ABSTRACTHydroxychloroquine (HCQ) is a 4-aminoquinoline molecule used for the treatment of malaria, and more recently to treat rheumatoid arthritis, systemic lupus erythematosus, and cancer. In cancer, HCQ is being used in multiple cancer clinical trials as an inhibitor of autophagy, a cytosolic degradation process employing the lysosome. Importantly, more potent lysosomotropic agents are being developed as autophagy inhibitors. Additional studies revealed that acridine-based compounds such as quinacrine (QN) increased potency over the 4-aminoquinoline HCQ. In line with these initial discoveries, we performed chemical synthesis of acridine-based compounds and screened for potent autophagy inhibition. The novel compound VATG-027 increased potency and cytotoxicity over HCQ in osteosarcoma and melanoma cell lines, supporting further investigation in vivo. Here, we developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to investigate HCQ, QN, and VATG-027 compound concentrations across various tissue types in mice. This method detected compound concentrations in whole blood, lung, liver, kidney, and subcutaneous tumor tissues. Concentrations of HCQ, QN, and VATG-027 varied within and between tissue types, suggesting unique tissue distribution profiles for 4-aminoquinoline and acridine compounds.
CO oxidization catalyzed by B, N, and their co-doped fullerenes: a first-principles investigation