Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Nonsecosteroidal vitamin D receptor (VDR) ligands are promising drug candidates for multiple diseases, including osteoporosis, psoriasis, and certain cancers. We report here the design, synthesis, biological evaluation and crystallographic analysis of a series of 1,7-diphenyl-m-carborane derivatives as novel nonsecosteroidal VDR ligands. We found that the 1,7-diphenyl-m-carborane framework is a promising hydrophobic core of VDR ligands, and developed a series of potent compounds such as 12b and 13a. Interestingly, compounds with different chain length exhibited similar potencies. X-Ray co-crystal structure analysis revealed that the developed compounds exhibited various different interaction patterns depending on the structure of the carboxyalkyl chain, indicating that the ligand-binding pocket of the VDR possesses sufficient conformational plasticity to accommodate a wide variety of ligands without compromising activity. The developed carborane derivatives are promising leads for further structural development, and the findings on the diversity of binding modes will be helpful in the design of other VDR ligands.

DOI： 10.1016/j.ejmech.2025.118320

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PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Unsymmetrical 1,1’‐disubstituted ferrocene is a versatile scaffold for various functional molecules, including organic electronics, catalysts, and bioactive molecules. Herein, we report a facile synthesis of unsymmetrical 1,1’‐disubstituted ferrocene derivatives based on the desymmetrization of 1,1’‐diborylferrocene. We found that Suzuki‐Miyaura cross‐coupling (SMCC) reaction using 1,1’‐bis(Bpin)ferrocene affords the mono‐substituted product without significant loss of the second boryl group. Then, second SMCC reaction of the obtained 1‐aryl‐1’‐(Bpin)ferrocene affords the desired unsymmetrical 1,1’‐disubstituted ferrocene derivatives in reasonable yields. This method provides a versatile synthetic platform for tuning the electronic and steric properties of functional ferrocene derivatives and for the structural development of bioactive compounds.

DOI： 10.1002/chem.202501026

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Vitamin D receptor (VDR) is an attractive target of drug discovery for multiple diseases. In this study, we systematically designed and synthesized a series of diphenylsilane derivatives with diverse hydrophobic substituents and investigated their structure–activity relationship (SAR) as VDR agonists. The SAR study revealed that the activity is dependent on the type of substituent and the position of substitution, and the diethyl-di-m-tolylsilane scaffold was identified as the most suitable hydrophobic core structure of this type of VDR ligands. Interestingly, the small structural difference between n-propyl and allyl substituents resulted in a large difference in the activity. Comparison of the co-crystal structures of 14 diphenylsilane compounds, including less potent compounds, bound to the rat VDR ligand-binding domain suggested that the differences in activity are due to a combination of factors, including differences in hydrophilic and hydrophobic interactions, and ligand conformations.

DOI： 10.1016/j.bmc.2025.118261

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

<jats:p>We previously revealed that phosphine–boranes can function as molecular frameworks for biofunctional molecules. In the present study, we exploited the diversity of available phosphines to design and synthesize a series of B-(trifluoromethyl)phenyl phosphine–borane derivatives as novel progesterone receptor (PR) antagonists. We revealed that the synthesized phosphine–borane derivatives exhibited LogP values in a predictable manner and that the P–H group in the phosphine–borane was almost nonpolar. Among the synthesized phosphine–boranes, which exhibited PR antagonistic activity, B-(4-trifluoromethyl)phenyl tricyclopropylphosphine–borane was the most potent with an IC50 value of 0.54 μM. A docking simulation indicated that the tricyclopropylphosphine moiety plays an important role in ligand–receptor interactions. These results support the idea that phosphine–boranes are versatile structural options in drug discovery, and the developed compounds are promising lead compounds for further structural development of next-generation PR antagonists.</jats:p>

DOI： 10.3390/molecules29071587

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

<jats:title>Abstract</jats:title><jats:p>We previously identified nitrophenylferrocenes and cyanophenylferrocenes as promising lead structures of novel androgen receptor (AR) antagonists, based on the structural similarity between ferrocene and the steroidal skeleton. In the present research, we explored the structure‐activity relationship (SAR) of phenylferrocene derivatives. Introduction of a hydrophobic substituent such as a chlorine atom at the 2‐position or 3‐position of phenylferrocene derivatives significantly increased the antagonistic activity toward wild‐type AR, and among the synthesized compounds, 3‐chloro‐4‐cyanophenylferrocene (<jats:bold>29</jats:bold>) exhibited the most potent anti‐proliferative activity toward the androgen‐dependent growth of SC‐3 cells expressing wild‐type AR (IC<jats:sub>50</jats:sub> 14 nM). Like conventional antiandrogens such as hydroxyflutamide, the major active metabolite of flutamide, compound <jats:bold>29</jats:bold> exhibited agonistic activity toward T877A‐AR, a mutant AR expressed in human prostate cancer cell line LNCaP. Notably, however, the 2‐chloro isomer <jats:bold>27</jats:bold> showed potent antagonistic activity toward wild‐type AR (IC<jats:sub>50</jats:sub> 49 nM) and also exhibited antagonistic activity toward T877A‐AR. Our SAR data should prove helpful for the development of new‐generation AR antagonists based on phenylferrocene as candidate agents to treat drug‐resistant prostate cancer.</jats:p>

DOI： 10.1002/cmdc.202400040

Language：Japanese  

Language：Japanese