Activation and Reactivity of a Bispidine Analogue of Cisplatin: A

Article pubs.acs.org/JPCA

Activation and Reactivity of a Bispidine Analogue of Cisplatin: A Theoretical Investigation Valentina Graziani, Cecilia Coletti,* Alessandro Marrone, and Nazzareno Re Dipartimento di Farmacia, Università degli Studi “G. D’Annunzio” Chieti-Pescara, Via dei Vestini, I-66100 Chieti, Italy S Supporting Information *

ABSTRACT: The reactivity of a bispidine, 3,7diazabicyclo[3.3.1]nonane, analogue of cisplatin, a new anticancer drug with promising properties, is theoretically investigated to clarify the in vitro reactivity and in vivo mechanism of action of this compound. Thermodynamics and kinetics of the first and second aquation steps and of the reaction of the generated mono- and diaqua species with guanine, the main target of the platinum based antitumor compounds, have been studied. In agreement with the experimental evidence, the bispidine analogue is significantly less reactive than cisplatin toward aquation but the formed aquaspecies show a good reactivity with guanine, consistently with the promising anticancer properties of these new compounds.

1. INTRODUCTION The clinical efficacy of cis-diamminedichloro-platinum(II), or cisplatin, as a potent antineoplastic drug, in the treatment of a variety of tumors, particularly testicular, ovarian, neck and head cancers, has long been well-established.1−9 However, its therapeutic success is compromised by serious side effects that have led to the search for new platinum compounds with improved pharmacological properties such as the secondgeneration Pt-based anticancer drug carboplatin, cis-diammine(cyclo-butane-1,1-dicarboxylato)-platinum(II), or the thirdgeneration drug oxaliplatin, (1R,2R-diaminocyclohexane)oxalato-platinum(II).10,11 Carboplatin shows reduced toxicity, a similar spectrum of activity with respect to cisplatin,12 and is currently used in the clinical treatment of cancer, although its cross-resistance with cisplatin limits its application in otherwise cisplatin-treatable diseases. Oxaliplatin and its derivatives, Nedaplatin, Lobaplatin and Heptaplatin,13 instead, exhibit a different anticancer spectrum from that of cisplatin and have the further advantage to be active in tumor types that are intrinsically resistant to cisplatin and carboplatin.9 In spite of these differences, cisplatin, carboplatin and oxaliplatin, as well as other Pt-based anticancer compounds, are thought to share similar mechanisms of action.2−8 In particular, their cytotoxicity arises primarily from covalent binding to DNA after hydrolysis of the labile ligands (Cl, DACH, etc.) to form monoaqua and diaqua complexes.9,14 This chemistry initiates a series of biochemical cascades, eventually leading to cell death.15 For cisplatin, many of the processes involved in this mechanism have been deeply studied both experimentally16−21 and theoretically,22−27 and similar investigations have been recently carried out for related platinum based drugs.28−33 © XXXX American Chemical Society

There is still much interest in the search for new platinum anticancer drugs aiming at reducing side effects, overcoming inherent or acquired resistance, broadening the spectrum of anticancer activity, improving DNA targeting, and simplifying drug administration. A detailed study of structure activity relationship of the possible oxaliplatin isomers has shown that the steric constraints imposed by the cyclic diamine chelate ligand in oxaliplatin, DACH, appear to hinder recognition and repair of DNA damage by specific cell proteins leading to a reduced platinum resistance.34,35 This finding has led to interest in the synthesis of new platinum compounds where the amine carrier ligands are provided by rigid cyclic or bicyclic diamines. Indeed, these complexes may show stronger hydrogen bonds between the amine groups and DNA phosphates or nucleobase heteroatoms, such as oxygen in guanine, or different steric properties thus facilitating their approach and covalent binding to DNA. Moreover, the constraints imposed on the N−Pt−N bite angles by the rigid cyclic or bicyclic structure could modify the hydrolysis profile of the corresponding complexes and the binding properties of the Pt atom. Some of these complexes have been prepared and investigated with respect to their structure and cytostatic properties, such as cyclic monoamines, chelating acyclic and cyclic diamines. Although such complexes are generally expected to be less potent, a few of them have been shown to have interesting anticancer properties.36−38 Special Issue: Piergiorgio Casavecchia and Antonio Lagana Festschrift Received: January 26, 2016 Revised: April 11, 2016

