Development of Novel and Distinctive Biologically Active Compounds Using a Wide Variety of Elements: Exploring the Elements-based Chemical Space for Medicinal Chemistry

Because structural development studies have conventionally been conducted based on frameworks consisting of C, N, O, and S functionalities, the development of new structural options utilizing a wide variety of elements can dramatically expand the chemical space of medicinal chemistry. In order to explore the “elements-based chemical space” in medicinal chemistry and propose new methodologies for molecular design, the development of biologically active compounds using various multi-element structures was investigated. As a novel design methodology, structural development using silicon and phosphorus functionalities, as well as three-dimensional structural development using boron clusters and ferrocene, was explored. In the case of silicon functionalities, the correlation between the biological activity and changes in the physical properties induced by Si/C-exchange was quantitatively analyzed, revealing that differences in the atomic radii on the order of picometers resulted in large differences in the biological activity. Structural development methods using silyl alcohols and silanol structures were also developed. In the case of phosphorus functionalities, the P-B bond in phosphine boranes was found to be a versatile option for structural development. Boron clusters and ferrocenes are useful hydrophobic anchors for biologically active compounds, and developments in their three-dimensional structures have led to the development of highly potent compounds. The proposed expansion of the “elements-based chemical space” in medicinal chemistry is a promising approach for developing novel and distinctive drug candidates.