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

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 (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.

New 4,5-Diarylimidazol-2-ylidene–iodidogold(I) Complexes with High Activity against Esophageal Adenocarcinoma Cells

“…c -Myc inhibitors might also be suitable combination partners [ 40 ]. Moreover, our groups have recently identified highly active c -Myb inhibitors [ 49 , 50 , 51 ]. This transcription factor was found to be upregulated in EAC and crucial for the immune escape of EAC cells via the miR-145-5p/SPOP/PD-L1 axis [ 52 , 53 , 54 ].…”

Emerging role of MYB transcription factors in cancer drug resistance

“…BCR-TMP inhibited MYB transactivation by interference with p300 interaction, albeit probably not by targeting the KIX domain, and promoted MYB degradation [ 237 ] . Chemical fine-tuning of the BCR-TMP structure led to further halogen-substituted analogs with high antiproliferative and antiangiogenic activities against a panel of solid tumor cell lines (including multidrug-resistant cell lines) by combined MYB- and tubulin-targeting mechanisms [ 238 , 239 ] .…”

A Tandem Hydroformylation‐Organocatalyzed Friedel‐Crafts Reaction for the Synthesis of Diindolylmethanes

“…Nowadays, we know that the bioactive compound indole‐3‐carbinol (I3C) is formed by hydrolysis from its precursor. I3C is however unstable in aqueous and acidic conditions and converts in vivo to 3,3‘‐diindolylmethane (DIM), which is the major condensation product and the trigger for cancer cell death of various cancer types [5,6] . DIM and its derivatives are not only used as anti‐cancer treatment, but also as fungicides for phytopathogenic fungi, [7] anti‐bacterial compounds against phytopathogenic bacteria such as Streptococcus mutans in the oral biofilm, [8] as well as anti‐inflammatory as a part of the cannabinoid receptor subtype CB 2 , [9] among others.…”