PUBLICATION
Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities
- Authors
- Köhler, L.H.F., Reich, S., Yusenko, M., Klempnauer, K.H., Begemann, G., Schobert, R., Biersack, B.
- ID
- ZDB-PUB-230418-52
- Date
- 2023
- Source
- Cancer drug resistance (Alhambra, Calif.) 6: 597759-77 (Journal)
- Registered Authors
- Begemann, Gerrit
- Keywords
- Chromene, MYB inhibition, angiogenesis, anticancer drugs, microtubule, pyran
- MeSH Terms
- none
- PubMed
- 37065868 Full text @ Cancer Drug Resist
Citation
Köhler, L.H.F., Reich, S., Yusenko, M., Klempnauer, K.H., Begemann, G., Schobert, R., Biersack, B. (2023) Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities. Cancer drug resistance (Alhambra, Calif.). 6:597759-77.
Abstract
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.
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