Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
Metadatos
Mostrar el registro completo del ítemAutor
Luque Navarro, Pilar María; Rubbini, Gianluca; Aguilar-Troyano, Francisco José; Fasiolo, Alberto; Laso, Alejandro; Marco De La Calle, Carmen; Carrasco Jiménez, María Paz; López Cara, Luisa CarlotaEditorial
MDPI
Materia
Antitumoral drug Choline kinase inhibition Choline uptake
Fecha
2022-03-27Referencia bibliográfica
Luque-Navarro, P.M.; Mariotto, E.; Ballarotto, M.; Rubbini, G.; Aguilar-Troyano, F.J.; Fasiolo, A.; Torretta, A.; Parisini, E.; Macchiarulo, A.; Laso, A.; et al. Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors. Pharmaceutics 2022, 14, 715. https://doi.org/10.3390/pharmaceutics14040715
Patrocinador
Ministerio de Innovación y Ciencia PID2019-109294RB-I00; FEDER 2020 B-CTS-216-UGR20; European Regional Development Fund (ERDF) 1.1.1.5/19/A/004; Latvian Council of Science lzp-2020/2-001Resumen
Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the
development of new antitumor agents. In this work, we present a series of 41 compounds designed
based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as
bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that
some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature
substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed
by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head
have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the
growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in
inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound
induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate
that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential.