Imidazo[1,2-a]quinoxalines for melanoma treatment with original mechanism of action.

Autor: Patinote C; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France; Société d'Accélération du Transfert de Technologies (SATT AxLR), CSU, 950 rue Saint Priest, 34090, Montpellier, France., Deleuze-Masquéfa C; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France. Electronic address: carine.masquefa@umontpellier.fr., Kaddour KH; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France., Vincent LA; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France., Larive R; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France., Zghaib Z; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France; Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, EDST, BP 90656, Fanar Jdeideh, Lebanon., Guichou JF; CNRS, UMR 5048, INSERM, U105, Université de Montpellier, Centre de Biochimie Structurale, 34090, Montpellier, France., Assaf MD; Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, EDST, BP 90656, Fanar Jdeideh, Lebanon., Cuq P; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France., Bonnet PA; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Feb 15; Vol. 212, pp. 113031. Date of Electronic Publication: 2020 Nov 24.
DOI: 10.1016/j.ejmech.2020.113031
Abstrakt: The malignant transformation of melanocytes causes several thousand deaths each year, making melanoma an important public health concern. Melanoma is the most aggressive skin cancer, which incidence has regularly increased over the past decades. We described here the preparation of new compounds based on the 1-(3,4-dihydroxyphenyl)imidazo[1,2-a]quinoxaline structure. Different positions of the quinoxaline moiety were screened to introduce novel substituents in order to study their influence on the biological activity. Several alkylamino or alkyloxy groups were also considered to replace the methylamine of our first generation of Imiqualines. Imidazo[1,2-a]pyrazine derivatives were also designed as potential minimal structure. The investigation on A375 melanoma cells displayed interesting in vitro low nanomolar cytotoxic activity. Among them, 9d (EAPB02303) is particularly remarkable since it is 20 times more potent than vemurafenib, the reference clinical therapy used on BRAF mutant melanoma. Contrary to the first generation, EAPB02303 does not inhibit tubulin polymerization, as confirmed by an in vitro assay and a molecular modelisation study. The mechanism of action for EAPB02303 highlighted by a transcriptomic analysis is clearly different from a panel of 12 well-known anticancer drugs. In vivoEAPB02303 treatment reduced tumor size and weight of the A375 human melanoma xenografts in a dose-dependent manner, correlated with a low mitotic index but not with necrosis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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