Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study

We sought to determine the cyclodextrins (CDs) best suited to solubilize a patented succinimido-ferrocidiphenol (SuccFerr), a compound from the ferrociphenol family having powerful anticancer activity but low water solubility. Phase solubility experiments and computational modelling were carried out on various CDs. For the latter, several CD-SuccFerr complexes were built starting from combinations of one or two CD(s) where the methylation of CD oxygen atoms was systematically changed to end up with a database of ca. 13 k models. Modelling and phase solubility experiments seem to indicate the predominance of supramolecular assemblies of SuccFerr with two CDs and the superiority of randomly methylated & beta;-cyclodextrins (RAME & beta;CDs). In addition, modelling shows that there are several competing combinations of inserted moieties of SuccFerr. Furthermore, the models show that ferrocene can contribute to high stabilization by making atypical hydrogen bonds between Fe and the hydroxyl groups of CDs (single bond with one OH or clamp with two OH of the same glucose unit).

Automated summary

This study aimed to determine the most suitable cyclodextrins (CDs) for solubilizing a patented succinimido-ferrociphenol compound (SuccFerr) with powerful anticancer activity but low water solubility. Phase solubility experiments and computational modeling were conducted on various CDs. The modeling and experiments suggest that supramolecular assemblies of SuccFerr with two CDs, particularly randomly methylated β-cyclodextrins (RAME-β-CDs), are predominant and superior. Additionally, the modeling reveals competing combinations of inserted moieties of SuccFerr and the contribution of ferrocene to high stabilization through atypical hydrogen bonding with CD hydroxyl groups.