Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells

作者: Lisa Yu , Andres Lopez , Abderrahmane Anaflous , Brahim El Bali , Abdellah Hamal

DOI: 10.1371/JOURNAL.PGEN.1000284

关键词:

摘要: Small molecules have been shown to be potent and selective probes understand cell physiology. Here, we show that imidazo[1,2-a]pyridines imidazo[1,2-a]pyrimidines compose a class of compounds target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, discovered two closely related compounds, an imidazo[1,2-a]pyridine -pyrimidine differ by single atom, distinctly different mechanisms action vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic yeast strains with defects electron transport mitochondrial functions caused fragmentation, suggesting compound 13 acts disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as DNA poison, causing damage the nuclear inducing mutagenesis. We compared 15 known chemotherapeutics found resistance required intact repair pathways. Thus, subtle changes structure imidazo-pyridines -pyrimidines dramatically alter both intracellular targeting these their effects Of particular interest, modes were evident experiments on human cells, chemical–genetic profiles obtained are recapitulated cultured indicating our observations can: (1) leveraged determine mechanism mammalian cells (2) suggest novel structure–activity relationships.

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