PUBLICATION
Pyrazolo-benzothiazole hybrids: Synthesis, anticancer properties and evaluation of antiangiogenic activity using in vitro VEGFR-2 kinase and in vivo transgenic zebrafish model
- Authors
- Reddy, V.G., Reddy, T.S., Jadala, C., Reddy, M.S., Sultana, F., Akunuri, R., Bhargava, S.K., Wlodkowic, D., Srihari, P., Kamal, A.
- ID
- ZDB-PUB-190826-20
- Date
- 2019
- Source
- European Journal of Medicinal Chemistry 182: 111609 (Journal)
- Registered Authors
- Keywords
- Angiogenesis, Anticancer, Apoptosis, Benzothiazole, Pyrazole, VEGFR-2, Zebrafish
- MeSH Terms
-
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects
- Benzothiazoles/chemistry
- Benzothiazoles/pharmacology*
- Cell Cycle/drug effects
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- DNA Damage
- Disease Models, Animal*
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- HEK293 Cells
- Humans
- Membrane Potential, Mitochondrial/drug effects
- Molecular Structure
- Neovascularization, Pathologic/drug therapy*
- Neovascularization, Pathologic/metabolism
- Pyrazoles/chemistry
- Pyrazoles/pharmacology*
- Structure-Activity Relationship
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Wound Healing/drug effects
- Zebrafish
- PubMed
- 31445229 Full text @ Eur. J. Med. Chem.
Citation
Reddy, V.G., Reddy, T.S., Jadala, C., Reddy, M.S., Sultana, F., Akunuri, R., Bhargava, S.K., Wlodkowic, D., Srihari, P., Kamal, A. (2019) Pyrazolo-benzothiazole hybrids: Synthesis, anticancer properties and evaluation of antiangiogenic activity using in vitro VEGFR-2 kinase and in vivo transgenic zebrafish model. European Journal of Medicinal Chemistry. 182:111609.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping