Synthesis of anilino-monoindolylmaleimides as potent and selective PKCβ inhibitors

Tanaka, Masahiro; Sagawa, Shoichi; Hoshi, Jun‐ichi; Shimoma, Fumito; Matsuda, Isamu; Sakoda, Kenji; Sasase, Tomohiko; Shindo, Masanori; Inaba, Takashi

doi:10.1016/j.bmcl.2004.07.061

Cited by 58 publications

(46 citation statements)

References 16 publications

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“…Where cells exhibiting oscillations were first treated with either 300 nM Gö6976 or 500 nM PKC␤ inhibitor, conversion from oscillatory to sustained Ca 2ϩ i mobilization was observed in 40.1 and 27.5%, respectively, of the cells sensitive to subsequent GF109203X treatment. This concentration of PKC␤ inhibitor should also inhibit PKC␣ and PKC␥, whereas no change in the Ca 2ϩ i oscillations were seen in response to 50 nM PKC␤ inhibitor that should be selective for that isozyme (15).…”

Section: Carmentioning

confidence: 99%

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Protein Kinase C-mediated Phosphorylation of the Calcium-sensing Receptor Is Stimulated by Receptor Activation and Attenuated by Calyculin-sensitive Phosphatase Activity

Davies

Ozawa

McCormick

et al. 2007

Journal of Biological Chemistry

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The agonist sensitivity of the calcium-sensing receptor (CaR) can be altered by protein kinase C (PKC), with CaR residue Thr 888 contributing significantly to this effect. To determine whether CaR T888 is a substrate for PKC and whether receptor activation modulates such phosphorylation, a phospho-specific antibody against this residue was raised (CaR pT888 mobilization rather than oscillations (9). Whereas this suggests that PKC-mediated CaR phosphorylation regulates CaR function, no reagents have existed previously for investigating CaR phosphorylation directly. Thus, we have developed a phospho-specific antibody that recognizes the phosphorylated form of CaR T888 , this residue being chosen because its mutation elicited the greatest effect on CaR function of the putative PKC sites. EXPERIMENTAL PROCEDURESMaterials-The calcimimetics NPS R-467 and S-467 and the calcilytic NPS-89636 were a kind gift of Dr. E. F. Nemeth and NPS Pharmaceuticals, Inc. (Toronto, Canada). Fura-2/AM was from Invitrogen and Gö6976, PKC␤-selective inhibitor (anilinomonoindolylmaleimide), and endothall thioanhydride (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid) were from Calbiochem (EMD Biosciences, Inc., San Diego, CA). Horseradish peroxidase-conjugated anti-mouse and anti-rabbit secondary antibodies were from DakoCytomation (Ely, Cambridgeshire, UK). Unless stated otherwise, all other chemicals were purchased from Sigma.Cell Culture-HEK293 cells, stably transfected with human parathyroid CaR (6), were a gift from Dr. E. F. Nemeth (NPS Pharmaceuticals). Cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal * This work was supported in part by Biotechnology and Biological Sciences Research Council Grant BBSB04986. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Section: Carmentioning

confidence: 99%

“…Ca 2ϩ -dependent)-selective inhibitors namely Gö6976 and an anilinomonoindolylmaleimide ␤-selective PKC inhibitor (15). Addition of GF109203X to cells exhibiting Ca 2ϩ i oscillations produces sustained responses in most (Ն80%) of the cells (Fig.…”

Section: Carmentioning

confidence: 99%

Protein Kinase C-mediated Phosphorylation of the Calcium-sensing Receptor Is Stimulated by Receptor Activation and Attenuated by Calyculin-sensitive Phosphatase Activity

Davies

Ozawa

McCormick

et al. 2007

Journal of Biological Chemistry

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“…Sergheraert et al reported that PKC selectivity is promoted by the addition of amine substituents on the maleimide ring. [17] Thus, various polyamine-linked-, [17,18] alkylamino-, [19] arylalkylamino-, [20] anilinoindolylmaleimides, [21] indolylimidazolylmaleimides [6a,22] (e.g. didemnimides) and indolopyrrolemaleimides [7a,7d,7f,23] have been synthesized.…”

Section: Resultsmentioning

confidence: 99%

Catalytic and Stoichiometric Synthesis of Novel 3‐Aminocarbonyl‐, 3‐Alkoxycarbonyl‐, and 3‐Amino‐4‐indolylmaleimides

et al. 2008

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Novel nonsymmetrically substituted 4‐indolylmaleimides have been synthesized via palladium‐catalyzed alkoxy‐ and aminocarbonylation of 3‐bromo‐1‐methyl‐4‐(2‐methyl‐3‐indolyl)maleimide (1) with alcohols and amines in the presence of carbon monoxide. The resulting carboxamide derivatives represent a new class of potentially bioactive compounds. In addition, the direct amination reaction of 1 proceeded smoothly in the absence of catalyst and gave the desired 3‐amino‐4‐indolylmaleimides in good yields.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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“…Treatment of indole-3-acetamide with dimethyl oxalate under basic conditions provided 3-hydroxymaleimide 9. [10,11] Subsequent reaction with the same subset of amines employed for libraries 2 and 3, in refluxing aqueous acetic acid (AcOH), [11] furnished maleimidebridged analogues 4 a-d. However, none of these compounds displayed any efficacy in the SMB assay, underlining the importance of the glyoxylamide moiety to the potent antiprion activity of lead series 1.…”

Section: Modifications To the Glyoxylamide Substructurementioning

confidence: 99%

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

et al. 2010

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Structure-activity relationships within the indole-3-glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC₅₀ <10 nM). After examining a range of substituents at the para-position of the N-phenylglyoxylamide moiety, five-membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie-infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole-3-glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.

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Synthesis of anilino-monoindolylmaleimides as potent and selective PKCβ inhibitors

Cited by 58 publications

References 16 publications

Protein Kinase C-mediated Phosphorylation of the Calcium-sensing Receptor Is Stimulated by Receptor Activation and Attenuated by Calyculin-sensitive Phosphatase Activity

Protein Kinase C-mediated Phosphorylation of the Calcium-sensing Receptor Is Stimulated by Receptor Activation and Attenuated by Calyculin-sensitive Phosphatase Activity

Catalytic and Stoichiometric Synthesis of Novel 3‐Aminocarbonyl‐, 3‐Alkoxycarbonyl‐, and 3‐Amino‐4‐indolylmaleimides

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

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