Evaluation of series of isobenzofuranone dimers as PKCα ligands: implication for the distance between the two ligand binding sites

Baba, Yoshiyasu; Mayumi, Satoshi; Hirai, Go; Kawasaki, Hidekazu; Ogoshi, Yosuke; Yanagisawa, Takeshi; Hashimoto, Yuichi; Sodeoka, Mikiko

doi:10.1016/j.bmcl.2004.02.098

Cited by 10 publications

(3 citation statements)

References 11 publications

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“…Baba et al designed new isobenzofuranone template for PKC ligands retaining the same binding motifs as DAG (Fig. 4) [41,42]. The presence of a benzene ring delivered considerable scope for modification and was regarded as an asset in the development of isozyme-selective analogs.…”

Section: Design Of Bivalent Ligandsmentioning

confidence: 98%

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Nowak¹

2007

CTMC

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Protein kinase C is a family of ubiquitously expressed signal transducing proteins. The hallmark for PKC activation is its translocation to membranes following generation of lipid second messengers. This process is mediated by C1 and C2 membrane-targeting modules, whose engagement on membranes provides energy for a conformational change crucial to PKC activity. Novel and conventional subfamilies of PKC have two C1 domains, namely C1A and C1B, each of which contain a binding pocket for a messenger. Several studies addressed the issue of simultaneous activation of both C1 domains by specifically designed bivalent activators based on phorbol esters, benzolactam and other PKC ligands. Many bivalent ligands displayed 1-2 orders of magnitude higher potency then their monovalent congeners. Most effective were the "dimeric" ligands linked with 10-14 carbon spacers. Lower than predicted potency and lack of marked isoform selectivity indicate that those compounds do not activate both C1 domains at the same time, or that process is unfavored due to steric or conformational reasons. However, high binding affinity for some of them provides hope that related PKC activators that are isoform selective can be developed. As to the nature of the linkers: flexible and lipophilic oligomethylene chains proved superior over flexible and hydrophilic oligoethylene glycol or rigid and lipophilic benzene in recruiting PKC to the membranes.

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Section: Design Of Bivalent Ligandsmentioning

confidence: 98%

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Nowak¹

2007

CTMC

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“…To date, several bivalent PKC ligands based on naphthylpyrrolidone, phorbol ester, , and isobenzofuranone have been synthesized and evaluated for their PKC binding and membrane interaction. In no case has there been substantial capture of enhanced affinity suggestive of the simultaneous binding to both C1 domains.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol–Lactones as Protein Kinase C Ligands

et al. 2017

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Protein kinase C (PKC) mediates a central cellular signal transduction pathway involved in disorders such as cancer and Alzheimer's disease. PKC is regulated by binding of the second messenger sn-1,2-diacylglycerol (DAG) to its tandem C1 domains, designated C1a and C1b, leading both to PKC activation and to its translocation to the plasma membrane and to internal organelles. Depending on the isoform, there may be differences in the ligand selectivity of the C1a and C1b domains, and there is different spacing between the C1 domains of the conventional and novel PKCs. Bivalent ligands have the potential to exploit these differences between isoforms, yielding isoform selectivity. In the present study, we describe the synthesis of a series of dimeric derivatives of conformationally constrained diacylglycerol (DAG) analogs (DAG-lactones). We characterize the derivatives in vitro for their binding affinities, both to a single C1 domain (the C1b domain of PKCδ) as well as to the conventional PKCα isoform and the novel PKCδ isoform, and we measure their abilities to cause translocation of PKCδ and PKCε in intact cells. The dimeric compound with the 10-carbon linker was modestly more effective for the isolated PKCδ C1b domain than was the monomeric compound. For the intact PKCα and PKCδ, the shortest DAG-lactone dimer had similar affinity to the monomer and affinity decreased progressively up to the 16-carbon linker. The dimeric derivatives did not cause the Golgi accumulation of PKCδ. The present results provide important insights into the development of new chemical tools for biological studies on PKC.

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“…These responses regulate numerous cellular processes, , including proliferation, differentiation, migration, and apoptosis. , Membrane translocation of PKC is caused by binding of ligands to the C1b domain and has been recognized as an important phenomenon in signal transduction because the localization of PKC is key in determining isozyme-specific functions by defining binding partners for downstream signaling . Despite the complex regulatory mechanisms of PKC activation, considerable progress has been made in understanding isozyme-specific functions and several ligands with high specificity for PKC isozymes have been developed as potential drugs. − Through the development of DAG-lactones, whose design is based on the endogenous ligand DAG, the importance of maintaining intact the pharmacophore triad of two carbonyl groups ( sn -1 and sn -2) and the primary alcohol has been established as a requirement in high affinity ligands for PKC (Figure ) . Various PKC ligands have been synthesized and found to be inhibitors of tumor promotion or of other diseases.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence-Quenching Screening of Protein Kinase C Ligands with an Environmentally Sensitive Fluorophore

et al. 2011

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A novel fluorescence-quenching screening method for protein kinase C (PKC) ligands was developed utilizing solvatochromic fluorophores. Solvatochromic dyes, highly sensitive to the presence or the absence of competitive ligands in their binding to the C1b domain of PKCδ (δC1b), were combined with a known pharmacophoric moiety of 1,2-diacylglycerol (DAG) lactones, PKC ligands. Addition of δC1b to the fluorescent compounds caused a gradual increase in the fluorescent intensity in proportion to the increase of δC1b. As a competitive ligand was added to the complex of δC1b domain and fluorescent compounds, a gradual decrease in the fluorescent intensity was observed. The relative binding affinities of known ligands were successfully determined by this fluorescent method and corresponded well to the K(i) values measured by a radioisotope method. These results indicate that washing, which is a laborious step in binding evaluations, is not required for this environmentally sensitive fluorophore based system. Screening with the system was performed for 2560 preselected library compounds with possible pharmacophores, and some lead compounds were found. This fluorescence-based method could be applied widely to known ligand-receptor combinations.

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Evaluation of series of isobenzofuranone dimers as PKCα ligands: implication for the distance between the two ligand binding sites

Cited by 10 publications

References 11 publications

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol–Lactones as Protein Kinase C Ligands

Fluorescence-Quenching Screening of Protein Kinase C Ligands with an Environmentally Sensitive Fluorophore

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