scholarly journals Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

2019 ◽  
Vol 20 (10) ◽  
pp. 2489 ◽  
Author(s):  
Siqi Zhang ◽  
Qiaoling Song ◽  
Xueting Wang ◽  
Zhiqiang Wei ◽  
Rilei Yu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cancer Cell ◽  
Kinase Inhibitors ◽  
Antitumour Activity ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Signalling Pathways ◽  
Design Synthesis ◽  
Ic50 Values

c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.

Molecular Docking and In Vitro Anticancer Screening of Synthesized Arylthiazole linked 2H-indol-2-one Derivatives as VEGFR-2 Kinase Inhibitors

2021 ◽  
Vol 21 ◽  
Author(s):  
Nishtha Shalmali ◽  
Sandhya Bawa ◽  
Md Rahmat Ali ◽  
Sourav Kalra ◽  
Raj Kumar ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Active Sites ◽  
Colorectal Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Adenocarcinoma Cells ◽  
Ic50 Values

Background: Indoline-2,3-dione comprises a leading course group of heterocycles endowed with appealing biological actions, including anticancer activity. There are significant justifications for exploring the anticancer activity of Schiff base derivatives of isatin as a vast number of reports have documented remarkable antiproliferative action of isatin nucleus against various cancer cell lines. Aims and Objectives: A series of arylthiazole linked 2H-indol-2-one derivatives (5a-t) was designed and synthesized as potential VEGFR-2 kinase inhibitors keeping the essential pharmacophoric features of standard drugs, like sunitinib, sorafenib, nintedanib, etc. They were evaluated for their in vitro anticancer activity. The aim of this study was to investigate and assess the anticancer potential of isatin-containing compounds along with their kinase inhibition activity. Methods: The title compounds were synthesized by reacting substituted isatins with para-substituted arylthiazoles using appropriate reaction conditions. Selected synthesized derivatives went under preliminary screening against a panel of 60 cancer cell lines at NCI, the USA, for single-dose and five dose assays. Molecular docking was performed to explore the binding and interactions with the active sites of the VEGFR-2 receptor (PDB Id: 3VHE). Derivatives 5a, 5b, 5c, 5d, 5g, 5h, and 5m were assessed for in vitro inhibition potency against Human VEGFR-2 using ELISA (Enzyme-Linked Immunosorbent Assay) kit. All the target compounds were determined against human colon cancer cell line SW480 (colorectal adenocarcinoma cells). Cellular apoptosis/necrosis was determined by flow cytometry using annexin V-FITC. DNA content of the cells was analyzed by flow cytometry and the cycle distribution was quantified. Results: Compounds 5a and 5g exhibited noteworthy inhibition during a five-dose assay against a panel of 60 cell lines with MID GI50 values of 1.69 and 1.54 µM, respectively. Also, both the lead compounds 5a and 5g demonstrated promising VEGFR-2 inhibitory activity with IC50 values of 5.43±0.95 and 9.63±1.32 µM, respectively. The aforesaid potent compounds were found effective against SW480 (colorectal adenocarcinoma cells) with IC50 values of 31.44 µM and 106.91 µM, respectively. Compound 5a was found to arrest the cell cycle at the G2/M phase, increasing apoptotic cell death. The docking study also supported VEGFR-2 inhibitory activity as both compounds 5a and 5g displayed promising binding and interactions with the active sites of VEGFR-2 receptor (PDB: 3VHE) with docking scores -9.355 and -7.758, respectively. All the compounds obeyed Lipinski’s rule of five. Conclusion: Indoline-2,3-dione and thiazole have huge potential to be considered a steer combination approach for developing promising kinase inhibitors as cancer therapeutics.

