Environment-selective synergism using self-assembling cytotoxic and antimicrobial agents.
Environment-selective synergistic toxicity using combinations of aldehydes and hydrazine derivatives was demonstrated in two different model systems in vitro. Combinations of 5-nitro-2-furaldehyde with semi-carbazide and of 2-hydrazinopyridine with pyridine-2-carboxaldehyde, which can react in situ to form antimicrobial hydrazones, demonstrated greater degrees of synergism against the intracellular pathogen, Salmonella typhimurium, at pH 5 relative to pH 7.4. Combinations are more selectively toxic at pH 5 (vs pH 7.4) than individual precursors and preformed hydrazone products because acid catalysis of hydrazone formation plays a role only for the combinations. A combination of decanal and N-amino, N'-octylguanidine (AOG) exhibited more pronounced synergistic cytolytic activity against erythrocytes in 0% serum than in 1% serum. Serum protein binding of decanal inhibited the formation of the more cytotoxic hydrazone, N-decylidenimino,N'-1-octylguanidine (DIOG), from the less cytotoxic AOG and decanal, and serum protein binding of DIOG prevented this cytotoxin from reaching the cell membrane. Because decanal binding cannot play a role in the cytotoxicity of preformed DIOG, it was less selective for cells in 0% serum than the combination of AOG and decanal. The pH 5 and 0% serum environments represent very simple models for macrophage phagolysosomal compartments and poorly vascularized solid tumor interiors respectively. If environment-selective synergism can be used as a basis for target-selective synergism in other in vitro model systems and in vivo, self-assembling combinations could provide a basis for rational introduction of target-selective synergism into chemotherapeutic drug design.
Rideout
D
D
Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, CA 92037.
Jaworski
J
J
Dagnino
R
R
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004357:Drug Synergism; D005662:Furaldehyde / Q000031:analogs & derivatives / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D012486:Salmonella typhimurium / Q000187:drug effects
D000447:Aldehydes; D000900:Anti-Bacterial Agents; D006146:Guanidines; D006834:Hydrazines; C049574:N-decylidenimino-N'-1-octylguanidine; C015403:octylguanidine; C021170:decanaldehyde; C049575:N-amino-N'-1-octylguanidine; D005662:Furaldehyde; C052590:5-nitro-2-furaldehyde