| Added by | pcoopman |
|---|---|
| Group name | EquipePC |
| Item Type | Journal Article |
| Title | Imidazo[1,2-a]quinoxalines for melanoma treatment with original mechanism of action |
| Creator | Patinote et al. |
| Author | Cindy Patinote |
| Author | Kamel Hadj Kaddour |
| Author | Laure-Anaïs Vincent |
| Author | Romain Larive |
| Author | Zahraa Zghaib |
| Author | Jean-François Guichou |
| Author | Mona Diab Assaf |
| Author | Pierre Cuq |
| Author | Pierre-Antoine Bonnet |
| Abstract | 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. |
| Publication | European Journal of Medicinal Chemistry |
| Volume | 212 |
| Pages | 113031 |
| Date | 2021-02-15 |
| Journal Abbr | Eur J Med Chem |
| Language | eng |
| DOI | 10.1016/j.ejmech.2020.113031 |
| ISSN | 1768-3254 |
| Library Catalog | PubMed |
| Extra | PMID: 33309473 |
| Tags | A375?cells, Animals, Antineoplastic Agents, Cell Proliferation, Cell Survival, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Imidazo[1,2-a]pyrazine, Imidazo[1,2-a]quinoxaline, Imiqualines, Melanoma, Melanoma, Experimental, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Docking Simulation, Molecular Structure, original, Polymerization, Quinoxalines, Structure-Activity Relationship, Tubulin, Tubulin Modulators, Tumor Cells, Cultured |
| Date Added | 2023/11/20 - 17:00:02 |
| Date Modified | 2023/11/20 - 17:00:18 |
| Notes and Attachments | PubMed entry (Attachment) Version acceptée (Attachment) |
Institut de Recherche en Cancérologie de
