Synthesis and Modeling of New Benzofuranone Histone Deacetylase Inhibitors that Stimulate Tumor Suppressor Gene Expression

• Published in: Journal of medicinal chemistry Vol. 52; no. 9; pp. 3112 - 3115
• Main Authors: Charrier, Cédric, Clarhaut, Jonathan, Gesson, Jean-Pierre, Estiu, Guillermina, Wiest, Olaf, Roche, Joëlle, Bertrand, Philippe
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.05.2009; Amer Chemical Soc
• Subjects: Acetylation - drug effects; Antineoplastic agents; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - metabolism; Benzofurans - pharmacology; Biological and medical sciences; Cadherins - metabolism; Catalytic Domain; Cell Line, Tumor; Chemical Sciences; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Histone Deacetylase Inhibitors; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Histones - metabolism; Humans; Life Sciences & Biomedicine; Medical sciences; Medicinal Chemistry; Membrane Proteins - metabolism; Models, Molecular; Nerve Tissue Proteins - metabolism; Organic chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Tubulin - metabolism; Tumor Suppressor Proteins - metabolism; LUNG-CANCER; SAHA; DESIGN; MECHANISM; CRYSTAL-STRUCTURE; HOMOLOG; SELECTIVITY; Indan derivatives; Enzyme; Active site; Cell adhesion molecule; Hydroxamic acid; Enzyme inhibitor; Gene expression; Modeling; Biological activity; Histone deacetylase inhibitor; Molecular model; Hydrolases; Benzofuran derivatives; Chemical synthesis; E Cadherin; Aromatic amine; Tumor suppressor gene; Benzofuranone; tumor suppressor; histone deacetylase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9002439

New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments.