RESUMEN
New nucleoside derivatives with nitrogen substitution at the C-6 position were prepared and screened initially for their in vitro anticancer bioactivity against human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7) by the NCI-sulforhodamine B assay. N6-(4-trifluoromethylphenyl)piperazine analog (27) exhibited promising cytotoxic activity. The compound 27 was more cytotoxic (IC50â¯=â¯1-4⯵M) than 5-FU, fludarabine on Huh7, HCT116 and MCF7 cell lines. The most potent nucleosides (11, 13, 16, 18, 19, 21, 27, 28) were further screened for their cytotoxicity in hepatocellular cancer cell lines. The compound 27 demonstrated the highest cytotoxic activity against Huh7, Mahlavu and FOCUS cells (IC50â¯=â¯1, 3 and 1⯵M respectively). Physicochemical properties, drug-likeness, and drug score profiles of the molecules showed that they are estimated to be orally bioavailable. The results pointed that the novel derivatives would be potential drug candidates.
Asunto(s)
Antineoplásicos/farmacología , Nucleósidos de Purina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cladribina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/farmacología , Humanos , Estructura Molecular , Nucleósidos de Purina/síntesis química , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacocinética , Vidarabina/análogos & derivados , Vidarabina/farmacologíaRESUMEN
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.