A

DOI: 10.1021/acs.jpca.6b00844 J. Phys. Chem. A XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry A A recent study 39 has shown that bispidine (3,7diazabicyclo[3.3.1]nonane) analogues of cisplatin, carboplatin, and oxaliplatin (see Scheme 1) show significant cytotoxic activity

functional,41,42 which is known to give a good description of reaction profiles for transition metal-containing compounds.43,44 Minima and transition state structures were optimized in gas phase using the LACVP** basis set,45 consisting, for the platinum atom, of the 1s−4d core electrons described with the Hay and Wadt core−valence relativistic (i.e., with an implicit treatment of scalar-relativistic effects) effective core-potential (ECP), whereas the outer 18 electrons are explicitly treated by a basis set of double-ζ quality;46 the remaining atoms are described with the 6-31G** basis set. The correct nature of the stationary points was verified by carrying out frequency calculations, which were also used to estimate zero-point energy (ZPE) and thermal corrections to thermodynamic properties. Intrinsic reaction coordinate (IRC) calculations were employed to correctly locate reagents and products minima connected with the transition states for each considered reaction step. Solvation energies were evaluated using the Poisson−Boltzmann (PB) continuum solvent method implemented in Jaguar.47 The energies of all stationary points were evaluated performing single point calculations with a larger basis set: 6-311++G** for the main group elements and LACV3P++**, consisting of the Hay and Wadt core−valence ECP basis set of triple-ζ quality plus diffuse d function, for the metal atom. Solvation enthalpies were taken as the difference between the solution energies and the gas phase energies. For the calculation of solvation entropies, we followed the Werz approach,48 which proved to lead to solution entropies and free energies in excellent agreement with experimental values27,32,33,49−52 for, among others, SN2 substitution reactions of square planar Pt(II) complexes and cisplatin in particular.27,49 This treatment is relevant for bimolecular reactions involving separated reagents and products: in this case, the translational degree of freedom in the reagents/products becomes a loose vibration for adducts or transition states, leading to a loss/gain of entropy, much larger in the gas phase than in the confined condensed phase. The direct use of gas phase entropies in solution might thus produce values which are overestimated with respect to solution phase entropies. According to Werz scheme, a solute dissolved in a solvent loses a constant fraction of its entropy in vacuo. For water, this loss amounts to48,49

Scheme 1. Bispidine Analogues of Cisplatin (1), Carboplatin (2), and Oxaliplatin (3)

along with relatively low platinum resistance factors. In particular, the cisplatin analogue 1 is slightly more cytotoxic than cisplatin against cisplatin-resistant human cancer cell lines with a strong reduction of the resistance factor. It is worth noting that these bispidine analogues all show a low reactivity against hydrolysis: although no detailed kinetic study has been performed, this is clearly pointed out by the experimental procedure carried out to crystallize 1, involving initial dissolution in warm water. As the monoaqua and diaqua complexes resulting from the hydrolysis of the anionic chloride or carboxylate ligands are usually considered to be the reactive species responsible of the Pt covalent binding to DNA nucleobases, the good cytotoxic activities of these bispidine analogues appear, at first sight, quite surprising. It is therefore interesting to shed light from a molecular point of view to the reasons lying behind the low reactivity against hydrolysis of these analogues and how, in spite of this, they show good cytotoxic activities. In this paper, we carry out density functional theory (DFT) calculations on the thermodynamics and the kinetics of the key steps in the expected mechanism of action of the bispidine analogue of cisplatin, 1, in particular the first and second hydrolysis steps and the covalent binding to guanine of the resulting monoaqua and diaqua complexes. Moreover, we also consider the direct binding of 1 to guanine to check whether this reaction, assumed to be negligible for cisplatin and other Pt anticancer complexes, could be responsible of its anomalous cytotoxicity. Special attention is put to understand to which extent the different behavior toward hydrolysis and DNA binding of 1 is related to the strain within the diamine chelate and the different exposition of the tertiary amine proton toward incoming water or nucleobase molecules. A deeper insight into the mechanism of activation and DNA binding of 1 may be important to understand its mechanism of action in vivo and may be useful to design new platinum-based anticancer drugs relying on cyclic or bicyclic diamines.

