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

Title data

Köhler, Leonhard ; Reich, Sebastian ; Yusenko, Maria ; Klempnauer, Karl-Heinz ; Begemann, Gerrit ; Schobert, Rainer ; Biersack, Bernhard:
Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities.
In: Cancer Drug Resistance. Vol. 6 (2023) . - pp. 59-77.
ISSN 2578-532X
DOI: https://doi.org/10.20517/cdr.2022.90

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: Chromene; pyran; anticancer drugs; microtubule; angiogenesis; MYB inhibition
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology > Professor Developmental Biology > Professor Developmental Biology - Univ.-Prof. Dr. Gerrit Begemann
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors > Chair Organic Chemistry I - Univ.-Prof. Dr. Rainer Schobert
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 28 Nov 2023 12:00
Last Modified: 28 Nov 2023 12:00
URI: https://eref.uni-bayreuth.de/id/eprint/87893