Burak Servili

Novel imidazo[1,2‐ a ]pyridines bearing 1,2,3‐triazole moieties at the C3 position were synthesized. After the characterization of the synthesized compounds, their in vitro therapeutic activities were evaluated in various cancer cell lines (MCF7, A549, HePG2 and T98G). Methoxy substituted derivative was identified as the most potent compound based on the results of its anti‐proliferative activity on various cancer cell lines, as well as showing no cytotoxicity on the healthy human fibroblast cell line (MRC‐5). As an indicator of apoptosis, a significant decrease in the level of PARP protein was observed in the MCF7 cells treated with this derivative. Molecular docking studies were conducted on wide range of targets such as phosphoinositide 3‐kinase (PI3K), cyclin‐independent kinase 2 (CDK2), mitogen‐activated protein kinase (MEK), insulin‐like growth‐factor‐1 (IGF‐1), tubulin, DNA topoisomerase, poly (ADP‐ribose) polymerase (PARP) and B‐cell lymphoma‐2 (BCL2). All the compounds tested showed the lowest binding energies with target PARP1. Moreover, CDK2 and tubulin displayed relatively good binding scores. The docking poses and scores were cross‐checked with two different software and multiple protein conformations were included to incorporate flexible protein docking features. Finally, drug‐likeness properties of the compounds are further tested via Swiss‐ADME software.

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl-containing purine nucleobase analogs were tested for their in vitro anticancer activity against human cancer cells. Compounds 15, 17–24, 49, and 56 with IC₅₀ values less than 10 μM were selected for further examination on an enlarged panel of liver cancer cell lines. Experiments revealed that compound 19 utilizes its high cytotoxic potential (IC₅₀ < 5 μM) to induce apoptosis in vitro. Compound 19 displayed a KINOMEscan selectivity score S₃₅ of 0.02 and S₁₀ of 0.01 and demonstrated a significant selectivity against anaplastic lymphoma kinase (ALK) and Bruton's tyrosine kinase (BTK) over other kinases. Compounds 19, 21, 22, 23, and 56 complexed with ALK, BTK, and (discoidin domain-containing receptor 2) DDR2 were analyzed structurally for binding site interactions and binding affinities via molecular docking and molecular dynamics simulations. Compounds 19 and 56 displayed similar interactions with the activation loop of the kinases, while only compound 19 reached toward the multiple subsites of the active site. Cell cycle and signaling pathway analyses exhibited that compound 19 decreases phosho-Src, phospho-Rb, cyclin E, and cdk2 levels in liver cancer cells, eventually inducing apoptosis.