent and an acid.