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JBIC Journal of Biological Inorganic Chemistry https://doi.org/10.1007/s00775-018-1547-7

ORIGINAL PAPER

Are cucurbiturils better drug carriers for bent metallocenes? Insights from theory Dhurairajan Senthilnathan1 · Rajadurai Vijay Solomon2 · Shanmugam Kiruthika3 · Ponnambalam Venuvanalingam3 · Mahesh Sundararajan4 Received: 22 November 2017 / Accepted: 23 February 2018 © SBIC 2018

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. Keywords Anticancer drug · Bent metallocenes · Cucurbituril · Cyclodextrin · DFT · EDA · QTAIM

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00775-018-1547-7) contains supplementary material, which is available to authorized users. * Dhurairajan Senthilnathan [email protected]

2

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

Ponnambalam Venuvanalingam [email protected]

3

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

4

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

Mahesh Sundararajan [email protected] 1

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

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JBIC Journal of Biological Inorganic Chemistry

Introduction As titanocene dichloride [ Cp2TiCl2] progresses into the clinical trial phase I and II, bio-organometallic chemistry of bent metallocenes has stimulated a great deal of interest in recent years [1–11]. These bent metallocenes attract increased attention due to their structural novelty, metal tunability, viable-synthetic routes to prepare these complexes and wider applications in organic synthesis, polymer catalysis and in biology [12–18]. Though bent metallocenes have been used in clinical trials, their antitumor properties encounter a serious drug efficacy problem related to their solubility and specificity of its action [19, 20]. For instance, poor aqueous solubility and rapid hydrolysis of the Ti–Cl, and Ti–Cp bonds in the titanocene complex under physiological conditions leads to insoluble precipitates [9, 21–26]. Similarly, molybdocene is found to undergo unprecedented reaction with thiols which makes it ineffective under physiological conditions [19, 27–29]. One of the possible strategies to avoid the solubility and drug efficacy issues is to use macromolecules as drug carriers [30–35]. These host molecules encapsulate the drug molecules and can release them at the specific target site. Several macromolecules such as cyclodextrin, cucurbiturils, calixarenes, etc., are used as host molecules for different therapeutic agents [36–41]. The well-known drug carrier cyclodextrins [CD] was reported by several authors to solve this drug efficacy problem [42, 43]. While [CD]s

can reversibly encapsulate bent metallocenes, their applications are limited to oral and topical drug formulation due to its nephrotoxicity [1, 44, 45]. Particularly, [ Cp2TiCl2] has been found to be included in the hydrolyzed state, which is a biologically active state [46, 47], molybdocene and niobocene were not. This raises the serious question on the ability of [CD] as a good host for these bent metallocenes. Cucurbit[n]uril (CB[n], n = 5–10), a class of pumpkinshaped host molecules composed of n-glycoluril units bridged by methylene groups, can be alternative to CDs. Buck et al. reported the first and second hydrolysis of bent metallocene drugs in the presence of CB [37]. Particularly, Buck et al. propose that CBs can be better hosts for bent metallocenes and perform drug delivery efficiently in vivo for anti-tumor action [37]. Due to the strong affinities of several guests [48, 49] and low toxicity, CBs are preferred over CDs in drug delivery [37, 50]. The host–guest interactions in CB environment are dominated and dictated by electrostatic, hydrogen bonding, ion–dipole and hydrophobic interactions [51]. Hence, in the present work DFT computations have been performed on CB-BM systems to find out the mechanism of binding and understand the non-bonding interactions that control the reversible binding of BMs inside CB cavity. A proposed mechanism of in vivo action of bent metallocene drugs with CB capsules is shown in Fig. 1. Although isolated bent metallocenes undergo rapid hydrolysis under the physiological condition (Fig. 1), the CB encapsulated

Fig. 1 Proposed mechanism of binding of BMs with CB and drug delivery process

Cl

M Cl

M4+ +

2Cl- +

2Cp-

pH = 7

Cl

S1

M Cl

CB[n]

