The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Honghui Wang - One of the best experts on this subject based on the ideXlab platform.

Hideyuki Tanaka - One of the best experts on this subject based on the ideXlab platform.

Nicholas J Westwood - One of the best experts on this subject based on the ideXlab platform.

  • application of the copper catalysed n arylation of amidines in the synthesis of analogues of the chemical tool Blebbistatin
    Chemical Communications, 2011
    Co-Authors: Christopher P A T Lawson, Alexandra M Z Slawin, Nicholas J Westwood
    Abstract:

    A robust protocol for the CuI-catalysed arylation of amidines is presented. Whilst the initially identified conditions were useful for benzamidine-derived substrates, difficulties were encountered with more complex substrates. This problem was overcome following a change in ligand type, enabling the synthesis of analogues of the chemical tool, Blebbistatin.

  • the small molecule tool s Blebbistatin novel insights of relevance to myosin inhibitor design
    Organic and Biomolecular Chemistry, 2008
    Co-Authors: Cristina Lucaslopez, James R Sellers, John S Allingham, Tomas Lebl, Christopher P A T Lawson, Ruth Brenk, Ivan Rayment, Nicholas J Westwood
    Abstract:

    The small molecule Blebbistatin is now a front line tool in the study of myosin function. Chemical modification of the tricyclic core of Blebbistatin could deliver the next generation of myosin inhibitors and to help address this we report here on the impact of structural changes in the methyl-substituted aromatic ring of Blebbistatin on its biological activity. Chemical methods for the preparation of isomeric methyl-containing analogues are reported and a series of co-crystal structures are used to rationalise the observed variations in their biological activity. These studies further support the view that the previously identified binding mode of Blebbistatin to Dictyostelium discoideum myosin II is of relevance to its mode of action. A discussion of the role that these observations have on planning the synthesis of focused libraries of Blebbistatin analogues is also provided including an assessment of possibilities by computational methods. These studies are ultimately directed at the development of novel myosin inhibitors with improved affinity and different selectivity profiles from Blebbistatin itself.

  • absolute stereochemical assignment and fluorescence tuning of the small molecule tool Blebbistatin
    ChemInform, 2005
    Co-Authors: Cristina Lucaslopez, James R Sellers, Aaron F. Straight, Judit Toth, Timothy J Mitchison, Stephen Patterson, Till Blum, Alexandra M Z Slawin, Nicholas J Westwood
    Abstract:

    (-)-Blebbistatin (1), a recently discovered small molecule inhibitor of the ATPase activity of non-muscle myosin II has been prepared from methyl 5-methylanthranilate (6) in three steps. This flexible synthetic route has also been used to prepare a nitro group-containing analogue 12 that has modified fluorescence properties and improved stability under microscope illumination. The key step in the synthesis of 1 and its analogues was the asymmetric hydroxylation of the quinolone intermediate 3 using the Davis oxaziridine methodology. The absolute stereochemistry of (-)-Blebbistatin (1) was shown to be S by X-ray crystal structure analysis of a heavy atom (bromine) containing analogue 11, which was subsequently reduced and shown to be identical to 1.

  • dissecting temporal and spatial control of cytokinesis with a myosin ii inhibitor
    Science, 2003
    Co-Authors: Aaron F. Straight, James R Sellers, John Limouze, Nicholas J Westwood, Amy Cheung, Irene A Chen, Timothy J Mitchison
    Abstract:

    Completion of cell division during cytokinesis requires temporally and spatially regulated communication from the microtubule cytoskeleton to the actin cytoskeleton and the cell membrane. We identified a specific inhibitor of nonmuscle myosin II, Blebbistatin, that inhibited contraction of the cleavage furrow without disrupting mitosis or contractile ring assembly. Using Blebbistatin and other drugs, we showed that exit from the cytokinetic phase of the cell cycle depends on ubiquitin-mediated proteolysis. Continuous signals from microtubules are required to maintain the position of the cleavage furrow, and these signals control the localization of myosin II independently of other furrow components.

James R Sellers - One of the best experts on this subject based on the ideXlab platform.

  • the small molecule tool s Blebbistatin novel insights of relevance to myosin inhibitor design
    Organic and Biomolecular Chemistry, 2008
    Co-Authors: Cristina Lucaslopez, James R Sellers, John S Allingham, Tomas Lebl, Christopher P A T Lawson, Ruth Brenk, Ivan Rayment, Nicholas J Westwood
    Abstract:

    The small molecule Blebbistatin is now a front line tool in the study of myosin function. Chemical modification of the tricyclic core of Blebbistatin could deliver the next generation of myosin inhibitors and to help address this we report here on the impact of structural changes in the methyl-substituted aromatic ring of Blebbistatin on its biological activity. Chemical methods for the preparation of isomeric methyl-containing analogues are reported and a series of co-crystal structures are used to rationalise the observed variations in their biological activity. These studies further support the view that the previously identified binding mode of Blebbistatin to Dictyostelium discoideum myosin II is of relevance to its mode of action. A discussion of the role that these observations have on planning the synthesis of focused libraries of Blebbistatin analogues is also provided including an assessment of possibilities by computational methods. These studies are ultimately directed at the development of novel myosin inhibitors with improved affinity and different selectivity profiles from Blebbistatin itself.

