Synthesis, Biological evaluation, in silico modeling and Crystallisation of novel small monocationic molecules with potent antiproliferative activity by dual mechanism

Lucía SerránAguilera, ElenaMariotto, GianlucaRubbini, Francisco Fermín Castro Navasa, Carmen Marco, María Paz Carrasco-Jiménez, Marco Ballarotto, Antonio Macchiarulo, Ramón Hurtado-Guerrero, Giampietro Viola, Luisa Carlota Lopez-Cara.Synthesis. Biological evaluation, in silico modeling and Crystallisation of novel small monocationic molecules with potent antiproliferative activity by dual mechanism. European Journal of Medicinal Chemistry. Available online 6 September 2020, 112797

Seeking for new anticancer drugs with strong antiproliferative activity and simple molecular structure, we designed a novel series of compounds based on our previous reported pharmacophore model composed of five moieties. Antiproliferative assays on four tumoral cell lines and evaluation of Human Choline Kinase CKα1 enzymatic activity was performed for these compounds. Among tested molecules, those ones with biphenyl spacer showed betters enzymatic and antiproliferative activities (n-v). Docking and crystallization studies validate the hypothesis and confirm the results. The most active compound (t) induces a significant arrest of the cell cycle in G0/G1 phase that ultimately lead to apoptosis, following the mitochondrial pathway, as demonstrated for other choline kinase inhibitors. However additional assays reveal that the inhibition of choline uptake could also be involved in the antiproliferative outcome of this class of compounds.

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