Otto F. Schall

Structure–Activity Studies and the Design of Synthetic Superoxide Dismutase (SOD) Mimetics as Therapeutics

Publisher Summary This chapter describes highly stable Mn(II) complexes that possess high superoxide dismutase (SOD) activity—the two key attributes for an efficient SOD mimetic-based drug. Key to success in designing and synthesizing highly stable and highly active SOD mimetics is the development of a detailed understanding of the mechanism of action of this class of SOD mimetics, and the subsequent development of a computer-aided design (CAD) paradigm based on molecular mechanics (MM) that makes it possible to study and screen a large number of possible structures prior to embarking on complicated syntheses of highly substituted and constrained ligands. An understanding of the details of the mechanism of action of synthetic superoxide dismutase catalysts has made it possible to devise a computer modeling paradigm that allows one to design highly substituted (and hence highly stable) complexes that possess high catalytic activity. Molecular mechanics calculations have made it possible to correctly predict how substituents and their stereochemistry affect the energetics of ligand folding and thus catalytic activity. The chemistry presented for designing and synthesizing core catalyst structures optimized for stability and catalytic activity, are amenable to the construction of complexes that have pendant functionality; for example, alcohols, amines, amides, esters, acids, etc.

Solid-phase synthesis of methyl carboxymycobactin T 7 and analogues as potential antimycobacterial agents

A solid-phase approach for the total synthesis of methyl carboxymycobactins 1a-d, with an on-resin cyclization leading to azopine 5 as the key step, was developed. The iron-affinity of these compounds was assessed by a competitive sulfoxine-binding assay, and antimycobacterial activity was tested against the growth of Mycobacterium avium.

Combinatorial Syntheses of Polyhydroxamate Siderophores: Desferrioxamine, Exochelin, Mycobactin, and Aerobactin Libraries

Siderophores are natural products, often containing amino acid derivatives, that are produced by microorganisms to chelate ferric ion as part of an iron-uptake system essential for survival. In order to explore several therapeutic opportunities, we have developed a combinatorial synthetic strategy to prepare libraries of analogs of a number of different siderophores, including desferrioxamine (DFO), for potential treatment of iron overload [1]; and exochelin, mycobactin and aerobactin for potential antibiotic applications. These siderophores all contain hydroxamate groups as primary coordination sites for the ferric ion (Figure 1). Their typical stability constants (Ks) for ferric ion are from 1023 to 1032.