Development of Novel Hydrophobic Pharmacophores Based on Three-dimensional Molecular Architectures and Elements...

Hydrophobic interaction, as well as polar interactions such as hydrogen bonding and electrostatic interaction, plays an essential role in the interaction between biologically active compounds and their target molecules. Therefore, the application of novel hydrophobic structures other than simple hydrocarbons or aromatic rings is expected to be useful in the development of biologically active compounds with distinctive chemical and pharmacological properties. In this study, we developed various bioactive compounds bearing a boron cluster, silicon-containing or germanium-containing functionalities as novel hydrophobic structures. Regarding the boron cluster-based compounds, we developed highly potent nonsteroidal androgen receptor (AR) antagonists, progesterone receptor (PR) antagonists, and non-secosteroidal vitamin D receptor (VDR) agonists. Regarding the Group 14 elements, we systematically determined hydrophobicity parameters of various trialylmethyl, trialkylsilyl and trialkylgermyl substituents, and revealed that silicon and germanium containing compounds exhibited higher hydrophobicity than the corresponding carbon analogues, with a difference in log P value of approximately 0.6, independent of the alkyl species. We also revealed that sila- and germa-substitution of carbon could enhance their biological activity. Furthermore, we demonstrated that silyl substructures could function as mimetics of cis-diatomic substructures. These results are expected to expand the chemical space of hydrophobic pharmacophores and thus contribute to the development of novel and distinctive drug candidates.