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Diversity-oriented generation and biological evaluation of new chemical scaffolds bearing a 2,2-dimethyl-2H-chromene unit: Discovery of novel potent ANO1 inhibitors

[Display omitted] •New chemical space bearing a 2,2-dimethyl-2H-chromene unit was synthesized.•3n is a novel potent ANO1 inhibitor with an IC50 value of 1.23 μM.•3n exhibits good selectivity to ANO1 over ANO2 (>144).•3n reduced both cancer cell viability and protein expression levels of ANO1.•3n...

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Published in:Bioorganic chemistry 2020-08, Vol.101, p.104000, Article 104000
Main Authors: Seo, Yohan, Choi, Jiwon, Lee, Jeong Hwa, Kim, Tae Gun, Park, So-hyeon, Han, Gyoonhee, Namkung, Wan, Kim, Ikyon
Format: Article
Language:English
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Summary:[Display omitted] •New chemical space bearing a 2,2-dimethyl-2H-chromene unit was synthesized.•3n is a novel potent ANO1 inhibitor with an IC50 value of 1.23 μM.•3n exhibits good selectivity to ANO1 over ANO2 (>144).•3n reduced both cancer cell viability and protein expression levels of ANO1.•3n induced apoptosis via activation of caspase 3 and cleavage of PARP. Chemical territory bearing a 2,2-dimethyl-2H-chromene motif was expanded by utilizing an o-hydroxy aldehyde group of 5-hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde as a synthetic handle to install distinctive morphology and functionality of each scaffold. Cell based assays and in silico docking analysis led us to discover that these new compounds exhibit inhibitory effect on anoctamin1 (ANO1). ANO1 is amplified and highly expressed in various carcinomas including prostate cancer, esophageal cancer, breast cancer, and pancreatic cancer. Biological assays revealed that (E)-1-(7,7-dimethyl-7H-furo[2,3-f]chromen-2-yl)-3-(1H-pyrrol-2-yl)prop-2-en-1-one (3n, Ani-FCC) is a novel, potent and selective ANO1 inhibitor with an IC50 value of 1.23 μM. 3n showed 144 times stronger activity on ANO1 inhibition than ANO2 inhibition and did not alter the chloride channel activity of CFTR and the intracellular calcium signaling. Notably, 3n strongly decreased cell viability of PC-3 and FaDu cells expressing high levels of ANO1 with a decrease in ANO1 protein levels. In addition, 3n significantly enhanced apoptosis via activation of caspase 3 and cleavage of PARP in PC-3 and FaDu cells. This study shows that a novel ANO1 inhibitor, 3n, can be a potential candidate for the treatment of cancers overexpressing ANO1, such as prostate cancer and esophageal cancer.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2020.104000