M = Ti, V, Nb, Mo

S4

S2

Cl

M2+

M

13

S3

M Cl


bent metallocene drugs undergoes very slow and steady hydrolysis and finally the [Cp2M]2+ species are released at the target site which facilitates slow DNA replication [7, 52–54]. The following questions are addressed here using electronic structure calculations performed at the DFT level. (1) The mechanism of binding of BM with CB and CD and the nature forces that control the reversible binding of BMs with host systems. (2) The effect of cavity size on binding with CBs. This will eventually evaluate the better host for BMs. To understand the effect of size on the inclusion phenomena, CB[6] and CB[7] have been considered here. Due to inappropriate sizes of CB [5] (too small cavity) and CB[8] (too large cavity), they are not considered here. Twelve bent metallocenes including four neutral bent metallocenes (M=Ti, V, Nb and Mo) and their corresponding mono-(Cp2MCl+) and di-cations ( Cp2M2+) are considered for the present study. These would enrich the knowledge of the anti-tumor activity of bent metallocene vis-à-vis the drug-carrying ability of CBs.

Computational details Geometry optimizations have been carried out using the Amsterdam Density Functional (ADF 2007) package [55]. A generalized gradient approximation (GGA) functional consisting of the Becke’s exchange [56] and correlation expression proposed by Perdew, Burke [57], and Ernzerhof have been utilized [58]. Basis sets of triple-ζ and one set of polarization function (TZP) have been employed [59]. Relativistic effects were included by means of the Zero Order Regular Approximation (ZORA) [60, 61]. The host–guest interactions have been analyzed using energy decomposition scheme (EDA) of the ADF program, which is based on the partitioning method of Morokuma [62] and ETS method of Ziegler [63, 64]. The instantaneous interaction energy ΔEint can be divided into three components:

ΔEint = ΔEelstat + ΔEPauli + ΔEorb ΔEelstat gives the electrostatic interaction energy between the fragments and it accounts for the bonding interactions. The second term, ΔEPauli, gives the repulsive orbital interaction between the occupied orbitals of the two fragments due to anti-symmetrization, whereas ΔEorb gives the stabilizing orbital interactions, which can be considered as an estimate of covalent contribution to the bonding. Thus, the ratio ΔEelstat/ΔEorb may be used for the relative electrostatic/covalent character of the bond. To gain deeper insights into the interaction between CBs and bent metallocenes, topological analysis has been carried out on the optimized geometries of the host–guest complexes using AIM2000 package [65]. Bader’s Quantum Theory of Atoms in Molecules (QTAIM)

CB[6]

4.01 Å (3.91 Å)

CB[7]

5.49 Å (5.40 Å)

Fig. 2 BP86/TZP optimized geometries of CB[6] and CB[7]. The inner cavity diameter are indicated with experimental values in parenthesis

Fig. 3 Selected bond parameters of C p2MCl2(M=Ti, V, Nb and Mo) computed at BP86/TZP level

approach is used to identify and classify various non-covalent interactions present in chemical systems [66, 67] It is based on the electron density (ρ) estimated at bond critical points (BCPs). The appearance of BCPs between constituent atoms confirms the presence of bonding interactions and its ρ and Laplacian values reveal the nature of bonding [68–71]. Further, there are two critical points, namely (3, + 1) ring critical points and (3, + 3) cage critical points. Ring critical point (RCP) is used to be in the middle of several bonds forming a ring, while cage critical point (CCP) is found when several rings form a cage. The necessary wave functions have been generated at B3LYP/6-31 + g(d,p) level using Gaussian 03 [72].

Results and discussion Geometry The mechanism of binding and delivery of the drug is proposed here (Fig. 1). The optimized geometries of CB[6] and CB[7] are given in Fig. 2 and the inner diameters indicated in the figure. Computed inner diameters of CB[6] and CB[7] are 4.01 and 5.49, respectively, which agrees with the experimental data [67–70] (Fig. 2). Selected bond lengths and

