Are cucurbiturils better drug carriers for bent metallocenes? Insights from theory

Bent metallocenes (BM) have anti-tumor properties but they face a serious drug efficacy problem due to poor aqueous solubility and rapid hydrolysis under physiological conditions. These two problems can be fixed by encapsulating them in host molecules such as cyclodextrin (CD), cucurbituril (CB) etc. Experimentally, CD-BM, CB-BM host-guest complexes have been investigated to check the efficiency of the drug delivery and efficiency of the encapsulated drug. CB has been reported to be a better host than CD but the reasons for this has not been figured out. This can be done by finding out the mechanism of binding and the nature of the binding forces in both the inclusion complexes. This is exactly done here by performing a DFT study at BP86/TZP level on CB-BM host-guest systems. For comparison CD-BM with β-cyclodextrin as host have been studied. Four BMs (Cp₂MCl₂, M=Ti, V, Nb, Mo) and their corresponding cations (Cp₂MCl⁺, Cp₂M²⁺) are chosen as guests and they are encapsulated into cucurbit-[6]-uril (CB[6]) and cucurbit-[7]-uril(CB[7]) host systems. Computations reveal that CB[7] accommodates well the BMs over CB[6] due to their larger cavity size and also CB[7] is found to be a better host than β-cyclodextrin. BMs enter vertically rather than horizontally into the CB cavity. The reversible binding of BMs within CB[7] is controlled by various non-bonding interactions and mainly by hydrogen bonding between the portal oxygen atoms and Cp protons as revealed by QTAIM analysis. On the other hand, the interaction between the wall nitrogen atoms in CB[7] and chlorine atoms attached to the metal in BM strengthens the M-Cl bonds that prevents rapid hydrolysis of M-Cl and M-Cp bonds saving the drug. Comparatively, BMs experience less electrostatic attraction and more Pauli repulsion within β-cyclodextrin cavity and this affects the drug binding with CD. This makes β-cyclodextrin a less suitable drug carrier for BMs than CBs. Among the four BMs, niobocene binds strongly and titanocene binds weakly with CBs. EDA clearly shows that all the interactions between the guest and host are non-covalent in nature and electrostatic interactions outperform high-repulsion resulting in stable complexes. Cations form stronger complexes than neutral BMs. FMO analysis reveals that neutral BMs are less reactive compared to their cations and complexes are more reactive in CB[6] environment due to excess strain. QTAIM analysis helps to bring out the newer insights in these types of host-guest systems.