Pyrazolo-benzothiazole hybrids: Synthesis, anticancer properties and evaluation of antiangiogenic activity using in vitro VEGFR-2 kinase and in vivo transgenic zebrafish model

A series of new pyrazolo-benzothiazole hybrids (7–26) were synthesised and screened for their cytotoxic activity towards several cancer cell lines [colon (HT-29), prostate (PC-3), lung (A549), glioblastoma (U87MG)] and normal human embryonic kidney cell line (Hek-293T). Compounds 8, 9, 13, 14, 18, 1...

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Published in:European journal of medicinal chemistry 2019-11, Vol.182, p.111609-111609, Article 111609
Main Authors: Reddy, Velma Ganga, Reddy, T. Srinivasa, Jadala, Chetna, Reddy, M. Soumya, Sultana, Faria, Akunuri, Ravikumar, Bhargava, Suresh K., Wlodkowic, Donald, Srihari, P., Kamal, Ahmed
Format: Article
Language:English
Subjects:
Angiogenesis
Anticancer
Apoptosis
Benzothiazole
Pyrazole
VEGFR-2
Zebrafish
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Summary:A series of new pyrazolo-benzothiazole hybrids (7–26) were synthesised and screened for their cytotoxic activity towards several cancer cell lines [colon (HT-29), prostate (PC-3), lung (A549), glioblastoma (U87MG)] and normal human embryonic kidney cell line (Hek-293T). Compounds 8, 9, 13, 14, 18, 19, 23, and 24 displayed significant activity, with compound 14 being particularly potent towards all the tested cancer cell lines with IC50 values in the range 3.17–6.77 μM, even better than reference drug axitinib (4.88–21.7 μM). Compound 14 also showed the strongest growth inhibition in 3D multicellular spheroids of PC-3 and U87MG cells. The mechanism of cellular toxicity in PC-3 cells was found to be cell cycle arrest and apoptosis induction through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage. Further, compound 14 displayed significant in vitro (VEGFR-2 inhibition) and in vivo [transgenic zebrafish Tg(flila:EGFP) model] antiangiogenic properties. Overall, these results provide strong evidence that compound 14 could be considered for a lead candidate in anticancer and antiangiogenic drug discovery. [Display omitted] •20 pyrazole-benzothiazoles hybrids (7–26) were designed and synthesized.•Compound 14 showed significant cytotoxicity with IC50 ranges from 3.17 to 6.77 μM against various cancer cells.•Compound 14 induces G0/G1 cell cycle arrest and apoptosis in PC-3 cells.•Compound 14 showed notable antiangiogenic properties in vitro (VEGFR-2 inhibition) and in vivo (transgenic zebrafish models).•The binding modes were studied by molecular docking.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2019.111609