Multimodal 4-arylchromene derivatives with microtubule-destabilizing,anti-angiogenic,and MYB-inhibitory activities  

作　　者：Leonhard H.F.Kohler Sebastian Reich Maria Yusenko Karl-Heinz Klempnauer Gerrit Begemann Rainer Schobert Bernhard Biersack 

机构地区：[1]Organic Chemistry Laboratory,University of Bayreuth,Bayreuth 95440,Germany [2]Institute for Biochemistry,Westfalische-Wilhelms-Universitat,Munster 48149,Germany [3]Developmental Biology,University of Bayreuth,Bayreuth 95440,Germany

出　　处：《Cancer Drug Resistance》2023年第1期59-77,共19页癌症耐药（英文）

基　　金：supported by the Wilhelm-Sander-Stiftung(grant 2020.071.1).

摘　　要：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.

关 键 词：CHROMENE PYRAN anticancer drugs MICROTUBULE angiogenesis MYB inhibition 

分 类 号：O62[理学—有机化学]