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Cl–M–Cl distance of neutral BMs computed from optimized geometries are presented in Fig. 3. There are two possible approaches by which the BMs can enter CB, vertically or horizontally [38, 51] as shown in Fig. 4. From Fig. 4, it is clear that approach 2 is the possible mode where the bent metallocene approaches the CB via vertical insertion. In the horizontal approach, the Cp–Ti–Cp distance (5.89 Å) is much larger than the cavity diameter (5.49 Å) of CB[7] whereas, in the vertical approach, the Cl–Ti–Cl distance (4.80 Å) is much smaller than the cavity diameter. For the other three metallocenes, the Cl–M–Cl distance in the horizontal approach is smaller than the cavity diameter of CB[7], thus the vertical approach is favored for the inclusion over horizontal approach for all four metallocenes. In Fig. 5, the optimized geometries of the host–guest complexes with neutral guests and host CB[7] are presented (for corresponding CB[6] complexes refer SIF1). A much smaller cavity diameter (4.01 Å) of CB[6] is found to be insufficient for the complete encapsulation of bent metallocenes through both approaches 1 and 2. This is much clear from EDA of BM-CB[6] complexes discussed from the following section. From the optimized geometries, it is interesting to note that the inner cavity diameter of CB[7] is largely unaffected during host–guest complex formation. Yet the formation of host–guest complexes leads to shortening of M–Cl bonds. For instance, the M–Cl bond length of the free Cp2MCl2 molecule is 2.37 Å and the same inside the CB cavity is found to be 2.23 Å. The shortening of M–Cl bond of other BMs within the cavity follows a similar trend. This Fig. 4 Schematic representation of different (1, horizontal and 2, vertical) host–guest complexation approaches between host CB[7] and guest C p2TiCl2

Cp2VCl2@CB[7]

Cp2MoCl2@CB[7]

Cp2NbCl2@CB[7]

Fig. 5 BP86/TZP level optimized geometries for C p2MCl2@CB[7] (M=Ti, V, Nb, Mo) complexes

shortening of M–Cl bond inside the CB[7] host environment provides the aqueous stability of the bent metallocene drug formulation with CB delivery system. It is known that the CB cavity contains few water molecules which are known as high energy waters [73]. These high energy waters are released from the host during the

Cl-Ti-Cl

Cp-Ti-Cp

Ti Cl

5.83 Å

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Cp2TiCl2@CB[7]

Cl

Ti

4.80 Å

Cl

1

2

CB7 5.49 Å

CB7 5.49 Å

Cl


complex formation through favorable entropy so as the overall host–guest complexation is stabilized. Further, due to encapsulation of guest molecules to CB[7], the M–Cl bond of the guest is not exposed to water molecules, thus preventing hydrolysis.

Nature of interactions from energy decomposition analysis Energy decomposition analysis (EDA) based on Ziegler’s partitioning scheme has been used to understand the nature of interactions existing between various types of molecules in recent years [63]. Therefore, to gain more insights into the nature of host–guest interactions in these inclusion complexes, EDA has been carried out where the guest molecule (bent metallocene or their cations) is considered as one fragment and the host (CB[6] or CB[7]), as another fragment. The trends in the EDA components are summarized

in Figs. 6 and 7, respectively. In the CB[6] environment, the neutral guest molecules find it difficult to form stable host–guest complexes as their interaction energies (ΔEint) are found to be positive (~ 50 kcal/mol). It is interesting to note that the charged species (mono- and di-cationic metallocenes) are found to show reliable stability inside the CB[6] environment. The interaction energies lie in the range of 50 kcal/mol and ~ − 75 kcal/mol for the mono- and dicationic species, respectively. This reveals that the change from neutral to mono-cationic species leads to increase the stability by ~ 100 kcal/mol. There is an increase in the stability of ~ 25 kcal/mol upon moving from mono-cation to di-cation metallocenes. It is evident that the charged bent metallocenes are found to have higher interaction energy than that of neutral bent metallocenes. This is expected as CBs are classic cation binders through favorable ion–dipole interactions. In all the cases, the repulsion energy (ΔEPauli) is found to be ~ 200 kcal/mol irrespective of the metallocenes.

Fig. 6 Trend of variation of various terms of the energy decomposition analysis for the Cp2MCl2@CB[7], [Cp2MCl@CB[7]]+and [Cp2M@ CB[7]]2+ (M=Ti, V, Nb, Mo) host–guest complexes calculated at BP86/TZP

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Fig. 7 Trend of variation of various terms of the energy decomposition analysis for the C p2MCl2@CB-[7], [Cp2MCl@CB-[7]]+and [Cp2M@ CB-[7]]2+ (M=Ti, V, Nb, Mo) host–guest complex calculated at BP86/TZP level

