Synthesis and biological activity of simplified denoviose-coumarins related to novobiocin as potent inhibitors of heat-shock protein 90 (hsp90)

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 7; pp. 2495 - 2498
• Main Authors: Radanyi, Christine, Le Bras, Gaëlle, Messaoudi, Samir, Bouclier, Céline, Peyrat, Jean-François, Brion, Jean-Daniel, Marsaud, Véronique, Renoir, Jack-Michel, Alami, Mouâd
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2008; Elsevier
• Subjects: Anti-tumour; Antibiotics, Antineoplastic - chemical synthesis; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Binding Sites; Biological and medical sciences; Breast Neoplasms - pathology; Cell Line, Tumor - drug effects; Cell Proliferation - drug effects; Coumarin inhibitors; Coumarins - chemistry; Coumarins - pharmacology; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Estradiol - pharmacology; General aspects; hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Medical sciences; Novobiocin; Novobiocin - chemical synthesis; Novobiocin - pharmacology; Pharmacology. Drug treatments; Steroid receptors; Structure-Activity Relationship; Transcription, Genetic - drug effects; Coumarin inhibitors; hsp90; Novobiocin; Anti-tumour; Steroid receptors; Antineoplastic agent; Human; Steroid; Chaperone; Coumarine derivatives; Lactone; In vitro; Biological activity; Signal transduction; Cell line; Heat shock protein; Glycoside; Inhibitor; Mammary gland; Chemical synthesis; Tumor cell; Biological receptor
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.01.128

The synthesis and biological activity of a new series of denoviose-coumarins related to novobiocin are described. A new series of coumarin inhibitors of hsp90 lacking the noviose moiety as well as substituents on C-7 and C-8 positions of the aromatic ring was synthesised and their hsp90 inhibitory activity has been delineated: for example, their capacity to induce the degradation of client proteins and to inhibit estradiol-induced transcription in human breast cancer cells. In cell proliferation assay, the most active compound 5g was ∼8 times more potent than the parent novobiocin natural compound.