Chemical epigenetics to assess the role of HDAC1–3 inhibition in macrophage pro-inflammatory gene expression
| Autor: | Kim Krist, Frank J. Dekker, Niek G. J. Leus, Alessia Lenoci, Antonello Mai, Maria E. Ourailidou |
|---|---|
| Přispěvatelé: | Chemical and Pharmaceutical Biology, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Medicinal Chemistry and Bioanalysis (MCB) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
ACETYLATION NF-KAPPA-B Pharmaceutical Science Biology Biochemistry ACTIVATION 03 medical and health sciences chemistry.chemical_compound ACETYLTRANSFERASES Drug Discovery Gene expression TRANSCRIPTION Epigenetics Pharmacology Reporter gene Entinostat Organic Chemistry NFKB1 HISTONE DEACETYLASE INHIBITORS CANCER HDAC1 3. Good health 030104 developmental biology Histone SELECTIVITY chemistry Acetylation DISEASES Cancer research biology.protein ENTINOSTAT Molecular Medicine |
| Zdroj: | MedChemCommun, 7(11), 2184-2190. ROYAL SOC CHEMISTRY |
| ISSN: | 2040-2511 2040-2503 |
| DOI: | 10.1039/c6md00375c |
| Popis: | Histone deacetylases (HDACs) have been used as pharmacological targets for the treatment of various diseases. Some non-selective HDAC inhibitors (HDACi) have been clinically-used as therapeutic agents for treatment of hematological cancers but their cytotoxic side effects are an important downside. The discovery of more selective inhibitors has certified the involvement of individual HDACs in pathological processes but the elucidation of the role of specific family members in inflammatory responses still remains a challenge. Here, we report the development of closely related, structural analogues of the clinically-used HDACi Entinostat via a chemical epigenetic approach. Three compounds were designed and synthesized in which the cap moiety of Entinostat was replaced by an azobenzene group that is either para, meta or ortho substituted. The compounds were then evaluated for selectivity towards HDACs 1-3 and their effect on pro-inflammatory gene expression in macrophages. One analogue, compound 4, lacked selectivity and demonstrated inhibition of NF-kappa B reporter gene activity and pro-inflammatory gene expression in RAW264.7 macrophages, thus indicating that there is a delicate balance between the selectivity of HDACi over specific family members and their pro-or anti-inflammatory effects. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|