2,3-Difunctionalized Benzo[ b ]thiophene Scaffolds Possessing Potent Antiangiogenic Properties.
Himalaya SinghAnnaram ThirupathiBishwaprava DasManojkumar JanniRenu KumariSandeep SinghMamunur RashidMohammad WahajuddinMusuvathi Motilal BalamuraliKumaravelu JagaveluSaravanan PeruncheralathanPublished in: Journal of medicinal chemistry (2021)
A new class of 2-anilino-3-cyanobenzo[ b ]thiophenes (2,3-ACBTs) was studied for its antiangiogenic activity for the first time. One of the 2,3-ACBTs inhibited tubulogenesis in a dose-dependent manner without any toxicity. The 2,3-ACBTs significantly reduced neovascularization in both ex vivo and in vivo angiogenic assays without affecting the proliferation of endothelial cells. Neovascularization was limited through reduced phosphorylation of Akt/Src and depolymerization of f-actin and β-tubulin filaments, resulting in reduced migration of cells. In addition, the 2,3-ACBT compound disrupted the preformed angiogenic tubules, and docking/competitive binding studies showed that it binds to VEGFR2. Compound 2,3-ACBT had good stability and intramuscular profile, translating in suppressing the tumor angiogenesis induced in a xenograft model. Overall, the present study suggests that 2,3-ACBT arrests angiogenesis by regulating the Akt/Src signaling pathway and deranging cytoskeletal filaments of endothelial cells.
Keyphrases
- endothelial cells
- signaling pathway
- vascular endothelial growth factor
- high glucose
- induced apoptosis
- pi k akt
- epithelial mesenchymal transition
- cell cycle arrest
- tyrosine kinase
- cell proliferation
- molecular dynamics
- oxidative stress
- diabetic retinopathy
- diabetic rats
- molecular dynamics simulations
- dna binding
- tissue engineering
- cardiac arrest
- anti inflammatory
- transcription factor
- cardiopulmonary resuscitation
- case control