New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action.

Autor: Luque-Navarro PM; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain; Department of Pharmaceutical Sciences, University of Perugia, Perugia, 06123 Italy., Carrasco-Jiménez MP; Department of Biochemistry and Molecular Biology I, University of Granada, Campus of Fuentenueva s/n, Granada, 18071, Spain. Electronic address: mpazcj@ugr.es., Goracci L; Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, 06123, Italy., Paredes JM; Department of Physical-Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain., Espinar-Barranco L; Department of Physical-Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain., Valverde-Pozo J; Department of Physical-Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain., Torretta A; Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, Milano, 20133, Italy., Parisini E; Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, Milano, 20133, Italy; Department of Biotechnology, Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV, 1006, Latvia; Department of Chemistry 'G. Ciamician', University of Bologna, Via Selmi 2, Bologna, 40126, Italy., Mariotto E; Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Padova, 35128, Italy., Marchioro C; Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Padova, 35128, Italy., Laso A; Department of Biochemistry and Molecular Biology I, University of Granada, Campus of Fuentenueva s/n, Granada, 18071, Spain., Marco C; Department of Biochemistry and Molecular Biology I, University of Granada, Campus of Fuentenueva s/n, Granada, 18071, Spain., Viola G; Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Padova, 35128, Italy; Istituto di Ricerca Pediatrica (IRP) Fondazione Città della Speranza, Corso Stati Uniti 4, Padova, 35128, Italy. Electronic address: giampietro.viola.1@unipd.it., Lanari D; Department of Pharmaceutical Sciences, University of Perugia, Perugia, 06123 Italy. Electronic address: daniela.lanari@unipg.it., López Cara LC; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Campus of Cartuja s/n, Granada, 18071, Spain. Electronic address: lcarlotalopez@ugr.es.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Jan 15; Vol. 246, pp. 115003. Date of Electronic Publication: 2022 Dec 05.
DOI: 10.1016/j.ejmech.2022.115003
Abstrakt: Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg 2+ cofactor, or its destabilization. The most active compounds of the two series are capable of inducing apoptosis following the mitochondrial pathway and to significantly reduce the expression of anti-apoptotic proteins such as the Mcl-1. The fluorescence properties of the compounds of the PL library allowed the tracking of their mode of action, while PAINS (Pan Assays Interference Structures) filtration databases suggest the lack of any unspecific biological response.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luisa Carlota Lopez-Cara reports financial support was provided by University of Granada. Luisa Carlota Lopez-Cara reports financial support was provided by University of Granada Faculty of Pharmacy. Emilio Parisini reports financial support was provided by University of Latvia. Luisa carlota Lopez-Cara reports a relationship with University of Granada Faculty of Pharmacy that includes: board membership. Emilio Parisini reports a relationship with University of Latvia that includes: board membership. This research was funded by Convocatoria 2019 Proyectos de I + D + i − RTI Tipo B “Ministerio de Innovación y Ciencia” [grant number PID2019-109294RB-I00] and “Convocatoria 2020 Proyectos I + D + i del Programa Operativo FEDER 2020”, [grant number B-CTS-216-UGR20]. E.P. thanks the ERDF project BioDrug [No. 1.1.1.5/19/A/004] and the Latvian Council of Science [grant number lzp-2020/2-0013] for financial support.
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Databáze: MEDLINE
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