  • absolute stereochemical assignment and fluorescence tuning of the small molecule tool Blebbistatin
    ChemInform, 2005
    Co-Authors: Cristina Lucaslopez, James R Sellers, Aaron F. Straight, Judit Toth, Timothy J Mitchison, Stephen Patterson, Till Blum, Alexandra M Z Slawin, Nicholas J Westwood
    Abstract:

    (-)-Blebbistatin (1), a recently discovered small molecule inhibitor of the ATPase activity of non-muscle myosin II has been prepared from methyl 5-methylanthranilate (6) in three steps. This flexible synthetic route has also been used to prepare a nitro group-containing analogue 12 that has modified fluorescence properties and improved stability under microscope illumination. The key step in the synthesis of 1 and its analogues was the asymmetric hydroxylation of the quinolone intermediate 3 using the Davis oxaziridine methodology. The absolute stereochemistry of (-)-Blebbistatin (1) was shown to be S by X-ray crystal structure analysis of a heavy atom (bromine) containing analogue 11, which was subsequently reduced and shown to be identical to 1.

  • Blebbistatin a myosin ii inhibitor is photoinactivated by blue light
    Biochemistry, 2005
    Co-Authors: Takeshi Sakamoto, John Limouze, Christian A Combs, And Aaron F Straight, James R Sellers
    Abstract:

    Blebbistatin is a small molecule inhibitor discovered in a screen for inhibitors of nonmuscle myosin IIA. Blebbistatin inhibits the actin-activated MgATPase activity and in vitro motility of class II myosins. In cells, it has been shown to inhibit contraction of the cytokinetic ring. Blebbistatin has some photochemical properties that may affect its behavior in cells. In particular, we have found that exposure to light at wavelengths below 488 nm rapidly inactivates the inhibitory action of Blebbistatin using the in vitro motility of myosin as an assay. In addition, the inhibition of cytokinetic ring contraction can be reversed by exposure of the cells to blue light. This property may be useful in locally reversing the action of Blebbistatin treatment in a cell. However, caution should be exercised as free radicals may be produced upon irradiation of Blebbistatin that could result in cell damage.

  • mechanism of Blebbistatin inhibition of myosin ii
    Journal of Biological Chemistry, 2004
    Co-Authors: Mihály Kovács, Judit Toth, Csaba Hetenyi, Andras Malnasicsizmadia, James R Sellers
    Abstract:

    Blebbistatin is a recently discovered small molecule inhibitor showing high affinity and selectivity toward myosin II. Here we report a detailed investigation of its mechanism of inhibition. Blebbistatin does not compete with nucleotide binding to the skeletal muscle myosin subfragment-1. The inhibitor preferentially binds to the ATPase intermediate with ADP and phosphate bound at the active site, and it slows down phosphate release. Blebbistatin interferes neither with binding of myosin to actin nor with ATP-induced actomyosin dissociation. Instead, it blocks the myosin heads in a products complex with low actin affinity. Blind docking molecular simulations indicate that the productive Blebbistatin-binding site of the myosin head is within the aqueous cavity between the nucleotide pocket and the cleft of the actin-binding interface. The property that Blebbistatin blocks myosin II in an actin-detached state makes the compound useful both in muscle physiology and in exploring the cellular function of cytoplasmic myosin II isoforms, whereas the stabilization of a specific myosin intermediate confers a great potential in structural studies.

  • Specificity of Blebbistatin, an inhibitor of myosin II
    Journal of Muscle Research & Cell Motility, 2004
    Co-Authors: John Limouze, Aaron F. Straight, Timothy Mitchison, James R Sellers
    Abstract:

    Blebbistatin is a small molecule inhibitor discovered in a screen for inhibitors of nonmuscle myosin IIA. We have examined the specificity and potency of the drug by assaying its effects on the actin-activated MgATPase assay of diverse members of the myosin superfamily. Blebbistatin potently inhibits several striated muscle myosins as well as vertebrate nonmuscle myosin IIA and IIB with IC_50 values ranging from 0.5 to 5 μM. Interestingly, smooth muscle which is highly homologous to vertebrate nonmuscle myosin is only poorly inhibited (IC_50=80 μM). The drug potently inhibits Dictyostelium myosin II, but poorly inhibits Acanthamoeba myosin II. Blebbistatin did not inhibit representative myosin superfamily members from classes I, V, and X.

