REVERSAL OF DOXORUBICIN RESISTANCE AND CATALYTIC NEUTRALIZATION OF LYSOSOMES BY A LIPOPHILIC IMIDAZOLE

A number of lipophilic nitrogenous bases, designed to act as membrane-active, catalytic proton transfer agents, were tested for their ability to neutralize the acidity of lysosomes, a model for other acidic intracellular vesicles involved in drug sorting. The most successful of these, an imidazole 1, caused a 1.7 unit rise in lysosomal pH of RAW cells at 100 mu M, compared to a 0.2 and 1.4 unit rise for ammonium chloride at 100 mu M and 10 mM, respectively. Compound 1 also exhibited potent reversal of doxorubicin (DOX) resistance in the HCT116-VM46 cell line by a factor of 14 over the sensitive strain, and superior to that of widely used verapamil (VRP) by a factor of 1.75 at 20 CLM. It also has antiviral properties, and potential applications in other lysosome-related areas such as immunotoxin potentiation and the control of bacterial toxins, immune response, prion replication, malaria and intralysosomal microorganisms.