IN-SILICO AND IN VITRO ASSESSMENT OF SYNTHESIZED DIAZENYLSULFONAMIDES AS APOPTOSIS INDUCERS AND RADICAL SCAVENGERS

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (06) ◽  
pp. 49-59
Author(s):  
Priyambada Kshiroda Nandini Sarangi ◽  
Jyotirmaya Sahoo ◽  
Chita Ranjan Sahoo ◽  
Sudhir Kumar Paidesetty ◽  
Guru Prasad Mohanta
Keyword(s):  
Cell Line ◽  
Cancer Cell ◽  
Radical Scavenging ◽  
Cancer Cell Line ◽  
Scavenging Effect ◽  
Ic50 Values ◽  
Radical Scavenging Effect ◽  
The Individual ◽  
Mcf 7

A series of eight quinoline-thiazole hybrid-bearing diazenylsulfonamides, 4a-4h, were synthesized and characterized by UV-Vis, FT/IR, 1H NMR and lC-MS. These compounds were formed when two prepared intermediate precursors of Schiff-base compounds, (E)-N-((2-chloroquinolin-3-yl)methylene)-4phenylthiazol-2-amine (3a) and (E)-N-((2-chloroquinolin-3-yl)methylene)-4-chlorophenylthiazol-2-amine (3b) were converted to the corresponding diazenyl compounds 4a-4h by treating and coupling with the individual diazonium salts of sulfa-drugs. The results of in vitro cytotoxic activity of the synthesized compounds in two cancer cell lines MCF 7 (human breast cancer cell line) and K562 (myelogenousleukemia cell line) have shown the IC50 values as given: 4b against MCF 7 19.52 and against K562 20.55µM; 4d against MCF 7 15.96 and against K562 13.05µM. Moreover, the compound 4-(((Z)-(2-chloroquinolin-3yl)(4-phenylthiazol-2-ylimino)methyl)diazenyl)benzenesulfonic acid (4d) induced maximum percentage of apoptosis. Furthermore, the in vitro antioxidant activity study revealed that among all the synthesized compounds, compound 4d has an excellent radical scavenging effect. Molecular docking was additionally performed to investigate the binding affinity of H-bonding interaction of synthesized compounds with a targeted enzyme and to compare it with the anticancer drugs, dasatinib, bosutinib and dacarbazine.

In vitro antitumour activity of two ferrocenyl metallodendrimers in a colon cancer cell line

2018 ◽  
Vol 98 ◽  
pp. 75-79 ◽  
Author(s):  
Nadia Baartzes ◽  
Cristina Szabo ◽  
Mihai Cenariu ◽  
Florica Imre-Lucaci ◽  
Sorin Aurel Dorneanu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Antitumour Activity ◽  
Cancer Cell Line ◽  
Colon Cancer Cell Line ◽  
Colon Cancer Cell

scholarly journals A New Potent Anti-cancer Corosolic Ester Identified from the Super Miracle Plant Hippophae rhamnoides (Sea buckthorn)

2019 ◽  
pp. 24-29
Author(s):  
Irfan Ali ◽  
Noor-ul-Ain Zahra ◽  
Reazuddin R ◽  
Huma Sharif ◽  
Mudassar M ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cell ◽  
Weak Interactions ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Sea Buckthorn ◽  
Hippophae Rhamnoides ◽  
Hippophaë Rhamnoides ◽  
Anti Cancer ◽  
Ic50 Values

Hippophae rhamnoides L, commonly called Sea buckthorn, is native to Asia and Europe and and known for its nutritional and medicinal values. The aim of the present study was to investigate the anti-cancer constituents of H. rhamnoides. Among the three isolated compounds namely: 1-(2-hydroxynaphthalen-1-yl) ethan-1-one (1), Oleanolic acid (2), and Hippocorosolate (3), compound 3 was a new corosolic ester derivative. The isolated compounds (2 and 3) displayed anticancer activity against lung (NCI-H460) and breast (MCF-7) cancer cell lines with IC50 values of ~3 µM and ~6 µM, respectively. However, compound 1 was active only against breast cancer cells with IC50 value of ~43 µM. These compounds displayed only weak interactions with minor groove of DNA in DNA-ligand conformational studies and therefore, structural DNA damage was not noted in electrophoretic mobility experiments. It was concluded that new compound 2 possessed more potent anticancer activity than that of known compound 3 against lung cancer cell line.

IN VIVO AND IN VITRO ANTITUMOR EFFECT OF A UNIQUE NUTRIENT MIXTURE ON LUNG CANCER CELL LINE A-549

2006 ◽  
Vol 32 (9) ◽  
pp. 441-453 ◽  
Author(s):  
M. Waheed Roomi ◽  
Vadim Ivanov ◽  
Tatiana Kalinovsky ◽  
Aleksandra Niedzwiecki ◽  
Matthias Rath
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Antitumor Effect ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Lung Cancer Cell
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