Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells.
Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharom...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-11-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2583946?pdf=render |
| _version_ | 1828238268864397312 |
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| author | Lisa Yu Andres Lopez Abderrahmane Anaflous Brahim El Bali Abdellah Hamal Elke Ericson Lawrence E Heisler Angus McQuibban Guri Giaever Corey Nislow Charles Boone Grant W Brown Mohammed Bellaoui |
| author_facet | Lisa Yu Andres Lopez Abderrahmane Anaflous Brahim El Bali Abdellah Hamal Elke Ericson Lawrence E Heisler Angus McQuibban Guri Giaever Corey Nislow Charles Boone Grant W Brown Mohammed Bellaoui |
| author_sort | Lisa Yu |
| collection | DOAJ |
| description | Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical-genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure-activity relationships. |
| first_indexed | 2024-04-12T21:00:57Z |
| format | Article |
| id | doaj.art-ffb2b8f362c147fca718d579f4668230 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T21:00:57Z |
| publishDate | 2008-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-ffb2b8f362c147fca718d579f46682302022-12-22T03:16:50ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042008-11-01411e100028410.1371/journal.pgen.1000284Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells.Lisa YuAndres LopezAbderrahmane AnaflousBrahim El BaliAbdellah HamalElke EricsonLawrence E HeislerAngus McQuibbanGuri GiaeverCorey NislowCharles BooneGrant W BrownMohammed BellaouiSmall molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical-genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure-activity relationships.http://europepmc.org/articles/PMC2583946?pdf=render |
| spellingShingle | Lisa Yu Andres Lopez Abderrahmane Anaflous Brahim El Bali Abdellah Hamal Elke Ericson Lawrence E Heisler Angus McQuibban Guri Giaever Corey Nislow Charles Boone Grant W Brown Mohammed Bellaoui Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells. PLoS Genetics |
| title | Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells. |
| title_full | Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells. |
| title_fullStr | Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells. |
| title_full_unstemmed | Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells. |
| title_short | Chemical-genetic profiling of imidazo[1,2-a]pyridines and -pyrimidines reveals target pathways conserved between yeast and human cells. |
| title_sort | chemical genetic profiling of imidazo 1 2 a pyridines and pyrimidines reveals target pathways conserved between yeast and human cells |
| url | http://europepmc.org/articles/PMC2583946?pdf=render |
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