期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 12, 页码 8511-8524出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00658
关键词
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资金
- Israeli Prime Minister's office
Systematically studying the lipophilicity of phosphorus compounds is crucial in various chemical and biological fields, especially in medicinal chemistry. In this study, a straightforward log P determination method for phosphorus compounds based on P-31-NMR spectroscopy was developed. Trends in the lipophilicity of different phosphorus compounds relevant to drug design were investigated, and the observed trends were interpreted using a DFT study and pK(HB) measurements.
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 P-31-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 (pK(HB)) measurements of selected compounds. Clear signal separation in P-31-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 P-31-NMR analysis.
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