TY - JOUR
T1 - Studying Lipophilicity Trends of Phosphorus Compounds by 31P-NMR Spectroscopy
T2 - A Powerful Tool for the Design of P-Containing Drugs
AU - Columbus, Ishay
AU - Ghindes-Azaria, Lee
AU - Chen, Ravit
AU - Yehezkel, Lea
AU - Redy-Keisar, Orit
AU - Fridkin, Gil
AU - Amir, Dafna
AU - Marciano, Daniele
AU - Drug, Eyal
AU - Gershonov, Eytan
AU - Klausner, Ziv
AU - Saphier, Sigal
AU - Elias, Shlomi
AU - Pevzner, Alexander
AU - Eichen, Yoav
AU - Parvari, Galit
AU - Smolkin, Boris
AU - Zafrani, Yossi
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/6/23
Y1 - 2022/6/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85133101076&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c00658
DO - 10.1021/acs.jmedchem.2c00658
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C2 - 35678759
AN - SCOPUS:85133101076
SN - 0022-2623
VL - 65
SP - 8511
EP - 8524
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 12
ER -