Christian V Stevens - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of c ring modified Blebbistatin derivatives and evaluation of their myosin ii atpase inhibitory potency
    Bioorganic & Medicinal Chemistry Letters, 2018
    Co-Authors: Bart Roman, Sigrid Verhasselt, Christophe W Mangodt, Olivier De Wever, Christian V Stevens
    Abstract:

    (S)-Blebbistatin is a micromolar myosin II ATPase inhibitor that is extensively used in research. In search of analogs with improved potency, we have synthesized for the first time C-ring modified analogs. We introduced hydroxymethyl or allyloxymethyl functionalities in search of additional favorable interactions and a more optimal filling of the binding pocket. Unfortunately, the resulting compounds did not significantly inhibit the ATPase activity of rabbit skeletal-muscle myosin II. This and earlier reports suggest that rational design of potent myosin II inhibitors based on the architecture of the Blebbistatin binding pocket is an ineffective strategy.

  • medicinal chemistry and use of myosin ii inhibitor s Blebbistatin and its derivatives
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Bart Roman, Sigrid Verhasselt, Christian V Stevens
    Abstract:

    (S)-Blebbistatin, a chiral tetrahydropyrroloquinolinone, is a widely used and well-characterized ATPase inhibitor selective for myosin II. The central role of myosin II in many normal and pathological biological processes has been revealed with the aid of this small molecule. The first part of this manuscript provides a summary of myosin II and (S)-Blebbistatin literature from a medicinal chemist’s perspective. The second part of this perspective deals with the physicochemical deficiencies that trouble the use of (S)-Blebbistatin in advanced biological settings: low potency and solubility, fluorescence interference, (photo)toxicity, and stability issues. A large toolbox of analogues has been developed in which particular shortcomings have been addressed. This perspective provides a necessary overview of these developments and presents guidelines for selecting the best available analogue for a given application. As the unmet need for high-potency analogues remains, we also propose starting points for medic...

  • Data_Sheet_1_Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin.PDF
    2018
    Co-Authors: Bart I. Roman, Christian V Stevens, Rita C. Guedes, Alfonso T. García-sosa
    Abstract:

    In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of (S)-Blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof. Standard and augmented structure-based design techniques could not recover the observed activity profiles. A ligand-based method using molecular fingerprints was, however, able to select actives for myosin II inhibition. Using further ligand- and structure-based methods, we also evaluated toxicity through androgen receptor binding, affinity for an array of antitargets and the ADME profile (including assay-interfering compounds) of the series. In conclusion, in the search for (S)-Blebbistatin analogs, the dissimilarity distance of molecular fingerprints to known actives and the computed antitarget and physicochemical profile of the molecules can be used for compound design for molecules with potential as tools for modulating myosin II and motility-related diseases.

  • improved synthesis and comparative analysis of the tool properties of new and existing d ring modified s Blebbistatin analogs
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Sigrid Verhasselt, Bart Roman, Marc Bracke, Christian V Stevens
    Abstract:

    (S)-Blebbistatin is a widely used research tool to study myosin II, an important regulator of many motility based diseases. Its potency is too low to be of clinical relevance, but identification of analogs with enhanced potency could deliver leads for targeted pharmacotherapeutics. This, however, requires a profound insight into the structure-activity relationship of the (S)-Blebbistatin scaffold. Therefore, new D-ring modified (S)-Blebbistatin derivatives were prepared to extend the existing small library of analogs. These molecules were obtained via an improved synthesis pathway and their myosin II inhibitory properties were evaluated in vitro. Finally, all new and known D-ring modified (S)-Blebbistatin analogs were compared and the most potent ones underwent a screening of their physicochemical properties.

  • insights into the myosin ii inhibitory potency of a ring modified s Blebbistatin analogs
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Sigrid Verhasselt, Marc Bracke, Christian V Stevens, Tom Van Den Broecke, Bart Roman
    Abstract:

    Myosin II is an interesting target for therapeutic intervention, as it is involved in a large number of motility-based diseases. (S)-Blebbistatin is a known micromolar inhibitor of this protein. A new series of (S)-Blebbistatin derivatives with a modified A-ring was synthesized and the myosin II inhibitory properties were evaluated in vitro. In this way, we gained insight into the influence of structural modifications in this part of the scaffold on myosin II inhibitory potency. Our results indicate there are few possibilities for potency enhancement via ring A modification of the Blebbistatin scaffold.