Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma.
Antineoplastic Agents
/ chemical synthesis
Benzimidazoles
/ chemistry
Benzoxazoles
/ chemistry
Carcinoma, Hepatocellular
/ drug therapy
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Liver Neoplasms
/ drug therapy
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Triazines
/ chemical synthesis
Triazolotriazine
VEGFR-2
anticancer
benzimidazole
benzoxazole
c-Met.
Journal
Anti-cancer agents in medicinal chemistry
ISSN: 1875-5992
Titre abrégé: Anticancer Agents Med Chem
Pays: Netherlands
ID NLM: 101265649
Informations de publication
Date de publication:
2019
2019
Historique:
received:
09
04
2019
revised:
31
05
2019
accepted:
13
07
2019
pubmed:
9
8
2019
medline:
7
8
2020
entrez:
9
8
2019
Statut:
ppublish
Résumé
Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer. The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents. A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells. Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition. Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.
Sections du résumé
BACKGROUND
Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer.
OBJECTIVE
The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents.
METHODS
A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells.
RESULTS
Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition.
CONCLUSION
Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.
Identifiants
pubmed: 31393257
pii: ACAMC-EPUB-100226
doi: 10.2174/1871520619666190808152051
doi:
Substances chimiques
Antineoplastic Agents
0
Benzimidazoles
0
Benzoxazoles
0
Triazines
0
benzimidazole
E24GX49LD8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2120-2129Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.