Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 16; pp. 6073 - 6084
• Main Authors: Aubry, Carine, Wilson, A. James, Emmerson, Daniel, Murphy, Emma, Chan, Yu Yam, Dickens, Michael P., García, Marcos D., Jenkins, Paul R., Mahale, Sachin, Chaudhuri, Bhabatosh
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.08.2009; Elsevier
• Subjects: Anti-cancer; Antineoplastic agents; Binding Sites; Biological and medical sciences; CDK4 inhibitors; Computer Simulation; Cyclin A - antagonists & inhibitors; Cyclin A - metabolism; Cyclin D1 - antagonists & inhibitors; Cyclin D1 - metabolism; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Drug Design; Fascaplysin; General aspects; Humans; Indoles; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; CDK4 inhibitors; Indoles; Anti-cancer; Fascaplysin; Antineoplastic agent; Enzyme; Nitrogen heterocycle; Isozyme; Transferases; Chain length; Enzyme inhibitor; Inhibitor enzyme complex; Selectivity; In vitro; Modeling; Alkaloid; Structure activity relation; Molecular model; Bicyclic compound; Aromatic compound; Indole derivatives; Chemical synthesis; Cyclin dependent kinase; Halogen Organic compounds
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.06.070

The design, synthesis and biological activity of a new series of substituted 3-(2-(1 H-indol-1-yl)ethyl)-1 H-indoles of type I and 1,2-di(1 H-indol-1-yl)alkanes of type II as selective inhibitors of CDK4/cyclin D1 is presented. The compounds were designed to explore the relationship between the connection mode of the indolyl moieties and their CDK inhibitory activities. We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC 50s for the best compounds 10m (type I, R 1, R 2 = Cl) and 13a (type II, n = 1) being 39 and 37 μm, respectively. We present the design, synthesis and biological activity of a new series of substituted 3-(2-(1 H-indol-1-yl)ethyl)-1 H-indoles and 1,2-di(1 H-indol-1-yl)alkanes as selective inhibitors of CDK4/cyclin D1. The compounds were designed to explore the relationship between the connection mode of the indolyl moieties and their CDK inhibitory activities. We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC 50 for the best compounds 10m and 13a being 39 and 37 μm, respectively.