ΔSsolvation = −0.46(S° − 14.3) cal mol−1 K−1 − 6.32 cal mol−1 K−1

The use of this approach has led to values of activation enthalpies and entropies for the aquation of cisplatin in excellent agreement (i.e., within 1 kcal mol−1) with experimental results (see, for instance, Table S1).

3. RESULTS AND DISCUSSION A preliminary investigation was carried out on the isolated bispidine dichloro Pt(II) complex, showing a very good agreement between the minimized structure and the crystallographic data,39 with bond distances within 0.06 Å and bond angles within 6°, thus indicating that the B3LYP functional provides a reliable description of the molecular structures of these systems (see Table 1). In analogy with cisplatin, the mechanism of action of the bispidine analogue has been assumed to consist of an initial twostep activation process consisting of the stepwise substitution of the two chloride ions by two water molecules followed by covalent binding of the more reactive mono- or diaqua complexes to a guanine nucleobase (Scheme 2).

2. COMPUTATIONAL DETAILS All calculations were performed with the Jaguar 7.7 quantum chemistry package40 using DFT with the B3LYP hybrid B


Article

The Journal of Physical Chemistry A

for cisplatin and other Pt anticancer complexes, could play a significant role. Substitution reactions in square planar Pt(II) complexes are generally thought to proceed according to the Eigen-Wilkins mechanism of ligand interchange, which sees the formation of intermediate adducts between reagents and the incoming ligand and between products and the outgoing ligand. Indeed, such encounter complexes have recently been detected through IR multiple photon dissociation spectroscopy.53 For this reason, in the theoretically investigated mechanism we also minimized the geometries of the reagents (RA) and products (PA) adduct intermediates, and calculated their energies with respect to the isolated species. Reaction and activation enthalpies and free energies have then been evaluated relatively to the lowest between these adducts, and the reactants or products infinitely apart. Hydrolysis. Activation of cisplatin-like drugs proceeds in the first place through the replacement of one chloride ligand by water, as in Scheme 2a, preceded by the formation of the reactants adduct RA1. The minimized geometry of RA1 for the bispidine analogue is depicted in Figure 1, panel I(a), together with that of the corresponding adduct for cisplatin (Figure 1,

Table 1. Calculated and Experimental Main Geometrical Parameters of 1a theoretical Pt−N Pt−Cl N1···N2 N1−Pt− N2 Cl1−Pt− Cl2

experimental

B3LYP

solvent-free

DMF

water

2.095−2.096 2.353−2.354 2.842 85.4

2.038−2.041 2.310−2.314 2.777 85.79

2.029−2.037 2.322 2.772 85.99

2.029 2.326 2.758 85.63

98.0

92.21

93.65

92.11

a

Experimental X-ray data are shown for solvent-free crystals and those crystallized with one DMF or three water solvent molecules.39 (Distances in Ångstrom, angles in degrees).

DFT calculations were therefore carried out on the thermodynamics and the kinetics of the first and second hydrolysis steps of the bispidine dichloro Pt(II) complex 1 and the covalent binding to guanine of the resulting monoaqua and diaqua species. We also considered the direct binding of 1 to guanine to check whether this reaction, assumed to be negligible

Scheme 2. Investigated Mechanism of Action for the Cytotoxic Activity of 1a

first (a) and second (b) hydrolysis steps; covalent binding to guanine of the corresponding mono- (c) or bi- (d) aqua complex; direct covalent binding of 1 to guanine (e). a

