Physicochemical characterization of B-hydroxyphenyl phosphine borane derivatives and their evaluation as nuclear estrogen receptor ligands

Abstract

This is the first report of biologically active B-substituted phosphineborane derivatives. Phosphine boranes could be versatile structural options in medicinal chemistry for expanding the chemical space available for drug discovery.

Design, Synthesis, and Evaluation of B-(Trifluoromethyl)phenyl Phosphine–Borane Derivatives as Novel Progesterone Receptor Antagonists

“…The trimethylphosphine-borane derivatives 16 and 28 exhibited a LogP value of 3.65. In our previous study, the corresponding phenol derivative B-4-hydroxyphenyl trimethylphosphine-borane exhibited a LogP value of 2.44 [12]. The reported substituent constants of hydrophobicity of the CF 3 and phenolic OH groups were 0.88 and −0.67, respectively [47], and therefore, the difference between the LogP values of trifluoride and the corresponding phenol derivative moderately agreed with the reported difference.…”

“…To develop a novel nonsteroidal PR antagonist, we adopted the (trifluoromethyl)phenyl group as the key structural motif, which has been found to function as a pharmacophore for PR antagonists such as 14. Our recent results indicated that the electronic profile of the B-substituents of phosphine-boranes partly influences the stability of the compounds, and an increase in the electrophilicity of the boron atom can increase the stability of the phosphine-borane adducts [12]. Thus, the introduction of an electron-withdrawing trifluoromethyl group onto the B-phenyl moiety is a reasonable approach for designing novel biologically active phosphine-borane derivatives.…”

“…Thus, the introduction of an electron-withdrawing trifluoromethyl group onto the B-phenyl moiety is a reasonable approach for designing novel biologically active phosphine-borane derivatives. In addition, phosphine-borane frameworks are less hydrophobic than the corresponding carbon-based frameworks [11,12]; therefore, the introduction of a highly hydrophobic trifluoromethyl group on the phosphine-borane framework can provide appropriate hydrophobicity to the compounds. Regarding the phosphine moiety, various phosphines with diverse shapes and bulkiness are available because of their utility as phosphine ligands in catalysts.…”

“…The designed B-(trifluoromethyl)phenyl phosphine-borane derivatives 16-39 were synthesized from the corresponding phosphines and 3-or 4-(trifluoromethyl)phenyl boronic acid under reductive conditions (Scheme 1) [12,42,43]. Interestingly, we could obtain phosphine-borane derivatives 26 and 38 containing the P-H moiety under normal preparation conditions using an aqueous workup.…”

“…From a structural arrangement perspective, the P-B substructures in phosphine-boranes can be regarded as isosteric with alkanes because of their tetrahedral sp 3 -sp 3 character. Based on this consideration, we recently developed phosphine-borane-containing estrogen receptor (ER) modulators such as 3 and 4 [11,12]. Subsequently, we had revealed that the P-BH 2 -Ph moiety as well as P-BH 3 moieties are useful structural options for the development of biologically active compounds, particularly for the optimization of hydrophobic substructures by controlling the hydrophobicity of the compounds.…”