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Micromolar Inhibitors (micromolar + inhibitor)

Distribution by Scientific Domains

Chemistry	83%

Selected Abstracts

Synthesis of Monosaccharide-Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase Inhibitors

HELVETICA CHIMICA ACTA, Issue 9 2003
Christian Blüchel
The glucose-, mannose-, and galactose-derived spirocyclic cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4,:,5,:,1,:,20 mixture of the ethyl cyclopropanecarboxylates 7a,7d, while the Cu-catalysed cycloaddition of ethyl diazoacetate to the exo -glycal 6 afforded 7a,7d (6,:,2,:,5,:,3) in 93,98% yield (Scheme,1). Saponification, Curtius degradation, and subsequent addition of BnOH or t- BuOH led in 60,80% overall yield to the Z- or Boc-carbamates 11a,11d and 12a,12d, respectively. Hydrogenolysis of 11a,11d afforded 1a,1d, while 12a,12d was debenzylated to 13a,13d prior to acidic cleavage of the N -Boc group. The manno - and galacto -isomers 2a,2d and 3a,3d, respectively, were similarly obtained in comparable yields (Schemes,2 and 4). Also prepared were the differentially protected manno- configured esters 24a,24d; they are intermediates for the synthesis of analogous N -acetylglucosamine-derived cyclopropanes (Scheme,3). The cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d are very weak inhibitors of several glycosidases (Tables,1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl is, indeed, a reversible, micromolar inhibitor for the ,- glucosidases from C. saccharolyticum and sweet almonds (non-competitive), the , -galactosidases from bovine liver and from E. coli (both non-competitive), the , -galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the , -glucosidase from yeast and the , -galactosidase from coffee beans. The cyclopropylamines derived from 1a,1d or 3a,3d significantly enhance the inhibition of the ,- glucosidase from C. saccharolyticum by PdCl, lowering the Ki value from 40,,M (PdCl) to 0.5,,M for a 1,:,1 mixture of PdCl and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines. [source]

Adenosine binding to low-molecular-weight purine nucleoside phosphorylase: the structural basis for recognition based on its complex with the enzyme from Schistosoma mansoni

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2010
Humberto M. Pereira
Schistosomes are unable to synthesize purines de novo and depend exclusively on the salvage pathway for their purine requirements. It has been suggested that blockage of this pathway could lead to parasite death. The enzyme purine nucleoside phosphorylase (PNP) is one of its key components and molecules designed to inhibit the low-molecular-weight (LMW) PNPs, which include both the human and schistosome enzymes, are typically analogues of the natural substrates inosine and guanosine. Here, it is shown that adenosine both binds to Schistosoma mansoni PNP and behaves as a weak micromolar inhibitor of inosine phosphorolysis. Furthermore, the first crystal structures of complexes of an LMW PNP with adenosine and adenine are reported, together with those with inosine and hypoxanthine. These are used to propose a structural explanation for the selective binding of adenosine to some LMW PNPs but not to others. The results indicate that transition-state analogues based on adenosine or other 6-amino nucleosides should not be discounted as potential starting points for alternative inhibitors. [source]

Synthesis of New C(2) -Substituted gluco -Configured Tetrahydroimidazopyridines and Their Evaluation as Glucosidase Inhibitors

HELVETICA CHIMICA ACTA, Issue 10 2005
Bhagavathy Shanmugasundaram
The gluco -configured C(2) -substituted tetrahydroimidazopyridines 8,14 were prepared and tested as inhibitors of the , -glucosidases from Caldocellum saccharolyticum and from sweet almonds, and of the , -glucosidase from brewer's yeast. All new imidazopyridines are nanomolar inhibitors of the , -glucosidases and micromolar inhibitors of the , -glucosidase. The 3-phenylpropyl derivative 14 proved the strongest inhibitor of the Caldocellum , -glucosidase (Ki,=,0.9,nM), only slightly weaker than the known 2-phenylethyl analogue 7, and the propyl derivative 13 is the strongest inhibitor of the sweet almond , -glucosidases (Ki,=,3.2,nM), again slightly weaker than 7. There is no strong dependence of the inhibition on the nature of the C(2) -substituent and no clear correlation between the inhibitory strength of the known manno -configured imidazopyridines 2,6 and the gluco -analogues 8,12. While most manno -imidazopyridines are competitive inhibitors, the gluco -analogues proved non-competitive inhibitors of the Caldocellum , -glucosidase and mixed-type or partial mixed-type inhibitors of the sweet almond , -glucosidases. [source]

Synthesis of N -Acetylglucosamine-Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

HELVETICA CHIMICA ACTA, Issue 1 2005
Miroslav Terinek
The gluco -configured analogue 15 of nagstatin (1) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the , -amino ester 19. The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23; these alcohols were directly obtained by condensing 18 and 19. The attempted substitution of the C(8)OH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated , -azido esters 24. The desired azide 25 was obtained by treating the manno -configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15. The imidazole-2-acetates 14 and 15 are nanomolar inhibitors of the N -acetyl- , -glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the , -glucosidase from Caldocellum saccharolyticum, and rather weak inhibitors of the snail , -mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their gluco -configuration, both imidazopyridines 14 and 15 are stronger inhibitors of the , - N -acetylglucosaminidase from bovine kidney than nagstatin. [source]

Phenolic Oxime Oligomers Inhibit Alzheimer's Amyloid Fibril Formation and Disaggregate Fibrils In Vitro

CHEMBIOCHEM, Issue 8 2009
Gunnar T. Dolphin Dr.
Abstract See you later amyloid ,: A screen of a small library of oxime oligomers with an HTS fluorescence assay for amyloid fibril inhibition and subsequent investigation by atomic force microscopy revealed two new micromolar inhibitors of amyloid fibril formation. These new inhibitors have IC50 values in the 10 ,M range. [source]

Discovery and Design of Novel HSP90 Inhibitors Using Multiple Fragment-based Design Strategies

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2007
Jeffrey R. Huth
The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an ,open' and ,closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers. [source]