Enzyme mimics for activated ester or phosphate hydrolysis remain at the center of interest. Janda and his group synthesized and screened novel transition metal complexes as enzyme mimics that catalyze the hydrolysis of carboxylic esters . A hydroxy-substituted azacrown ether was modified in a conventional solution-phase three-step sequence to give three additional macrocylic ligands (Scheme 32.5). The ligands were then complexed with ten transition metal ion sources. The 40-member transition metal complex library was screened in parallel, without prior purification or isolation of the intermediates, for hydrolytic activity towards p-nitrophenyl acetate and N-methoxycarbonyl-L-phenylalanine-p-nitrophenyl ester as model substrates. Initial reaction rates were determined by repetitive photometric scanning of the absorption of the released p-nitrophenolate. Zinc and cobalt complexes gave only moderate rate enhancements (kcat/feuncat = @3). The kinetic data implied that the systems do not behave like hydrolytic enzymes because of their linear dependence on both substrate and metal complex concentration.
Scheme 32.5. General structure of transition metal complexes of hydroxy or alkoxy azacrown ethers efficient for hydrolysis of activated carboxylic acid esters.
The researchers extended their methodology towards the synthesis of the corresponding azacrown ether-lanthanide complexes that were capable of hydrolyzing phosphate esters, a crucial chemical transformation in areas such as nucleic acid chemistry . The lanthanide complexes synthesized catalyzed the cleavage of phospho di- and triesters and double-stranded DNA as well, which opens up the possibility of using this class of chemicals as therapeutics. Another important potential application is the hydrolytic decontamination of toxic organophosphates, phosphonates, and fluorophosphates which are widely used as insecticides and are stockpiled as chemical warfare agents.
A 625-member library of undecapeptides has recently been assayed for catalytic activity in phosphate hydrolysis, using test substances that in the presence of oxygen form insoluble indigo dyes. Using a split-and-mix approach, Berkessel and Herault synthesized on solid support sequences Phe-X-GlyGly-X-GlyGly-X-GlyGly-X, where X is one of Arg, His, Tyr, Trp, or Ser . About 2500 beads were incubated with Cu(II), Zn(II), Fe(III), Co(III), Eu(III), Ce(IV), and Zr(IV) solutions; only in the presence of Zr(IV) did the observation of the blue indigo color indicate catalytic hydrolysis activity. The most promising candidates were isolated, identified, and synthesized on solid support and in solution to confirm the library screening results.
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