In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

Abstract

Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC50 = 3.105 and 2.15 μM) and 4c (IC50 = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC50 = 0.075 and 4.60 μM, respectively, while 3b showed IC50 = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.

Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation

“…Moreover, compound 3e showed more than 3 times selective cytotoxicity against the colorectal cancer cells over the normal cells. Compounds 3c and 3e as well as cabozantinib exhibited considerable safety as the values of SI of all of them are more than 2 39 .…”

Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers

“…Compound 1c was selected as a potent candidate, its effect on cell cycle phases of HL60 and leukaemia SR cells was investigated using propidium iodide staining and flow cytometric analysis according to the cell cycle kit (Abcam ®, ab139418-) 90 , 91 . Briefly, HL60 and leukaemia SR cells were cultured under optimum conditions.…”

Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey

“…Molecular docking was done according to the reported procedures (Abdelnaby et al 2022 ; El-Dydamony et al 2022 ) using Discovery Studio 4.1 software (Accelrys, Inc., San Diego, CA, USA). The X-ray 3D structures of caspase-3 (PDB ID 1RHR) (Gadelmawla et al 2022 ) and NO synthase (PDB ID 4NOS) (Fischmann et al 1999 ) were obtained from the PDB site ( http://www.rscb.org/pdb ) and prepared for docking by cleaning the protein and fixing missing chains.…”