New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships.
Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France; Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, BP 90656, Fanar Jdeideh, Lebanon.
Zahraa
Z
Zghaib
CNRS, UMR5048 - Université de Montpellier, Centre de Biochimie Structurale, F-34090 Montpellier, France; INSERM, U1054, F-34090 Montpellier, France.
Jean-François
JF
Guichou
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.
Johanna
J
Vappiani
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, 34298 Montpellier, France.
Nicole
N
Bec
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.
Kamel
K
Hadj-Kaddour
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.
Laure-Anaïs
LA
Vincent
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.
Stéphanie
S
Paniagua-Gayraud
IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, 34298 Montpellier, France.
Christian
C
Larroque
Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, BP 90656, Fanar Jdeideh, Lebanon.
Georges
G
Moarbess
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.
Pierre
P
Cuq
Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, BP 90656, Fanar Jdeideh, Lebanon.
Issam
I
Kassab
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France. Electronic address: carine.masquefa@umontpellier.fr.
Carine
C
Deleuze-Masquéfa
Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, BP 90656, Fanar Jdeideh, Lebanon.
Mona
M
Diab-Assaf
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.
Pierre-Antoine
PA
Bonnet
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007093:Imidazoles; D011810:Quinoxalines; D014404:Tubulin
Antiproliferative activity; Human melanoma cancer cell line (A375); Imidazo[1,2-a]quinoxaline; Molecular docking; Structure–activity relationship; Tubulin depolymerization