Triazolo-linked benzimidazoles as tubulin polymerization inhibitors and DNA intercalators: Design, synthesis, cytotoxicity, and docking studies.
Arch Pharm (Weinheim)
; 356(5): e2200449, 2023 May.
Article
em En
| MEDLINE
| ID: mdl-36807372
ABSTRACT
A simple "click" protocol was employed in the quest of synthesizing 1,2,3-triazole-linked benzimidazoles as promising anticancer agents on various human cancer cell lines such as A549, HCT116, SK-Mel-28, HT-29, and MCF-7. Compound 12j demonstrated significant cytotoxic potential towards SK-Mel-28 cancer cells (IC50 4.17 ± 0.09 µM) and displayed no cytotoxicity (IC50 > 100 µM) against normal human BEAS-2B cells inferring its safety towards normal healthy cells. Further to comprehend the underlying apoptosis mechanisms, AO/EB, dichlorodihydrofluorescein diacetate (DCFDA), and 4',6-diamidino-2-phenylindole (DAPI) staining were performed, which revealed the nuclear and morphological alterations. Compound 12j displayed impairment in cellular migration and inhibited colony formation. The annexin V binding assay and JC-1 were implemented to evaluate the scope of apoptosis and the loss of the mitochondrial transmembrane potential in SK-Mel-28 cells. Cell-cycle analysis revealed that compound 12j arrested the cells at the G2/M phase in a dose-dependent manner. Target-based assays established the inhibition of tubulin polymerization by 12j at an IC50 value of 5.65 ± 0.05 µM and its effective binding with circulating tumor DNA as a DNA intercalator. The detailed binding interactions of 12j with tubulin and DNA were examined by docking studies on PDB ID 3E22 and DNA hexamer (PDB ID 1NAB), respectively.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Moduladores de Tubulina
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Arch Pharm (Weinheim)
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Índia