55 / 2023-08-14 23:43:30

P－B Bond as a Novel Structural Option in Medicinal Chemists' Toolbox: Physicochemical Properties and Estrogenic Activity of Phosphine Borane-Based Phenols

Phosphine borane,Chemical space,Hydrophobicity,Estrogen

Phosphorus Chemistry and Life & Health science > 2) Phosphorus chemistry in medicine

Expanding the chemical space of biologically active compounds is a promising strategy to develop novel and distinctive drug candidates, and the application of organic multi-elemental compounds is a reasonable approach to increase the options for structural development. In this study, we systematically investigated the structure-property relationship and structure-activity relationship of phosphine derivatives in order to throw light on their potential utility in drug discovery chemistry.

Firstly, using 4-phosphinophenol substructure as the common platform, we designed and synthesized a series of phosphine and related compounds, and investigated their physicochemical properties and activity for estrogen receptors (ERs). Several compounds exhibited ER ligand activity, and interestingly, phosphine borane derivatives bearing P-BH₃ substructure exhibited significant ER antagonistic activity more potent than the corresponding phosphine oxide and other chalcogenide derivatives.[1]

Next, in order to investigate the utility of phosphine borane derivatives, we designed and synthesized phosphine borane derivatives bearing a B-hydroxyphenyl group, and investigated the physicochemical properties such as stability in phosphate buffered saline (PBS), hydrophobicity (LogP), membrane affinity (LogK_IAM), and acidity (pK_a). The synthesized phosphineborane derivatives exhibited comparable stability in PBS compared to the corresponding isoelectronic silane and alkane derivatives, with a slight decrease in hydrophobicity and membrane affinity, as well as a decrease in acidity. Biological evaluation revealed that compounds bearing PEt₃, P(i-Pr)₃, or P(c-Pr)₃ structure showed significant ERα agonistic activity.[2] These results indicated that the phosphine borane substructure is a new option in the structural development study of biologically active compounds, and also the information of physicochemical properties is useful for the rational molecular design of unique bioactive compounds bearing a P−B bond. The detailed structure-activity relationships and biological evaluation will be discussed.