Three metalloenzyme mimics will be examined for their potential to catalyze selective oxidation and hydrolysis of specifically coordinated substrates. These synthetic molecules may extend the realm of antibiotics, enzymes and inhibitors by combining new host molecules with novel catalysts. Applications of these compounds include the oxidative cleavage peptidoglycans, the selective hydrolysis of peptides and new pathways for the synthesis or regulation of neurotransmitters. The compounds incorporate discrete binding sites for both transition metal ions [Fe(II) or Zn(II)] and organic substrates (amines or carboxylates) and are designed to deliver a reactive metal catalyst to a particular site of the bound substrate. Two of these compounds contain chiral 18-crown-6 polyethers as substrate receptor sites for the coordination of organic cations; the third is based on a macrocyclic polyamine structure. As such, these functionalized macrocycles will be the first of their type to act as true catalysts since the substrate will be bound reversibly and the metal ion can function catalytically. The fundamental goal of this work is the investigation of weak inter- and intramolecular forces which determine the conformation of an activated complex and hence the specificity of a reaction. These studies will not only provide important mechanistic information about enzymatic processes but will also facilitate biomimetic synthesis of physiologically active substances. For example, regioselective oxidations of arachidonic acid lead to the various families of prostaglandins, thromboxanes and leukotrienes. In the long term, the design of modern pharmaceutical agents based on our knowledge of the reactivity and specificity of intermolecular interactions will be possible. Analogs of antibiotics such as bleomycin and other drugs effecting for substrate lysis can be envisioned.
