Cage-shaped silsesquioxane with multiactive sites for impeding aggregation of small insoluble organic molecule

Organic drug small molecules with rigid π-electron conjugated structures have relatively strong dipole–dipole and π-π stacking interactions causing the drug aggregation in solution, the efficacy of which is limited. In this study, molecular aggregation was inhibited by increasing the spacing of organic molecules to more than 7 Å. Thiol-polyhedral olisesquioxane (POSS-SH) with eight active sites was selected as a stabilizer to increase the molecular spacing through a large number of density functional theory (DFT). After non-pharmacologically acting amino/hydroxyl groups in poorly soluble drugs was double-bonded with acryloyl chloride. The drugs were modified by POSS-SH through “click chemistry” to increase molecular spacing, so as to prevent π - π stacking and charge transfer. DFT and spectroscopic property studies showed that the molecular spacing of the drug modified by POSS-SH exceeded 8.063 Å, the increased spacing effectively inhibited the H- or J-aggregation then increasing the solubility of poorly soluble molecules to greater than 6.24 g/100 g (H 2 O). The introduction of POSS-SH improved the solubility of insoluble molecules and so the therapeutic effects exerted by POSS-SH-modified hybrid molecules on cells were superior to the unmodified drug. Improving the solubility of insoluble drugs through POSS-SH may represent an important breakthrough in small-molecule drug research and development.