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

Lucía Serrán-Aguilera; Elena Mariotto; Gianluca Rubbini; Francisco Fermín Castro Navas; Carmen Marco; María Paz Carrasco-Jiménez; Marco Ballarotto; Antonio Macchiarulo; Ramón Hurtado-Guerrero; Giampietro Viola; Luisa Carlota Lopez-Cara

doi:10.1016/j.ejmech.2020.112797

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

Eur J Med Chem. 2020 Dec 1:207:112797. doi: 10.1016/j.ejmech.2020.112797. Epub 2020 Sep 6.

Affiliations

¹ Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus Cartuja S/n. University of Granada, 18010, Granada, Spain.
² Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, 35128, Padova, Italy.
³ Department of Biochemistry and Molecular Biology I, Faculty of Sciences, 18071, Granada, Spain.
⁴ Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06123, Italy.
⁵ Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Institute for Biocomputation and Physics of Complex Systems (BIFI) and Laboratorio de Microscopías Avanzada (LMA), Mariano Esquillor S/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, 50018, Zaragoza, Spain; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus Cartuja S/n. University of Granada, 18010, Granada, Spain. Electronic address: lcarlotalopez@ugr.es.

PMID: 32977218
DOI: 10.1016/j.ejmech.2020.112797

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.

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Choline Kinase / antagonists & inhibitors
Choline Kinase / chemistry
Choline Kinase / metabolism
Computer Simulation*
Drug Design*
G1 Phase Cell Cycle Checkpoints / drug effects
Humans
Molecular Docking Simulation*
Protein Conformation
Resting Phase, Cell Cycle / drug effects
Small Molecule Libraries / chemical synthesis*
Small Molecule Libraries / chemistry
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology*

Substances

Antineoplastic Agents
Small Molecule Libraries
CHKA protein, human
Choline Kinase