Cross metathesis with hydroxamate and benzamide BOC-protected alkenes to access HDAC inhibitors and their biological evaluation highlighted intrinsic activity of BOC-protected dihydroxamates
| العنوان: | Cross metathesis with hydroxamate and benzamide BOC-protected alkenes to access HDAC inhibitors and their biological evaluation highlighted intrinsic activity of BOC-protected dihydroxamates |
|---|---|
| المؤلفون: | Judit Ovádi, Claudia A. Simões-Pires, Attila Lehotzky, Alessandra Nurisso, Philippe Bertrand, Muriel Cuendet, Nadine Martinet, Samuel Bouchet, Vincent Zwick, Christophe Blanquart |
| المساهمون: | School of Pharmaceutical Sciences, Université de Lausanne (UNIL)-University of Geneva [Switzerland], Réseau épigénétique, Cancéropôle Grand-Ouest, Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institute of Enzymology [Budapest], Research Centre for Natural Sciences, Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Authors thank the Centre National de la Recherche Scientifique– France, University of Poitiers, Region Poitou-Charentes (S.B. financial support), the Ligue Contre le Cancer: Committees of Vendée, et Charente-Maritime – France, ARSMeso44 – France, COST Actions CM1406 and CM1106 – Belgium and Hungarian OTKA Founds K-101039 and K-112144 for financial support. A.N. thanks the Excellence programme of the University of Geneva –Switzerland for financial support., Bernardo, Elizabeth, Université de Lausanne = University of Lausanne (UNIL)-Université de Genève = University of Geneva (UNIGE), Université Nice Sophia Antipolis (1965 - 2019) (UNS) |
| المصدر: | Bioorganic and Medicinal Chemistry Letters Bioorganic and Medicinal Chemistry Letters, Elsevier, 2016, ⟨10.1016/j.bmcl.2015.11.011⟩ Bioorganic and Medicinal Chemistry Letters, 2016, ⟨10.1016/j.bmcl.2015.11.011⟩ Bioorganic & Medicinal Chemistry Letters, Vol. 26, No 1 (2016) pp. 154-159 |
| بيانات النشر: | HAL CCSD, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Models, Molecular, 0301 basic medicine, Intrinsic activity, Formic Acid Esters, Stereochemistry, Clinical Biochemistry, Convergent synthesis, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Alkenes, Hydroxamic Acids, Metathesis, Biochemistry, Histone Deacetylases, Catalysis, Dose-Response Relationship, Formic Acid Esters/chemistry, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, Models, Drug Discovery, Humans, Structure–activity relationship, Benzamides/chemistry, Benzamide, Molecular Biology, ddc:615, Dose-Response Relationship, Drug, Molecular Structure, biology, Organic Chemistry, Molecular, Alkenes/chemistry, 3. Good health, Histone Deacetylase Inhibitors, 030104 developmental biology, Tubulin, Histone Deacetylase Inhibitors/chemistry/pharmacology, Hydroxamic Acids/chemistry, chemistry, Benzamides, biology.protein, Molecular Medicine, Histone Deacetylases/metabolism, Drug, Selectivity |
| الوصف: | International audience; Conditions for the metathesis of alkenes in the convergent synthesis of HDAC inhibitors have been improved by continuous catalyst flow injection in the reaction media. Intermediate and target compounds obtained were tested for their ability to induce HDAC inhibition and tubulin acetylation, revealing the key role of the tert-butyloxycarbonyl (BOC) group for more HDAC6 selectivity. Molecular modelling added rationale for this BOC effect. Epigenetic mechanisms are able to provide regulatory information to the genome without altering its primary nucleotide sequence. Such mechanisms are implicated in various processes, including gene silencing and expression, apoptosis, maintenance of stem cell pluripotency, and X-chromosome inactivation. 1 At the molecular level, epigenetic regulators include covalent modification to DNA (e.g., DNA methylation) and to histone proteins (e.g., histone acetylation, methylation and ubiquitination). 1,2 More than 350 epigenetic regulators are known to date, and classified as writers (enzymes adding groups to DNA/histones), erasers (enzymes removing groups from DNA/histones) and readers (recognition of modified protein domains). 3–5 The post-translational modifications (PTM) observed in histone proteins and DNA are known as epigenetic marks. 1 Epigenetic mechanisms are nowadays correlated to several human diseases, including cancer, neurodegenerative and metabolic disorders, as well as memory impairment and parasitic infections. In the field of cancer, mutations, abnormal expression and domain translocation in epigenetic enzymes lead to abnormal PTM levels and participate to diseases progression. The renormal-ization of aberrant PTM is thus one of the goals in epigenetic cancer therapy. Amongst the several possible marks, histone acetylation was identified as a major player. Histone acetylation is controlled by the activity of histone acetyl transferases (HAT) 6 in balance with histone deacetylases (HDAC), 7 and recognized by bromodomain-containing proteins. 8 HDAC are over expressed in several cancer cell lines where they silence some tumor suppressor genes, 9 while therapeutically active HDAC inhibitors facilitate apoptosis of tumor cells. 10 Those observations led to the development of HDAC inhibi-tors for cancer therapy. 11 HDAC enzymes are grouped in three zinc-dependent classes, classes I (HDAC1–3, 8), II (HDAC 4–7, 9, 10) and IV (HDAC11), and the NAD +-dependent class III (SIRT1– 7). There is currently four compounds targeting HDAC approved for clinical uses: 12 romidepsin 13 and vorinostat 14 (SAHA 1, suberoyl anilide hydroxy amide) for cutaneous T-cell lymphoma |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0960-894X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::acc9fefa73c13b45a09cef22d951db0cTest https://www.hal.inserm.fr/inserm-01299475/documentTest |
| حقوق: | EMBARGO |
| رقم الانضمام: | edsair.doi.dedup.....acc9fefa73c13b45a09cef22d951db0c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 0960894X |
|---|