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  3. New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships

New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships

  • Bioorg Med Chem. 2016 Jun 1;24(11):2433-2440. doi: 10.1016/j.bmc.2016.04.004.
Zahraa Zghaib 1,  Jean-François Guichou 2,  Johanna Vappiani 3,  Nicole Bec 4,  Kamel Hadj-Kaddour 3,  Laure-Anaïs Vincent 3,  Stéphanie Paniagua-Gayraud 3,  Christian Larroque 4,  Georges Moarbess 5,  Pierre Cuq 3,  Issam Kassab 5,  Carine Deleuze-Masquéfa 6,  Mona Diab-Assaf 5,  Pierre-Antoine Bonnet 3
Affiliations

Affiliations

  • 1 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.
  • 2 CNRS, UMR5048 - Université de Montpellier, Centre de Biochimie Structurale, F-34090 Montpellier, France; INSERM, U1054, F-34090 Montpellier, France.
  • 3 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.
  • 4 IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, 34298 Montpellier, France.
  • 5 Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, BP 90656, Fanar Jdeideh, Lebanon.
  • 6 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.
PMID: 27094151 DOI: 10.1016/j.bmc.2016.04.004
Abstract

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.

Keywords

Antiproliferative activity; Human melanoma cancer cell line (A375); Imidazo[1,2-a]quinoxaline; Molecular docking; Structure–activity relationship; Tubulin depolymerization.

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