Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties

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• 作者：Bj枚rn Over ; Patrick McCarren ; Per Artursson ; Michael Foley ; Fabrizio Giordanetto ; Gunnar Gr枚nberg ; Constanze Hilgendorf ; Maurice D. Lee ; IV ; P盲r Matsson ; Giovanni Muncipinto ; M茅lanie Pellisson ; Matthew W. D. Perry ; Richard Svensson ; Jeremy R. Duvall ; Jan Kihlberg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2746-2754
• 全文大小：379K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pK_a, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH鈫扤R₃ hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pK_a difference that accounts for the other structure鈥損roperty relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski鈥檚 rule of 5.