C


Article


Figure 1. First aquation step: minimized structures for the reactant intermediate adducts RA1 (panel I), transition states TS1 (panel II), with an imaginary frequency of −155.97 cm−1 for bispidine and of −179.75 cm−1 for cisplatin, and product intermediate adducts PA1 (panel III) for bispidine (a), cisplatin (c) and their superposition (b).

panel I(c)). In the figure, panel I(b), a superposition of the two geometries is also shown to gain insights on the effect of the smaller N−Pt−N bite angle and of the steric hindrance of bispidine on the resulting structure. In both cases, the incoming water molecule bridges the chloride ligand to the neighboring amino group. In the bispidine analogue, RA1, the water is farther

from the platinum atom with respect to cisplatin (3.971 Å vs 3.646 Å), probably due to possibility of forming more effective in-plane hydrogen bonds with chloride and the amino hydrogen, leading to a slightly more stable adduct (3.2 vs 3.5 kcal/mol higher in free energy with respect to separated reagents, Table S1). The transition state structure, TS1 (with an imaginary D


Article


Figure 2. Second aquation step: minimized structures for the reactant intermediate adducts RA2 (panel I), transition states TS2 (panel II), with an imaginary frequency of −148.68 cm−1 for bispidine and of −175.78 cm−1 for cisplatin, and product intermediate adducts PA2 (panel III) for bispidine (a), cisplatin (c) and their superposition (b).

frequency of −155.97 cm−1), shown in Figure 1 panel II(a), is approximately trigonal bipyramidal (incoming ligand−metaloutgoing ligand angle of 67.6°), consistently with literature data, indicating that platinum planar square complexes undergo ligand substitution reactions through an associative interchange mechanism, via a pentacoordinate transition state.51,52 This geometry is very close to the corresponding cisplatin TS1 (Figure

1, panel II(c)) with little larger distances between Pt and the oxygen of the entering water molecule (2.466 vs 2.432 Å) and between Pt and the leaving chloride (2.812 vs 2.794 Å), leading to a slightly less stable transition state (25.1 vs 24.4 kcal/mol higher in free energy with respect to separated reagents, Table S1). In the product adduct PA1 structure (Figure 1, panel III(a)) the water molecule has replaced the leaving chloride ion (Pt−O E


Article


Figure 3. Free energy profiles (at 298.15 K) for the first (left) and second (right) aquation steps.

destabilization of RA2 for bispidine with respect to cisplatin (2.1 vs 2.7 kcal/mol higher in free energy with respect to separated reagents, Table S1). The structure of transition state for the bispidine analogue, TS2 (with an imaginary frequency of −148.68 cm−1), indicates again an approximate trigonal bipyramidal geometry with an acute Cl−Pt−O angle of 68.4°. Pt−O and Pt−Cl bond distances (2.44 and 2.74 Å) are shorter than those for TS1 and suggest a later transition state than for the first activation step. TS2 geometries for bispidine and cisplatin are very much alike (Figure 2, panel II(b)), with only small differences in bonding and hydrogen bonding distances. In the PA2 adduct, Figure 2, panel III(a), the leaving chloride ion is far from the platinum center (3.613 Å) but still interacts with the complex through hydrogen bonds with both aqua ligands and the geometry is very close to that of the corresponding cisplatin intermediate (Figure 2, panel III(b)). Reaction and activation enthalpies and free energies for the first and second hydrolysis reactions of 1, together with those calculated for the cisplatin counterpart, are reported in Table S1. The results refer to both reagents/products infinitely apart and reagents/products adducts and are illustrated in the free energy profile in Figure 3. As the free energies of the reagents/products adducts are above those of reagents/products infinitely apart, the activation free energies discussed below are referred to the latter configurations. Figure 3 shows that the activation free energy calculated for the first hydrolysis of the bispidine analogue, 25.1 kcal mol−1, is slightly but significantly higher than that calculated for cisplatin. Although the energy difference is of only ca. 1 kcal mol−1, it is large enough to lead to a kinetic constant (through the Eyring equation) almost 5 times smaller than for cisplatin, consistently with the experimental evidence. The value of reaction free energy, 1.7 kcal mol−1, indicates that the first hydrolysis step is a slightly endoergonic process, significantly more than cisplatin, 0.2 kcal mol−1. The second hydrolysis step has both an activation, 24.8 kcal mol−1, and a reaction free energy, 1.6 kcal mol−1, very close to those of the first hydrolysis, and similar to the corresponding values for cisplatin. The calculated values of the activation and reaction enthalpies and free energies for both steps suggest that the bispidine

