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

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Abstract

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.

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Acknowledgements

P. V. thanks, Council for Scientific and Industrial Research (CSIR), India for the award of EmeritusScientistship (Ref. no. 21(0936)/12/EMR–II). DS acknowledges the support and continuous encouragement from Centre for Research and development, PRIST University, Vallam campus, Thanjavur. RVS acknowledges the support and encouragement from the Department of Chemistry and the management of Madras Christian College (Autonomous), Chennai.

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Authors and Affiliations

  1. Center for Computational Chemistry, CRD, PRIST University, Vallam, Thanjavur, Tamilnadu, 613403, India

    Dhurairajan Senthilnathan

  2. Department of Chemistry, Madras Christian College (Autonomous), Tambaram East, Chennai, 600 059, India

    Rajadurai Vijay Solomon

  3. Theoretical and Computational Chemistry Laboratory, School of Chemistry, Bharathidasan University, Tiruchirappalli, 620 024, India

    Shanmugam Kiruthika & Ponnambalam Venuvanalingam

  4. Theoretical Chemistry Section, Bhabha Atomic Research Centre, Mumbai, 400 085, India

    Mahesh Sundararajan

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  1. Dhurairajan Senthilnathan
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Correspondence to Dhurairajan Senthilnathan.

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Senthilnathan, D., Solomon, R.V., Kiruthika, S. et al. Are cucurbiturils better drug carriers for bent metallocenes? Insights from theory. J Biol Inorg Chem 23, 413–423 (2018). https://doi.org/10.1007/s00775-018-1547-7

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