However, the repulsion energy is deceased by ~ 50–75 kcal/ mol as moving from neutral to mono- and di-cationic metallocenes. On the other hand, the favorable orbital energies (ΔEOrb) are found to remain constant in all the cases. Titanocene is found to show the largest electrostatic interaction with above 100 kcal/mol. It is observed to be greater electrostatic interactions upon an increase in the positive charge of the metallocenes (Fig. 8). Figure 7 gives the overall picture about the total interaction energies associated with the host–guest complexes of CB[7] with various contributing interactions. Unlike in the CB[6], the total interaction energy of neutral metallocenes is found to be closer to zero in general and in particular Cp2MoCl2 is found to show a stable host–guest complexation with a negative interaction energy (ΔEint) compared to other metallocenes in the CB[7] environment. Due to the larger size of CB[7] compared to that of CB[6], Pauli’s

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repulsion energy is found to be much lower (~ 60 kcal/mol). The orbital interaction energy is increased to ~ 20 kcal/mol upon moving from neutral to di-cationic metallocenes in CB[7]. The vanadium-based bent metallocenes show an increase in orbital interactions as the charge of the complex increases. Though this trend is similar in all the bent metallocenes, the vanadium-based bent metallocenes are found to show at least ~ 25 kcal/mol difference from neutral Cp2VCl2 to C p2V2+. However, the increase in the charge of the metallocene does not bring appreciable change in the electrostatic interactions inside the CB7. The change in the ΔEelstat is about only 5 kcal/mol in CB[7], while the same is about 20–40 kcal/mol in CB[6]. Thus, EDA provides useful clues to understand the kind of interactions that facilitate the host–guest complex formation in CBs.

JBIC Journal of Biological Inorganic Chemistry HOMO Cp 2MCl 2@CB[7]

LUMO Cp 2MCl 2@CB[7]

Cp2TiCl 2@CB[7]

Cp2TiCl2@CB[7]

-3.76 eV Cp2VCl 2@CB[7]

-2.25 eV Cp2NbCl2@CB[7]

-1.93 eV Cp2MoCl2@CB[7]

-2.49 eV

-1.68 eV Cp2VCl 2@CB[7]

-1.18 eV Cp2NbCl2@CB[7]

-1.06 eV Cp2MoCl 2@CB[7]

-1.09 eV

Fig. 8 Frontier molecular orbitals (FMO) of C p2MCl2@CB[7] (M=Ti, V, Nb, Mo) complexes computed at BP86/TZP level

Reactivity of host–guest complexes from FMO analysis The chemical reactivity and kinetic stability of a molecule are often characterized using frontier molecular orbitals (FMO) which provides qualitative information on the charge transfer properties of host–guest complexation (Fig. 8 and SIF2) [73–76]. Both in CB[6]-BM and CB[7]-BM complexes computed HOMO, and LUMO orbitals are dominantly localized on bent metallocene molecules. This shows that encapsulation does not alter their reactivity. Further, the host does not involve in any covalent interactions with a

guest molecule which would facilitate the reversible binding. This has been confirmed in the EDA where the orbital contributions are not predominant in these host–guest systems. Though host and guest do not encounter covalent interactions, functional groups of the host offer greater opportunity for non-covalent interactions thus favoring host–guest complex formation. To understand further, the FMO energies of free bent metallocenes and host–guest complexes have been calculated (Table 1). It is clear that the order of reactivity of the free bent metallocenes is as follows Cp2TiCl2 > Cp2VCl2 > Cp2MoCl2 > Cp2NbCl2 which is in line with the experimental reports [23]. Hydrolysis of first and second chloride ion from bent metallocene dichloride will lead to mono- and di-cationic complexes and this leads to the reduction of FMO energy gap. Thus, the order of FMO energy gap is M0 > M1+ > M2+ (M=Ti, V, Nb, and Mo), whereas the reactivity order is M0 Cp 2VCl 2@CB[6] > Cp 2NbCl2@CB[6] and this order is the same as the order of reactivity observed in free bent metallocenes (SIT1). However, it is interesting to note that the order of reactivity in charged species of bent metallocene inside CB[6] host (M0, M+1, M2+=Ti, V, Nb, Mo) shows a reverse trend with charge effect of free bent metallocene molecules. The order of FMO gap is [Cp2MCl2@CB[6]]0 CB[7]-BM2+and complexes are more reactive in CB[6] cavity than in CB[7] cavity revealing the excess strain experienced by BMs in CB[6] environment. 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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Cp2MCl2@CB[7]

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