Aim:Efficient and readily available anticancer drugs are sought as treatment options.For this reason,chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic pr...Aim:Efficient and readily available anticancer drugs are sought as treatment options.For this reason,chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties.Methods:2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds(2A-R)were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol,various aryl aldehydes,and malononitrile.We performed assays to study the inhibition of tumor cell growth[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromid(MTT)assay],effects on microtubules(immunofluorescence),cell cycle(flow-activated cell sorting analysis),angiogenesis(zebrafish model),and MYB activity(luciferase reporter assay).Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative.Results:Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines(50%inhibitory concentrations in the low nanomolar range)and showed potent MYB inhibition.The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation.Substantial microtubule disruption and G2/M cell-cycle arrest were observed,where compound 2F stood out as a promising microtubule-disrupting agent.The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo.Conclusion:The close interplay of various mechanisms,including cell-cycle arrest,MYB inhibition,and anti-angiogenic activity,led to identifying promising multimodal anticancer drug candidates.展开更多
基金supported by the Wilhelm-Sander-Stiftung(grant 2020.071.1).
文摘Aim:Efficient and readily available anticancer drugs are sought as treatment options.For this reason,chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties.Methods:2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds(2A-R)were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol,various aryl aldehydes,and malononitrile.We performed assays to study the inhibition of tumor cell growth[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromid(MTT)assay],effects on microtubules(immunofluorescence),cell cycle(flow-activated cell sorting analysis),angiogenesis(zebrafish model),and MYB activity(luciferase reporter assay).Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative.Results:Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines(50%inhibitory concentrations in the low nanomolar range)and showed potent MYB inhibition.The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation.Substantial microtubule disruption and G2/M cell-cycle arrest were observed,where compound 2F stood out as a promising microtubule-disrupting agent.The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo.Conclusion:The close interplay of various mechanisms,including cell-cycle arrest,MYB inhibition,and anti-angiogenic activity,led to identifying promising multimodal anticancer drug candidates.
