title: Increased hydrophobicity and estrogenic activity of simple phenols with silicon and germanium-containing substituents.
abstract: Here, we report the systematic synthesis and characterization of simple phenols bearing a trialkyl(aryl)silyl or trialkyl(aryl)germyl functional group as a hydrophobic substituent. These silicon and germanium analogues exhibited higher hydrophobicity than the corresponding carbon analogues, with a difference in log P value of approximately 0.6, independent of the alkyl(aryl) species. Trimethylsilylphenol and trimethylgermylphenol exhibited smaller pK(a) values than the corresponding carbon analogue or unsubstituted phenol, indicating that trialkylsilyl and trialkylgermyl functional groups have a negative substituent constant (σ). The trialkylsilyl- and trialkylgermylphenols exhibited more potent estrogenic activity as compared with the carbon analogues. The substituent parameters and structure-activity relationship reported here may be helpful for drug discovery utilizing the heavier group 14 elements.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.forename: Yu
authors.initials: Y
authors.lastname: Miyajima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
mesh_terms: D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D004967:Estrogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D005857:Germanium; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017646:Organosilicon Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D009942:Organometallic Compounds; D017646:Organosilicon Compounds; D010636:Phenols; D005857:Germanium; D004958:Estradiol; D008156:Luciferases