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A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N -containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound 7f was promising more than 4d with IC 50 = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚβ. Furthermore, in-vivo toxicity study indicated good safety profile for 7f . These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

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.

The VEGFR-2/AKT pathway is a crucial axis in tumor survival where it is highly dysregulated in many cancer types. In this research, novel coumarin-acid hydrazides were synthesized and assayed for...

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