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

Eur J Med Chem. 2019 Nov 15:182:111609. doi: 10.1016/j.ejmech.2019.111609.

Velma Ganga Reddy ¹, T Srinivasa Reddy ², Chetna Jadala ³, M Soumya Reddy ⁴, Faria Sultana ⁵, Ravikumar Akunuri ³, Suresh K Bhargava ⁶, Donald Wlodkowic ⁷, P Srihari ⁸, Ahmed Kamal ⁹

Affiliations

1 Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Ghaziabad, 201 002, Uttar Pradesh, India; Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India; Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne, 3001, Australia.
2 Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne, 3001, Australia. Electronic address: srinivasareddy.telukutla@rmit.edu.au.
3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.
4 Department of Chemistry, Keshav Memorial Institute of Commerce and Sciences, Narayanguda, Hyderabad, 500 029, India.
5 Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India.
6 Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne, 3001, Australia.
7 Phenomics Laboratory, School of Science, RMIT University, Plenty Road, PO Box 71, Bundoora, Victoria, 3083, Australia.
8 Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Ghaziabad, 201 002, Uttar Pradesh, India; Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India. Electronic address: srihari@iict.res.in.
9 Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Ghaziabad, 201 002, Uttar Pradesh, India; Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India; School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, 110 062, India. Electronic address: ahmedkamal@iict.res.in.

PMID: 31445229 DOI: 10.1016/j.ejmech.2019.111609

Abstract

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.

Keywords

Angiogenesis; Anticancer; Apoptosis; Benzothiazole; Pyrazole; VEGFR-2; Zebrafish.

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