120511-74-2Relevant articles and documents
Exploiting protein fluctuations at the active-site Gorge of human cholinesterases: Further optimization of the design strategy to develop extremely potent inhibitors
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
experimental part, p. 3154 - 3170 (2009/04/06)
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.
An efficient synthesis of 3,5-bis(2-cyanoisopropyl)toluene
Mei, Yu-Hua,Luo, Yu,Lu, Wei
scheme or table, p. 487 - 489 (2009/04/11)
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Dual aromatase-sulfatase inhibitors based on the anastrozole template: Synthesis, in vitro SAR, molecular modelling and in vivo activity
Jackson, Toby,Woo, L. W. Lawrence,Trusselle, Melanie N.,Chander, Surinder K.,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
, p. 2940 - 2952 (2008/04/02)
The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of inhibitory aromatase pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed SN2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC50 3.5 nM), comparable with that of Anastrozole (IC50 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase. This journal is The Royal Society of Chemistry.