Figure 4. Computed activation enthalpies for cisplatin and its bispidine analogue (this work), carboplatin,28 oxaliplatin,29 and nedaplatin.30 Experimental values for cisplatin are 20 kcal/mol,16 22 kcal/mol17 and 19 kcal/mol18 for the first aquation and 20 kcal/mol16 for the second aquation.

distance of 2.092 Å, compared to 2.067 Å for cisplatin), which has moved away from the metal center (Pt−Cl distance: 3.923 Å) but still interacts via a hydrogen bond with the amino ligand (N−H··· Cl distance: 2.020 Å) and with the water molecule (O−H···Cl distance: 1.889 Å). The geometry is again quite close to the corresponding cisplatin PA1, with slightly larger bonding and interacting distances, leading to a little less stable adduct than cisplatin (6.6 vs 5.6 kcal/mol higher in free energy with respect to separated reagents, Table S1). The second activation step, Scheme 2b, consists of the attack of a second water molecule on the monoaqua product of the first step. Figure 2 reports the minimized geometries of RA2 (panel I), TS2 (panel II) and PA2 (panel III) for bispidine, cisplatin, and their superposition. RA2 and TS2 geometries have a similar structure to those for the first step: the incoming water molecule bridges the chloride ion and the amino group through hydrogen bonds, with longer OH···Cl and shorter NH···OH distances, due to the different charge of the platinum moiety, which is neutral in the first step and positive in the second one. The RA2 adduct for bispidine is again structurally similar to the corresponding complex for cisplatin, with a longer entering water−platinum distance (3.908 vs 3.702 Å) accounting for the slight F


Article


Figure 5. Covalent binding of the monoaqua complex to guanine: minimized structures for the reactant intermediate adducts RA1 (panel I), transition states TS1 (panel II), with an imaginary frequency of −123.06 cm−1 for bispidine and of −149.08 cm−1 for cisplatin, and product intermediate adducts PA1 (panel III) for bispidine (a), cisplatin (c) and their superposition (b).

analogue hydrolysis activation process is significantly less favorable both kinetically and thermodynamically than that of cisplatin. These results are in agreement with the experimental evidence39 indicating a sufficient stability of 1 in warm water allowing its recrystallization upon cooling to room temperature. It might be interesting to compare activation enthalpies and/ or free energies with those calculated for other platinum based anticancer drugs that have entered or completed clinical trials, such as carboplatin, oxaliplatin, and nedaplatin. For these compounds, activation enthalpy values for first and second aquation processes have recently been calculated at a similar level of theory,28−30 though small differences, up to 2 kcal mol−1, can be ascribed to the use of a different solvation model, i.e., CPCM instead of Poisson−Boltzmann. The corresponding values are

compared with those obtained for cisplatin and for the bispidine analogue in this work in Figure 4. Carboplatin, oxaliplatin, and nedaplatin all present slower activation rates for first hydrolysis, the underlying process being rather different as it implies the opening of a malonate or glycolate ring. However, it is worth noting that the difference between the first hydrolysis activation enthalpies of oxaliplatin and nedaplatin is similar to that we calculated for cisplatin and bispidine. The two compounds do indeed show similar structural differences in their amino moiety: two NH3 molecules in nedaplatin (as in cisplatin) and a closed amino ring in oxaliplatin (which has in fact a bite angle of 83.5°, very close to that of bispidine). Correspondingly, the activation enthalpy for oxaliplatin is similar (within 1 kcal mol−1) to that of nedaplatin, as found between cisplatin and its bispidine analogue G


Article


Figure 6. Covalent binding of the diaqua complex to guanine: minimized structures for the reactant intermediate adducts RA2 (panel I), transition states TS2 (panel II), with an imaginary frequency of −118.89 cm−1 for bispidine and of −145.50 cm−1 for cisplatin, and product intermediate adducts PA2 (panel III) for bispidine (a), cisplatin (c), and their superposition (b).

