NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

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• 作者：Archimede Rotondo ; Roberta Ettari ; Silvana Grasso ; Maria Zappalà
• 关键词：Proteases inhibitors ; 1H ; 13C ; 15N NMR ; Solution chemical structure ; Conformational analysis
• 刊名：Structural Chemistry
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：26
• 期：4
• 页码：943-950
• 全文大小：1,076 KB
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• 作者单位：Archimede Rotondo (1)
  Roberta Ettari (2)
  Silvana Grasso (1)
  Maria Zappalà (2)
  
  1. Department of Chemical Sciences, University of Messina, via D’Alcontres 31, 98166, Messina, Italy
  2. Department of Drug Sciences and Products for Health, University of Messina, Viale Annunziata, 98168, Messina, Italy
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Physical Chemistry
  Theoretical and Computational Chemistry
  
• 出版者：Springer Netherlands
• ISSN：1572-9001

文摘

Conformational analysis of a potent class of cysteine protease inhibitors is thoroughly studied by NMR, in both, polar and apolar solvents to get a better insight over the known biological activity and migration through biological media. These molecules are composed by a benzodiazepine (BDZ) scaffold connected to a bromo-isoxazoline (IOX) ring through an alkyl spacer (AS) with up to four-carbon atoms. Data, supported by theoretical calculations at DFT level, reveal that both BDZ and IOX keep a pretty rigid and asymmetric conformation, so that four diastereo-atropisomers (two mirror-image couples) are generated. The relative stiffness of these substrates, maintained also in different solvents, is confirmed by: (a) remarkable separation of diastereotopic protons; (b) specific “through the space contacts-(NOESY); and (c) very good fitting of the coupling constants evaluations. The prototypic compound with the longer AS shows two main conformations and a certain dynamic freedom around the AS torsional angles close to IOX; according to our data, the AS length is not fundamental for the functional BDZ and IOX fitting into the macromolecular complex; however, it does play a crucial role to cross the parasite cell membranes.