An integrated computational approach to the phenomenon of potent and selective inhibition of Aurora kinases B and C by a series of 7-substituted indirubins

A variation of the bromine substitution from 6- to 7-position converts the glycogen synthase kinase-3α/β-(GSK-3-α/β) selective inhibitor 6-bromoindirubin-3′-oxime (6BIO) to a potent inhibitor of Aurora B and C kinases. The novel indirubin analogue 7-bromoindirubin-3′-oxime (7BIO) demonstrated unexpected selectivity against these two kinases since the homologous kinase Aurora A was poorly inhibited. A hypothesis regarding the 7BIO selectivity profile was stated and validated by docking, molecular dynamics, and free energy perturbation calculations. The residue (Thr217AurA, Glu161AurB, Glu127AurC) located in the active site was identified as a major contributor to the enhanced affinity of 7BIO for Aurora B and C versus Aurora A. Furthermore, the docking events of 7BIO and several of its analogues were approached by quantitative models based on semiempirical scoring functions. In the course of model construction and optimization, a number of important factors influencing the quality of each model like the application of force constraints or the sampling method were determined. Among these factors, the presence and treatment of structurally important water molecules had a pronounced impact on the quality of each model. The final model was validated by use of free energy perturbation calculations. © 2007 American Chemical Society

Synthesis of novel 5-substituted indirubins as protein kinases inhibitors

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Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period

Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3′-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3′ showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation. © 2008 American Chemical Society

3′-substituted 7-halogenoindirubins, a new class of cell death inducing agents

Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis and biological evaluation of 3′-substituted 7-halogenoindirubins. Molecular modeling and kinase assays suggest that steric hindrance prevents 3′-substituted 7-halogenoindirubins from interacting with classical kinase targets of other indirubins such as cyclin-dependent kinases and glycogen synthase kinase-3. Surprisingly 3′-substituted 7-halogeno-indirubins induce cell death in a diversity of human tumor cell lines. Although some 3′-substituted 7-halogenoindirubins appear to induce effector caspase-independent, nonapoptotic cell death, others trigger the landmarks of classical apoptosis. A structure-activity relationship study was performed to optimize 3′-substituted 7-halogenoindirubins with respect to solubility and cell death induction. Despite their unidentified targets, 3′-substituted 7-halogenoindirubins constitute a new promising family of antitumor agents. © 2006 American Chemical Society

Meriolins, a new class of cell death-inducing, cyclin dependent kinase inhibitors with enhanced selectivity for cyclin-dependent kinases,

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Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1

Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-β peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1δ provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-β in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers. © 2008 American Chemical Society

Photoreactivity of indirubin derivatives

Twenty-nine analogs of indirubin, an isomer of indigo, have been synthesized to optimize its promising kinase inhibitory scaffold. These compounds being also pigmented, have been tested for their photoreactivity. Absorption maxima were between 485 nm and 560 nm. Addition of fetal calf serum induced fluorescence and time dependent absorption modifications. Appropriate illumination induced Reactive Oxygen Species (ROS) production for nineteen compounds out of twenty-nine. The relationship between fluorescence and ROS production is discussed. Six compounds showed an important toxicity on F98 cells, a murine glioma cell line. Three of these were found to be also phototoxic, as four other non-toxic compounds. All but onze phototoxic compounds were detected as ROS producers by in vitro tests. Photoreactivity assessment is important to anticipate adverse reactions for compounds that might be clinically developed. The experimental assay was found to be the only way to evaluate the photoreactivity of this family of compounds since no predictive criteria on structures could be found. Combining the vascular tumor growth inhibition induced by kinase inhibitors with the massive local blood flow arrest following photodynamic treatment may be an efficient anti-cancer strategy. These data could orientate further syntheses of either non-photoreactive compounds or compounds displaying both kinase inhibitory activity and strong phototoxicity. © The Royal Society of Chemistry and Owner Societies