Synthesis, Biological and Computational Evaluation of Novel 2,3-dihydro-2-aryl-4-(4- isobutylphenyl)-1,5-benzothiazepine Derivatives as Anticancer and Anti-EGFR Tyrosine Kinase Agents.
Antineoplastic Agents
/ chemical synthesis
Cell Line
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors
/ antagonists & inhibitors
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors
/ chemical synthesis
Structure-Activity Relationship
Thiazepines
/ chemical synthesis
1
5-benzothiazepine
AHHRR model
EGFR tyrosine kinase
MTT assay
PHASETM
anticancer activity
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:
2020
2020
Historique:
received:
18
04
2019
revised:
22
11
2019
accepted:
31
12
2019
pubmed:
1
2
2020
medline:
29
5
2021
entrez:
1
2
2020
Statut:
ppublish
Résumé
Despite the availability of a variety of chemotherapeutic agents, cancer is still one of the leading causes of death worldwide because of the problems with existing chemotherapeutic agents like objectionable side effects, lack of selectivity, and resistance. Hence, there is an urgent need for the development of novel anticancer agents with high usefulness, fewer side effects, devoid of resistance and superior selectivity. The objective of this study is to synthesize a series of novel 1,5-benzothiazepine derivatives and evaluate their anticancer activity employing biological and computational methods. Twenty new benzothiazepines (BT1-BT20) were prepared by condensing different 1-(4- isobutylphenyl)ethanone chalcones with 2-amiothiophenol and evaluated for their anticancer activity by MTT assay against three cell lines including HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer). These compounds were also tested for their inhibitory action against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase enzyme by taking into account of their excellent action against colon and breast cancer cell lines. Further, the structural features responsible for the activity were identified by Pharmacophorebased modelling using Schrodinger's PHASETM software. Among the 20 benzothiazepine derivatives, three compounds viz., BT18, BT19 and BT20 exhibited promising activity against the cell lines tested and the activity of BT20 was more than the standard methotrexate. Again the above three compounds showed excellent inhibitory activity with the percentage inhibition of 64.5, 57.3 and 55.8 respectively against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase. PHASE identified a five-point AHHRR model for the proposed activity and the computational studies provided insights into the structural requirements for the anticancer activity and the results were consistent with the observed in vitro activity data. These novel benzothiazepines will be useful as lead molecules for the further development of new cancer therapies against colon and breast cancers.
Sections du résumé
BACKGROUND
Despite the availability of a variety of chemotherapeutic agents, cancer is still one of the leading causes of death worldwide because of the problems with existing chemotherapeutic agents like objectionable side effects, lack of selectivity, and resistance. Hence, there is an urgent need for the development of novel anticancer agents with high usefulness, fewer side effects, devoid of resistance and superior selectivity.
OBJECTIVE
The objective of this study is to synthesize a series of novel 1,5-benzothiazepine derivatives and evaluate their anticancer activity employing biological and computational methods.
METHODS
Twenty new benzothiazepines (BT1-BT20) were prepared by condensing different 1-(4- isobutylphenyl)ethanone chalcones with 2-amiothiophenol and evaluated for their anticancer activity by MTT assay against three cell lines including HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer). These compounds were also tested for their inhibitory action against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase enzyme by taking into account of their excellent action against colon and breast cancer cell lines. Further, the structural features responsible for the activity were identified by Pharmacophorebased modelling using Schrodinger's PHASETM software.
RESULTS
Among the 20 benzothiazepine derivatives, three compounds viz., BT18, BT19 and BT20 exhibited promising activity against the cell lines tested and the activity of BT20 was more than the standard methotrexate. Again the above three compounds showed excellent inhibitory activity with the percentage inhibition of 64.5, 57.3 and 55.8 respectively against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase. PHASE identified a five-point AHHRR model for the proposed activity and the computational studies provided insights into the structural requirements for the anticancer activity and the results were consistent with the observed in vitro activity data.
CONCLUSION
These novel benzothiazepines will be useful as lead molecules for the further development of new cancer therapies against colon and breast cancers.
Identifiants
pubmed: 32000647
pii: ACAMC-EPUB-104076
doi: 10.2174/1871520620666200130091142
doi:
Substances chimiques
1,5-benzothiazepine
0
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Thiazepines
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1115-1128Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.