Design, Synthesis, and Structure—Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C.

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

doi:10.1002/chin.200438115

Cited by 3 publications

(4 citation statements)

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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: 99%

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: 99%

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Nowak¹

2007

CTMC

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“…Alternatively, a Core might be designed based on physiological ligands or substrates. 9 Such a Core could be further optimized, if necessary (Figure 1C). Diversity structures could be selected randomly or could include structures expected to modulate the target activity and selectivity.…”

Section: Introductionmentioning

confidence: 99%

“…The Core could be simply extracted from a lead compound based on the structure of a cocrystal with the target protein, if available, or could be based on preliminary structure–activity relationship (SAR) data on a limited number of derivatives. Alternatively, a Core might be designed based on physiological ligands or substrates . Such a Core could be further optimized, if necessary (Figure C).…”

Section: Introductionmentioning

confidence: 99%

Focused Library with a Core Structure Extracted from Natural Products and Modified: Application to Phosphatase Inhibitors and Several Biochemical Findings

Hirai

Sodeoka

2015

Acc. Chem. Res.

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Synthesis of a focused library is an important strategy to create novel modulators of specific classes of proteins. Compounds in a focused library are composed of a common core structure and different diversity structures. In this Account, we describe our design and synthesis of libraries focused on selective inhibitors of protein phosphatases (PPases). We considered that core structures having structural and electronic features similar to those of PPase substrates, phosphate esters, would be a reasonable choice. Therefore, we extracted core structures from natural products already identified as PPase inhibitors. Since many PPases share similar active-site structures, such phosphate-mimicking core structures should interact with many enzymes in the same family, and therefore the choice of diversity structures is pivotal both to increase the binding affinity and to achieve specificity for individual enzymes. Here we present case studies of application of focused libraries to obtain PPase inhibitors, covering the overall process from selection of core structures to identification and evaluation of candidates in the focused libraries. To synthesize a library focused on protein serine-threonine phosphatases (PPs), we chose norcantharidin as a core structure, because norcantharidin dicarboxylate shows a broad inhibition profile toward several PPs. From the resulting focused library, we identified a highly selective PP2B inhibitor, NCA-01. On the other hand, to find inhibitors of dual-specificity protein phosphatases (DSPs), we chose 3-acyltetronic acid extracted from natural product RK-682 as a core structure, because its structure resembles the transition state in the dephosphorylation reaction of DSPs. However, a highly selective inhibitor was not found in the resulting focused library. Furthermore, an inherent drawback of compounds having the highly acidic 3-acyltetronic acid as a core structure is very weak potency in cellulo, probably due to poor cell membrane permeability. Therefore, we next modified the core structure from acidic to neutral by transformation to the enamine derivative and constructed a second-generation focused library (RE derivatives). The resulting compounds showed dramatically improved cell membrane permeability and inhibitory selectivity and included VHR (vaccinia VH1-related)-selective RE12 and CDC25A/B (cell division cycle 25A/B)-selective RE44. These inhibitors act on target enzymes in cellulo and do not generate reactive oxygen species, which is a potential problem with quinoid-type inhibitors of CDC25s. The cellular activity of RE12 was further improved by replacement of the side chain to afford RE176, which showed more potent antiproliferative activity than RE12 against HeLa cells. The dramatic change of inhibitory selectivity obtained by core structure modification from 3-acyltetronic acid to its enamine derivative was associated with a change in the mode of action. Namely, RE derivatives were found to be noncompetitive inhibitors with respect to a small-molecular substrate of CDC25A/...

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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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Design, Synthesis, and Structure—Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C.

Cited by 3 publications

References 1 publication

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Probing the Membrane Targeting C1 Subdomains of PKC with Bivalent Ligands

Focused Library with a Core Structure Extracted from Natural Products and Modified: Application to Phosphatase Inhibitors and Several Biochemical Findings

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

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