Covalent Binding to DNA. The covalent binding to DNA of the mono- and diaqua species was simulated through the replacement of one water ligand on the Pt center by a guanine

in the present work. The same holds for second aquation: bispidine shows an activation enthalpy ca. 1 kcal mol−1 smaller than cisplatin, and so does oxaliplatin with respect to nedaplatin. H


Article


Figure 7. Direct covalent binding to guanine: minimized structures for the reactant intermediate adducts RA (panel I), transition states TS (panel II), with an imaginary frequency of −112.34 cm−1 for bispidine and of −141.20 cm−1 for cisplatin, and product intermediate adducts PA (panel III) for bispidine (a), cisplatin (c) and their superposition (b).

nucleobase through its N7 atom. We first considered the monoaqua species, Scheme 2c, for which the optimized reactants adduct RA1 geometry (Figure 5, panel I(a)) shows the attacking guanine molecule interacting via hydrogen bonds to one amino group of bispidine and to the leaving water molecule, respectively, through the O6 ketone oxygen and the N7 atom, with calculated NH···O6 and N7···HO distances of 1.850 and 1.640 Å. This net of hydrogen bonds is, however, a little looser than in cisplatin, Figure 5 panel I(c), resulting in the N7 atom farther from the metal center with a Pt···N distance of 4.127 Å. In the transition state structure, TS1 (Figure 5 panel II(a), with an imaginary frequency of −123.06 cm−1), the N7 of the incoming guanine has approached the platinum center, whereas the water molecule is farther (Pt−N7 and Pt−O distances of 2.621 and

2.440 Å) and is stabilized by a hydrogen bond between the O6 ketone oxygen of guanine and the bispidine amino group, the same observed in the reactant adduct RA1. The geometry is again trigonal bipyramidal, with a leaving ligand-platinum-incoming ligand angle of 68.0°. The structure is very similar to that obtained for cisplatin (Figure 5, panel II(c)) and so are the corresponding activation free energies (20.8 kcal mol−1 for bispidine vs 20.4 kcal mol−1 for cisplatin, Table S2). The optimized product adduct PA1 geometry shows that the N7 atom of the entering guanine molecule has definitively replaced the water molecule (Pt−N7 distance: 2.121 Å), while the leaving water ligand has moved away from the metal center (Pt−O distance: 4.787 Å; see Figure 5, panel III(a)), and is still stabilized by the same hydrogen bond between the O6 ketone oxygen of I


Article


Figure 9. Computed activation free energies for cisplatin and its bispidine analogue (this work), carboplatin, oxaliplatin and nedaplatin31 for the reaction of their monoaqua derivative with the N7 nitrogen of guanine.

