Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish.
Yanqi XieLiliia M KrilTianxin YuWen ZhangMykhaylo S FrasinyukSvitlana P BondarenkoKostyantyn M KondratyukElizabeth HausmanZachary M MartinPrzemyslaw P WyrebekXifu LiuAgripina DeaciucLinda P DwoskinJing ChenHaining ZhuChang-Guo ZhanVitaliy M SviripaJessica BlackburnDavid S WattChunming LiuPublished in: Scientific reports (2019)
Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.
Keyphrases
- molecular docking
- cell proliferation
- prostate cancer
- tandem mass spectrometry
- liquid chromatography
- papillary thyroid
- acute lymphoblastic leukemia
- endothelial cells
- cell cycle arrest
- squamous cell
- pi k akt
- high glucose
- mass spectrometry
- high fat diet induced
- ultra high performance liquid chromatography
- cell death
- radical prostatectomy
- cell cycle
- simultaneous determination
- body mass index
- diabetic rats
- bone marrow
- transcription factor
- allogeneic hematopoietic stem cell transplantation
- acute myeloid leukemia
- gas chromatography
- type diabetes
- lymph node metastasis
- childhood cancer
- weight loss
- signaling pathway
- insulin resistance
- resting state
- high resolution
- deep learning
- body weight
- pluripotent stem cells
- case control