A dendrimer with a Ru(bpy)(3)(2+) (bpy = 2,2'-bipyridine) complex as a core and four diphenylanthracene units at the periphery was prepared from a scaffold based on a bipyridyl ligand bearing four ...terminal alkyne groups. Upon green light excitation, the dendrimer shows blue luminescence even in a rigid matrix at 77 K thanks to the dendritic multichromophoric structure.
Triazole‐containing Arg‐Gly‐Asp (RGD) peptidomimetics capable of interacting with αvβ3 integrin were developed through click chemistry. The role of the diverse range of guanidine bioisosteres for the ...arginine mimetic moiety was evaluated in vitro together with different appendages on the aspartic acid side of the peptidomimetic. The corresponding azides and alkynes were constructed through the application of simple modular reactions. Integrin binding assays allowed the best guanidine bioisostere for binding activity to be selected; the aromatic ring at the azide fragment bearing the aspartic acid moiety proved to be unnecessary. Molecular modelling calculations of a hit compound showed that the triazole and 2‐aminopyridine rings were involved in important π‐stacking interactions with Tyr178.
Click chemistry was used to build a series of nonpeptide Arg‐Gly‐Asp (RGD) peptidomimetics. Integrin binding assays revealed heterocyclic guanidine bioisosteres that showed binding activity and also indicated a minor role played by the aromatics on the azide fragment. Modelling showed that the triazole and 2‐aminopyridine rings interact with Tyr178 of αvβ3 integrin.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor beta 1 (TGF beta 1) play a central role. When ...exposed to TGF beta 1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of alpha v integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGF beta 1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with alpha v beta 3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGF beta 1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGF beta 1, and reduces both ALK5/TGF beta 1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing alpha -smooth muscle actin ( alpha -SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed ...to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Triazole-containing Arg-Gly-Asp (RGD) peptidomimetics capable of interacting with alphavbeta3 integrin were developed through click chemistry. The role of the diverse range of guanidine bioisosteres ...for the arginine mimetic moiety was evaluated in vitro together with different appendages on the aspartic acid side of the peptidomimetic. The corresponding azides and alkynes were constructed through the application of simple modular reactions. Integrin binding assays allowed the best guanidine bioisostere for binding activity to be selected; the aromatic ring at the azide fragment bearing the aspartic acid moiety proved to be unnecessary. Molecular modelling calculations of a hit compound showed that the triazole and 2-aminopyridine rings were involved in important π-stacking interactions with Tyr178.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Triazole‐containing Arg‐Gly‐Asp (RGD) peptidomimetics capable of interacting with α
v
β
3
integrin were developed through click chemistry. The role of the diverse range of guanidine ...bioisosteres for the arginine mimetic moiety was evaluated in vitro together with different appendages on the aspartic acid side of the peptidomimetic. The corresponding azides and alkynes were constructed through the application of simple modular reactions. Integrin binding assays allowed the best guanidine bioisostere for binding activity to be selected; the aromatic ring at the azide fragment bearing the aspartic acid moiety proved to be unnecessary. Molecular modelling calculations of a hit compound showed that the triazole and 2‐aminopyridine rings were involved in important π‐stacking interactions with Tyr178.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Fragment-based drug discovery is a valuable tool in hit identification, as well as the combination of different small fragments showing a minimal binding activity against biological receptors or ...enzymes to give merged hits. A high number of fragments on the same scaffold improve the probability to find a candidate showing single- or multi-target affinities. A rapid and versatile approach for synthesizing libraries of densely fragment-functionalized scaffolds is reported. Many fragments were assembled in few steps around a triazole ring starting from amino alcohols and other readily available building blocks. A binding assay against integrin αvβ3 was used as a test-bed in order to demonstrate the potential of such an approach in hit discovery strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor beta1 (TGFbeta1) play a central role. When ...exposed to TGFbeta1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of alphav integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFbeta1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with alphavbeta3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFbeta1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFbeta1, and reduces both ALK5/TGFbeta1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing alpha-smooth muscle actin (alpha-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pyrene‐Excimers‐Based Antenna Systems Cicchi, Stefano; Fabbrizzi, Pierangelo; Ghini, Giacomo ...
Chemistry : a European journal,
January 5, 2009, Volume:
15, Issue:
3
Journal Article
Peer reviewed
A series of dendrimeric compounds bearing pyrene units were synthesized to afford light‐harvesting antennae based on the formation of intramolecular excimers. The synthetic plan profited from the ...efficiency of the Huisgen reaction, the 1,3‐dipolar cycloaddition of azides and terminal alkynes, which allowed ready assembly of the different building blocks. The three molecular antennae obtained, of increasing generation, revealed efficient energy transfer both in solution and in the solid state.
Molecular antennae: A series of dendrimeric compounds bearing pyrene units synthesized through the Huisgen reaction afford light‐harvesting antennae based on the formation of intramolecular excimers (see picture). Three very efficient energy‐transfer multi‐emissive systems are obtained, one of which shows interesting, well‐balanced emissions in deep‐blue, blue‐green, and red.
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