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

DOI: 10.1016/j.ejmech.2020.112797 DOI Help

Authors: Lucía Serran Aguilera (University of Granada) , Elena Mariotto (University of Padova) , Gianluca Rubbini (University of Granada) , Francisco Fermín Castro Navas (University of Granada) , Carmen Marco (University of Granada) , María Paz Carrasco-jiménez (University of Granada) , Marco Ballarotto (University of Perugia) , Antonio Macchiarulo (University of Perugia) , Ramon Hurtado-guerrero (University of Zaragoza; University of Copenhagen) , Giampietro Viola (University of Padova) , Luisa Carlota Lopez-cara (University of Granada)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 207

State: Published (Approved)
Published: December 2020
Diamond Proposal Number(s): 8035

Abstract: 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.

Journal Keywords: Antitumoral drug; Choline kinase inhibition; Choline uptake

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: Beamline XALOC at ALBA