Studying Lipophilicity Trends of Phosphorus Compounds by 31P-NMR Spectroscopy: A Powerful Tool for the Design of P-Containing Drugs

Ishay Columbus, Lee Ghindes-Azaria, Ravit Chen, Lea Yehezkel, Orit Redy-Keisar, Gil Fridkin, Dafna Amir, Daniele Marciano, Eyal Drug, Eytan Gershonov, Ziv Klausner, Sigal Saphier, Shlomi Elias, Alexander Pevzner, Yoav Eichen, Galit Parvari, Boris Smolkin, Yossi Zafrani

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4 Scopus citations

Abstract

Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on 31P-NMR spectroscopy. The log P values measured ranged between -3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pKHB) measurements of selected compounds. Clear signal separation in 31P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to -250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and 31P-NMR analysis.

Original languageEnglish
Pages (from-to)8511-8524
Number of pages14
JournalJournal of Medicinal Chemistry
Volume65
Issue number12
DOIs
StatePublished - 23 Jun 2022
Externally publishedYes

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