bonds. The transition state structure, TS2 (Figure 6 panel II(a), and imaginary frequency of −118.89 cm−1) presents the characteristic distorted bipyramidal geometry, with an acute leaving ligand−platinum−incoming ligand angle of 66.1° and Pt−N7 and Pt−O distances of 2.629 and 2.485 Å, respectively. The structure is stabilized by a hydrogen bond between the O6 ketone oxygen of guanine and the remaining aqua ligand, the same observed in RA2, as in the corresponding structure of cisplatin, Figure 6, panel II(c). In the product adduct intermediate, PA2, the incoming guanine molecule has definitively substituted the water molecule (Pt−N7 distance: 2.102 Å), which has moved away from the metal center (Pt−O distance: 4.381 Å) and interacts with one amino ligand via a hydrogen bond (with a O−H distance of 1.955 Å; see Figure 6, panel III(a)), and the structure remains stabilized by the hydrogen bond between the O6 ketone oxygen of guanine and the remaining aqua ligand. The main difference with respect to the structure of the cisplatin analogue is again in the position of the leaving water molecule, which, in bispidine, can only interact with the one hydrogen in the amino group, forced to lie in the Pt coordination plane, due to the rigidity of bispidine structure. We then turned to consider the direct covalent binding of 1 to DNA, consisting of the straightforward replacement of one chloride ligand by a guanine nucleobase through its N7 atom, Scheme 2e. The structure of the reactants adduct, RA1, (Figure 7, panel I(a)) sees the incoming guanine molecule interacting only to one amino group of bispidine, with the O6 ketone oxygen atom, with calculated NH···O6 distance of 1.921 Å. In this case, the interaction mode of the approaching moieties is quite different with respect to cisplatin (Figure 7, panel I(c)), where the number of amino hydrogens and the smaller steric hindrance result in a much larger stabilization of this encounter adduct (4.5 for cisplatin vs 9.0 kcal mol−1 for bispidine higher in free energy than infinitely separated reactants). Indeed, the rigidity of the bispidine cycle forces the N−H bond into the Pt coordination plane and thus limits its possibility to establish stronger hydrogen bonds, especially when more encumbered ligands, like guanine, are involved. The transition state, TS1, Figure 7 panel II(a), with an imaginary frequency of −112.34 cm−1, has distorted trigonal bipyramidal geometry, with Pt−N7 and Pt−Cl distances of 2.448 and 2.730 Å, respectively, and an angle of 74.9° for the outgoing ligand−platinum−incoming ligand. The geometry is more

Figure 8. Free energy profiles (at 298.15 K) for the binding of guanine to the mono- (a) and diaqua (b) complexes, and for its direct binding to 1 (c).

guanine and the bispidine amino group, observed in the reactant adduct RA1 and in the transition state TS1. This geometry is again very close to that relative to cisplatin, the main difference being the position of the leaving water molecule, which, in bispidine, can only hydrogen bond to the hydrogen of the amino group not interacting with guanine. For the diaqua species, Scheme 2d, the replacement of one water ligand on the Pt center by a guanine nucleobase follows essentially the same pathway calculated for the monoaqua complex. In the reactants adduct RA2 geometry (Figure 6, panel I(a)) the attacking guanine molecule interacts via hydrogen bonds with the two aqua ligands through the O6 ketone oxygen atom and the N7 atom. The calculated O6···HO and N7···HO distances of 1.455 and 1.454 Å, as well as the good stabilization of RA2 with respect to separated R2 and guanine molecules (by 9.5 kcal mol−1 in enthalpy, Table S2), indicate quite strong hydrogen J


Article


formed aquaspecies show a good reactivity with guanine consistently with the promising anticancer properties of these new compounds.

