Synthesis and evaluation of modified oximidine analogues as anticancer agents and of terephthalaldehyde-bis-guanylhydrazones as endotoxin sequestering agents

Abstract

Part I. The natural products oximidine I and II are potent and selective anticancer agents at nanomolar concentrations. Their structures and potent cytotoxicity are similar to the recently discovered natural products salicylihalamides, apicularens, and lobatamides, which are members of the benzolactone enamide family. However, it is believed that the enamide, a crucial moiety for anticancer activity, will be labile under physiological conditions. This has led to our hypothesis that the replacement of the enamide moiety with a stable warhead will allow the discovery of novel anticancer agents with improved pharmacokinetics. We selected three different warheads that are likely to be stable under physiological conditions and that could undergo nucleophilic addition like the enamide. We prepared by total synthesis oximidine analogues that carry a vinyl sulfone, a boronic acid and an α -keto oxadiazole instead of the enamide side chain. Based on CoMSIA/QSAR analysis, we have designed, prepared and evaluated new analogs of oximidine II. Part II. Lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities. These first-generation compounds bind and neutralize lipopolysaccharide with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS.