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

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.

HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

Epigenetic mechanisms play an important role in the development and persistence of cancer,and histone deacetylase(HDAC)inhibitors are promising anticancer drugs targeting epigenetic modes.Efficient anticancer drugs for the treatment of castration-resistant prostate cancer(CRPC)are sought,and approved HDAC inhibitors have shown promising results on the one hand and severe drawbacks on the other hand.Hence,ways to break the drug resistance mechanisms of existing HDAC inhibitors as well as the design of new promising HDAC inhibitors which can overcome the disadvantages of the classic HDAC inhibitors are of great importance.In this work,HDAC inhibitors with the potential to become a mainstay for the treatment of CRPC in the future as well as suitable combination treatments of HDAC inhibitors with other anticancer drugs leading to considerable synergistic effects in treated CRPCs are discussed.

Alkylating anticancer agents and their relations to microRNAs

Alkylating agents represent an important class of anticancer drugs.The occurrence and emergence of tumor resistance to the treatment with alkylating agents denotes a severe problem in the clinics.A detailed understanding of the mechanisms of activity of alkylating drugs is essential in order to overcome drug resistance.In particular,the role of non-coding microRNAs concerning alkylating drug activity and resistance in various cancers is highlighted in this review.Both synthetic and natural alkylating agents,which are approved for cancer therapy,are discussed concerning their interplay with microRNAs.

3,3’-Diindolylmethane and its derivatives: nature-inspired strategies tackling drug resistant tumors by regulation of signal transduction, transcription factors and microRNAs

Indoles of cruciferous vegetables are promising anti-tumor agents.Studies with indole-3-carbinol and its dimeric product,3,3’-diindolylmethane(DIM),suggest that these compounds have the ability to deregulate multiple cellular signaling pathways that are essential for tumor growth and spread.These natural compounds are also effective modulators of transcription factors and non-coding RNAs.These effects explain their ability to inhibit tumor spread and to overcome drug resistance.In this work,pertinent literature on the effects of DIM and its synthetic derivatives on resistant tumors and resistance mechanisms in tumors is highlighted.