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      Carbazole scaffolds in cancer therapy: a review from 2012 to 2018

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          Abstract

          For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic–carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.

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          Isolation and synthesis of biologically active carbazole alkaloids.

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            Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids.

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              Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance.

              The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. Here we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in models of crizotinib resistance. Alectinib led to tumor size reduction in EML4-ALK-positive xenograft tumors that failed to regress fully during the treatment with crizotinib. In addition, alectinib inhibited the growth of some EML4-ALK mutant-driven tumors, including the G1269A model. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations.
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                Author and article information

                Journal
                J Enzyme Inhib Med Chem
                J Enzyme Inhib Med Chem
                IENZ
                ienz20
                Journal of Enzyme Inhibition and Medicinal Chemistry
                Taylor & Francis
                1475-6366
                1475-6374
                2019
                22 July 2019
                : 34
                : 1
                : 1321-1346
                Affiliations
                [a ]Ecole de Biologie Industrielle, EBInnov , Cergy-Pontoise, France;
                [b ]Faculté de Pharmacie - ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, Université de Lyon, Université Claude Bernard Lyon 1 , Lyon, France;
                [c ]Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo , Oslo, Norway;
                [d ]Université Lille, Inserm, CHU Lille, UMR-S 1172 JPArc Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer , Lille, France
                Author notes
                CONTACT Samar Issa s.issa@ 123456hubebi.com Ecole de Biologie Industrielle, EBInnov , 49 Avenue des Genottes Cergy-Pontoise CS90009 95895, France;
                Zouhair Bouaziz zouhair.bouaziz@ 123456univ-lyon1.fr Faculté de Pharmacie - ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, Université Claude Bernard Lyon 1 , 8 avenue Rockefeller, Lyon cedex 8 F-69373, France
                [*]

                These authors contributed equally to this article.

                Author information
                http://orcid.org/0000-0003-2446-3512
                http://orcid.org/0000-0002-7624-7654
                http://orcid.org/0000-0001-6678-1952
                http://orcid.org/0000-0001-9221-6535
                http://orcid.org/0000-0003-1398-075X
                http://orcid.org/0000-0002-9948-0272
                Article
                1640692
                10.1080/14756366.2019.1640692
                6691762
                31328585
                aee638f4-65f3-4dff-845d-f6fcf0848ee3
                © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 January 2019
                : 11 June 2019
                : 27 June 2019
                Page count
                Figures: 69, Tables: 1, Pages: 26, Words: 9665
                Funding
                Funded by: “Partenariats Hubert Curien” (PHC)
                Award ID: 27460VC
                Funded by: Norwegian Research Council
                Award ID: 213191/F11
                Funded by: Norwegian Cancer Society
                Award ID: 4529447
                Funded by: Institut Français d’Oslo
                Funded by: Explo’ra Sup scholarship
                This work was supported by the “Partenariats Hubert Curien” (PHC) (Campus France, Program Aurora, Grant Agreement No. 27460VC), by the Norwegian Research Council (Grant Agreement No. 213191/F11) and the Norwegian Cancer Society (Project no.: 4529447). Pr. Marc Le Borgne also thanks the “Institut Français d’Oslo” for their support via the Åsgard Program 2010. This scientific work was also supported by financial support from Rhône-Alpes region through an Explo’ra Sup scholarship on 2013.
                Categories
                Review Article

                Pharmaceutical chemistry
                carbazole,cancer,cytotoxicity,targeted therapy,enzyme inhibitors
                Pharmaceutical chemistry
                carbazole, cancer, cytotoxicity, targeted therapy, enzyme inhibitors

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