Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

A scalable process for the preparation of high purity dimethyl 1,4-cubanedicarboxylate (3) is reported. The work described herein builds on previous synthetic work from this and other laboratories, to provide a reliable process that can be used to prepare multigram quantities of 3 in a partially telescoped, 8 step process, with minimal purification of intermediates.

The copolymer poly(isocyanatoethyl methacrylate-co-methyl methacrylate-co-ethylene glycol dimethacrylate) (poly(IEM-co-MMA-co-EGDMA)) was developed as a novel, facile, highly reactive and versatile monolithic matrix, which was amenable to surface functionalization with a variety of nucleophilic modifiers based on the reactive isocyanate group, producing monoliths of various chemistries suitable for chromatography. The specific surface area, pore size distribution, porosity and morphology of the monolithic matrix were characterized using a mercury intrusion porosimeter and scanning electron microscopy (SEM), respectively. Thermal analysis results revealed that the monolith was thermally stable up to 307 °C. The success of the chemical modification of the monolithic matrix was confirmed by FT-IR, solid state (13) C NMR and XPS elemental analysis, showing the high ligand density of the modified monoliths. A ligand density of up to 2.33 mmol·mL(-1) was obtained for the 1-octanol modified monolith (M1) with an isocyanate group conversion of 96.9%, indicating a high efficiency of the modification reaction. The potential application of the monoliths was demonstrated by the separation of a series of compounds. The novel monolithic columns exhibited high mechanical stability, column efficiency and good repeatability and reproducibility.

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.