- Exploiting protein fluctuations at the active-site Gorge of human cholinesterases: Further optimization of the design strategy to develop extremely potent inhibitors
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Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
- Butini, Stefania,Campiani, Giuseppe,Borriello, Marianna,Gemma, Sandra,Panico, Alessandro,Persico, Marco,Catalanotti, Bruno,Ros, Sindu,Brindisi, Margherita,Agnusdei, Marianna,Fiorini, Isabella,Nacci, Vito,Novellino, Ettore,Belinskaya, Tatyana,Saxena, Ashima,Fattorusso, Caterina
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experimental part
p. 3154 - 3170
(2009/04/06)
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- Facile synthesis of monoacetylated spermidines, illustrating selective deacetylation and application of a common precursor.
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The synthesis of all three monoacetylated spermidines is reported. N4-Acetylspermidine was obtained in four steps from spermidine via the triacetylated intermediate by selective deacetylation after exhaustive t-butoxycarbonylation as well as directly from
- Lurdes,Almeida,Grehn,Ragnarsson
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p. 990 - 994
(2007/10/02)
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- CONVENIENT ROUTES TO ALKYL-SUBSTITUTED POLYAMINES
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Alkyl-substituted polyamines, valuable for biological studies, can be prepared from N-phenylmethoxycarbonyl-1,4-diaminobutane (1b) and N-phenylmethoxycarbonyl-4-azidobutanamine (4a) by utilising the following reactions: (i) reduction of the phenylmethoxycarbonyl group to methyl by borane and (ii) combination of the Staudinger and aza-Wittig reactions .
- Golding, Bernard T.,O"Sullivan, Mary C.,Smith, Lewis L.
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p. 6651 - 6654
(2007/10/02)
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