|
| ||
|
|
||
Central Scaffold (central + scaffold)
Selected AbstractsSecond-Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X-Ray Crystal-Structure AnalysisHELVETICA CHIMICA ACTA, Issue 4 2005Stefan Sahli A new class of nonpeptidic inhibitors of the ZnII -dependent metalloprotease neprilysin with IC50 values in the nanomolar activity range (0.034,0.30,,M) were developed based on structure-based de novo design (Figs.,1 and 2). The inhibitors feature benzimidazole and imidazo[4,5- c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable , - , stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the ZnII ion and an aryl residue to occupy the hydrophobic S1, pocket, but lack a substituent for binding in the S2, pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)- 1, (+)- 2, (+)- 25, and (+)- 26 were accomplished using Evans auxiliaries (Schemes,2, 4, and 5). The inhibitors (+)- 2 and (+)- 26 with an imidazo[4,5- c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)- 1 and (+)- 25) (Table,1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with (+)- 2 at 2.25-Å resolution (Fig.,4 and Table,2). The ligand coordinates with its sulfanyl residue to the ZnII ion, and the benzyl residue occupies the S1, pocket. The 1H -imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes ,-, stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazo-pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1, pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors. [source] Photophysical and self-assembly behavior of poly(amidoamine) dendrons with chromophore as scaffold: The effect of dendritic architectureJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 13 2008Bing-Bing Wang Abstract Two series of amphiphiles composed of hydrophilic poly(amidoamine) dendrons (from the first to the third generation) as the shell and hydrophobic aromatic chromophores (3,6-di(maleimidyl)-9-phenyl carbazole and 9-(4,-maleimidyl phenyl)-3-maleimidyl carbazole) as the central scaffold were synthesized. The effect of dendritic architecture on the photophysical properties and the self-assembly behavior of these amphiphiles were studied by UV,vis absorption spectroscopy, fluorescence spectroscopy, and transmission electron microscopy (TEM) measurements. Both the generation of dendritic shell and the location of dendrons at the chromophoric scaffold had great effect on the photophysical properties of these amphiphiles. In addition, different spherical aggregates were formed from these amphiphiles in the aqueous solution at different concentrations. Because of the combined effects of steric hindrance and architecture of dendritic shells, the amphiphiles from G2 dendron with central chromophore self-organized into ordered aggregates more readily than that from G1 and G3. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4584,4593, 2008 [source] A Multimeric Quinacrine Conjugate as a Potential Inhibitor of Alzheimer's ,-Amyloid Fibril FormationCHEMBIOCHEM, Issue 6 2008Gunnar T. Dolphin Abstract Amyloid formation and accumulation of the amyloid ,-peptide (A,) in the brain is associated with Alzheimer's disease (AD) pathogenesis. Therefore, among the therapeutic approaches in development to fight the disease, the direct inhibition of the A, self-assembly process is currently widely investigated and is one of the most promising approaches. In this study we investigated the potential of a multimeric display of quinacrine derivatives, as compared to the monomer quinacrine, as a design principal for a novel class of inhibitors against A, fibril formation. The presented multimeric conjugate exhibits a cluster of four quinacrine derivatives on a rigid cyclopeptidic scaffold. Herein is reported the synthesis of the conjugate, together with the in vitro inhibitory evaluation of A,1,40 fibrils using the thioflavin T fluorescence assay, and imaging with atomic force microscopy. Our data show that the multimeric compound inhibits A,1,40 fibril formation with an IC50 value of 20±10 ,M, which contrasts with the nonactive monomeric analogue. This work suggests that assembling multiple copies of acridine moieties to a central scaffold, for multiple interactions, is a promising strategy for the engineering of inhibitors against A, fibril formation. [source] Second-Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X-Ray Crystal-Structure AnalysisHELVETICA CHIMICA ACTA, Issue 4 2005Stefan Sahli A new class of nonpeptidic inhibitors of the ZnII -dependent metalloprotease neprilysin with IC50 values in the nanomolar activity range (0.034,0.30,,M) were developed based on structure-based de novo design (Figs.,1 and 2). The inhibitors feature benzimidazole and imidazo[4,5- c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable , - , stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the ZnII ion and an aryl residue to occupy the hydrophobic S1, pocket, but lack a substituent for binding in the S2, pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)- 1, (+)- 2, (+)- 25, and (+)- 26 were accomplished using Evans auxiliaries (Schemes,2, 4, and 5). The inhibitors (+)- 2 and (+)- 26 with an imidazo[4,5- c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)- 1 and (+)- 25) (Table,1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with (+)- 2 at 2.25-Å resolution (Fig.,4 and Table,2). The ligand coordinates with its sulfanyl residue to the ZnII ion, and the benzyl residue occupies the S1, pocket. The 1H -imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes ,-, stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazo-pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1, pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors. [source] | ||||||||||