ABSTRACT
A structurally simplified macrolactone analogue of halichondrin B was identified that retains the potent cell growth inhibitory activity of the natural product in vitro.
Subject(s)
Ethers, Cyclic/chemistry , Ethers, Cyclic/pharmacology , Lactones/chemistry , Lactones/pharmacology , Animals , Cell Division/drug effects , Cell Line, Tumor , Ethers, Cyclic/chemical synthesis , Humans , Lactones/chemical synthesis , Macrolides , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.
Subject(s)
Ethers, Cyclic/chemistry , Ethers, Cyclic/pharmacology , Ketones/chemistry , Ketones/pharmacology , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Animals , Cell Division/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Ethers, Cyclic/chemical synthesis , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , Humans , Ketones/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrolides , Mice , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
Subject(s)
Bacterial Outer Membrane Proteins/antagonists & inhibitors , Drug Resistance, Bacterial/drug effects , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Pseudomonas aeruginosa/drug effects , Acrylates/pharmacology , Drug Stability , Isomerism , Microbial Sensitivity Tests , Photochemistry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
