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Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 6, 2746-2754 p.Article in journal (Refereed) Published
Abstract [en]

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 -> NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure property 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's rule of 5.

Place, publisher, year, edition, pages
2014. Vol. 57, no 6, 2746-2754 p.
National Category
Medical and Health Sciences Natural Sciences
URN: urn:nbn:se:uu:diva-224357DOI: 10.1021/jm500059tISI: 000333578400045OAI: oai:DiVA.org:uu-224357DiVA: diva2:716779
Available from: 2014-05-12 Created: 2014-05-09 Last updated: 2014-05-12Bibliographically approved

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Artursson, PerMatsson, PärSvensson, RichardKihlberg, Jan
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Department of PharmacyScience for Life Laboratory, SciLifeLabPhysical Organic Chemistry
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