scholarly journals Design, Synthesis and Characterization of Novel sn-1 Heterocyclic DAGlactones as PKCe Activators

2020 ◽  
Author(s):  
Eleonora Elhalem ◽  
Ana Bellomo ◽  
Mariana Cooke ◽  
Antonella Scravaglieri ◽  
Larry V. Pearce ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Synthesis And Characterization ◽  
Design Synthesis ◽  
Kinase C ◽  
Cytoskeleton Reorganization ◽  
C1 Domain ◽  
Ester Moiety ◽  
Labile Group ◽  
C1 Domains

<p>In this study we describe the synthesis and characterization of novel diacylglycerol (DAG)-lactones that bind to protein kinase C (PKC). DAG-lactones proved to be useful templates for the design of potent and selective C1 domain ligands. The ester moiety at <i>sn-1</i> position, a common feature in this template, is relevant for interaction with the PKC C1 domains, although it represents a labile group susceptible to endogenous esterases. Our studies identified the DAG-lactone 10B12 with an isozazole ring as a nanomolar affinity PKC ligand. This compound shows preferential selectivity for PKCepsilon, and strongly activates actin cytoskeleton reorganization into peripheral ruffles in cancer cells, an effect mediated by PKCepsilon. Therefore, introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC selectivity.</p><div><br></div>

scholarly journals Design, Synthesis and Characterization of Novel sn-1 Heterocyclic DAGlactones as PKCe Activators

2020 ◽  
Author(s):  
Eleonora Elhalem ◽  
Ana Bellomo ◽  
Mariana Cooke ◽  
Antonella Scravaglieri ◽  
Larry V. Pearce ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Synthesis And Characterization ◽  
Design Synthesis ◽  
Kinase C ◽  
Cytoskeleton Reorganization ◽  
C1 Domain ◽  
Ester Moiety ◽  
Labile Group ◽  
C1 Domains

<p>In this study we describe the synthesis and characterization of novel diacylglycerol (DAG)-lactones that bind to protein kinase C (PKC). DAG-lactones proved to be useful templates for the design of potent and selective C1 domain ligands. The ester moiety at <i>sn-1</i> position, a common feature in this template, is relevant for interaction with the PKC C1 domains, although it represents a labile group susceptible to endogenous esterases. Our studies identified the DAG-lactone 10B12 with an isozazole ring as a nanomolar affinity PKC ligand. This compound shows preferential selectivity for PKCepsilon, and strongly activates actin cytoskeleton reorganization into peripheral ruffles in cancer cells, an effect mediated by PKCepsilon. Therefore, introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC selectivity.</p><div><br></div>

scholarly journals Design, Synthesis, and Biological Activity of Isophthalic Acid Derivatives Targeted to the C1 Domain of Protein Kinase C

2009 ◽  
Vol 52 (13) ◽  
pp. 3969-3981 ◽  
Author(s):  
Gustav Boije af Gennäs ◽  
Virpi Talman ◽  
Olli Aitio ◽  
Elina Ekokoski ◽  
Moshe Finel ◽  
...  
Keyword(s):  
Biological Activity ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Isophthalic Acid ◽  
Design Synthesis ◽  
Kinase C ◽  
C1 Domain

Synthesis and Characterization of New Photolabile Phorbol Esters for Affinity Labeling of Protein Kinase C

1996 ◽  
Vol 61 (6) ◽  
pp. 2164-2173 ◽  
Author(s):  
Kazuhiro Irie ◽  
Takashi Ishii ◽  
Hajime Ohigashi ◽  
Paul A. Wender ◽  
Benjamin L. Miller ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
Synthesis And Characterization ◽  
Affinity Labeling ◽  
Kinase C

scholarly journals p23/Tmp21 Differentially Targets the Rac-GAP β2-Chimaerin and Protein Kinase C via Their C1 Domains

2010 ◽  
Vol 21 (8) ◽  
pp. 1398-1408 ◽  
Author(s):  
HongBin Wang ◽  
Marcelo G. Kazanietz
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Interactions ◽  
Phorbol Esters ◽  
Lipid Binding ◽  
Kinase C ◽  
C1 Domain ◽  
Pkc Isozymes ◽  
Domain Docking ◽  
C1 Domains

The C1 domains in protein kinase C (PKC) isozymes and other signaling molecules are responsible for binding the lipid second messenger diacylglycerol and phorbol esters, and for mediating translocation to membranes. Previous studies revealed that the C1 domain in α- and β-chimaerins, diacylglycerol-regulated Rac-GAPs, interacts with the endoplasmic reticulum/Golgi protein p23/Tmp21. Here, we found that p23/Tmp21 acts as a C1 domain-docking protein that mediates perinuclear translocation of β2-chimaerin. Glu227 and Leu248 in the β2-chimaerin C1 domain are crucial for binding p23/Tmp21 and perinuclear targeting. Interestingly, isolated C1 domains from individual PKC isozymes differentially interact with p23/Tmp21. For PKCε, it interacts with p23/Tmp21 specifically via its C1b domain; however, this association is lost in response to phorbol esters. These results demonstrate that p23/Tmp21 acts as an anchor that distinctively modulates compartmentalization of C1 domain-containing proteins, and it plays an essential role in β2-chimaerin relocalization. Our study also highlights the relevance of C1 domains in protein–protein interactions in addition to their well-established lipid-binding properties.

Elucidating the interaction of γ-hydroxymethyl-γ-butyrolactone substituents with model membranes and protein kinase C–C1 domains

2015 ◽  
Vol 11 (5) ◽  
pp. 1389-1399
Author(s):  
Rituparna Borah ◽  
Narsimha Mamidi ◽  
Subhankar Panda ◽  
Sukhamoy Gorai ◽  
Suraj Kumar Pathak ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Small Molecule ◽  
Model Membranes ◽  
Endogenous Ligand ◽  
Kinase C ◽  
C1 Domain ◽  
C1 Domains

Investigation of γ-hydroxymethyl-γ-butyrolactone substituents as protein kinase C ligands, in an effort to develop small molecule-based regulators with higher specificity for C1 domain than the endogenous ligand, diacylglycerols.

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