similar to that of the corresponding transition state for cisplatin with respect to RA1, but the hydrogen bonding pattern is again less effective and the free energy activation barrier is more than 4 kcal mol−1 higher than that of cisplatin (Table S2). In the optimized product adduct PA1 geometry, the N7 atom of the entering guanine molecule has definitively replaced the chloride ion (Pt−N7 distance: 2.068 Å) that has moved away from the metal center, while the O6 guanine atom forms a hydrogen bond with one of the bispidine amino groups (with a O−H distance of 1.985 Å; see Figure 7, panel III(a)). Free energy profiles for the covalent binding of guanine to 1 and its mono- and diaqua derivatives are illustrated in Figure 8, whereas the complete collection of activation and reaction enthalpies and free energies are reported in Table S2, together with those calculated for cisplatin as reference. The values are referred to both the reagents and products infinitely apart and to the reagent and product adducts. Table S2 shows that the activation free energy calculated for the binding of guanine to the monoaqua complex of the bispidine analogue is very close to that for the monoaqua complex of cisplatin, 20.8 vs 20.4 kcal mol−1, indicating similar reactivity for these two monoaqua species. Also the activation free energy calculated for the binding of guanine to the diaqua complex of the bispidine analogue is similar to that calculated for the monoaqua complex of cisplatin, 21.3 vs 20.9 kcal mol−1, indicating a similar reactivity for the cisplatin and bispidine analogue diaqua complexes. The reaction free energies for the binding of guanine to both mono- and diaqua complexes are similar −8/-9 kcal mol−1, indicating a moderately exothermic reaction, and are a little higher than those for the corresponding cisplatin aquaspecies, −11/−12 kcal mol−1. The activation free energy calculated for the direct binding of guanine to 1 is rather high (28.7 kcal mol−1, even higher than that to cisplatin), thus ruling out this mechanism as responsible for its anticancer activity. Figure 9 compares the activation free energies for the covalent binding of guanine to the monoaqua derivatives of cisplatin and its bispidine analogue calculated in this work with those obtained for carboplatin, oxaliplatin, and nedaplatin in ref 31. The reaction rate for bispidine is expected to be slower than that of carboplatin and oxaliplatin, but significantly faster than nedaplatin.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.6b00844. Table S1 with activation and reaction enthalpies and free energies for first and second aquation processes for cisplatin and its bispidine analogue. Table S2 with activation and reaction enthalpies and free energies for the platination processes for cisplatin and its bispidine analogue. Cartesian coordinates of all bispidine species described in the paper. (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*Author e-mail address: [email protected]. Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS Funding from University “G. d’Annunzio” is gratefully acknowledged. REFERENCES

(1) Rosenberg, B.; Van Camp, L.; Trosko, J. E.; Mansour, V. H. Platinum compounds: a new class of potent antitumour agents. Nature 1969, 222, 385−386. (2) Sherman, S. E.; Lippard, S. J. Structural aspects of platinum anticancer drug interactions with DNA. Chem. Rev. 1987, 87, 1153− 1181. (3) Reedijk, J. Improved understanding in platinium antitumour chemistry. Chem. Commun. 1996, 801−806. (4) Jamieson, E. R.; Lippard, S. J. Structure, Recognition, and Processing of Cisplatin-DNA Adducts. Chem. Rev. 1999, 99, 2467− 2498. (5) Wang, D.; Lippard, S. J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discovery 2005, 4, 307−320. (6) Jung, Y.; Lippard, S. J. Direct cellular responses to platinuminduced DNA damage. Chem. Rev. 2007, 107, 1387−1407. (7) Arnesano, F.; Natile, G. Mechanistic insight into the cellular uptake and processing of cisplatin 30 years after its approval by FDA. Coord. Chem. Rev. 2009, 253, 2070−2081. (8) Klein, A. V.; Hambley, T. W. Platinum drug distribution in cancer cells and tumors. Chem. Rev. 2009, 109, 4911−4920. (9) Clarke, M. J.; Zhu, F.; Frasca, D. R. Non-Platinum Chemotherapeutic Metallopharmaceuticals. Chem. Rev. 1999, 99, 2511−2534. (10) Harrap, K. R. Preclinical studies identifying carboplatin as a viable cisplatin alternative. Cancer Treat. Rev. 1985, 12, 21−33. (11) Boulikas, T.; Vougiouka, M. Cisplatin and platinum drugs at the molecular level. Oncol. Rep. 2003, 10, 1663−1682. (12) Knokhar, A. R.; Al-Baker, S.; Krakoff, I. H.; Perez-Soler, R. Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2diaminocyclohexane) platinum(II) complexes entrapped in liposomes. Cancer Chemother. Pharmacol. 1989, 23, 219−224. (13) Galanski, M.; Jakupec, M. A.; Keppler, B. K. Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr. Med. Chem. 2005, 12, 2075−2094. (14) De Petris, A.; Ciavardini, A.; Coletti, C.; Re, N.; Chiavarino, B.; Crestoni, M. E.; Fornarini, S. Vibrational Signatures of the Naked Aqua Complexes from Platinum(II) Anticancer Drugs. J. Phys. Chem. Lett. 2013, 4, 3631−3635.

4. CONCLUSION A DFT study has been carried out to investigate the reactivity of a bispidine, 3,7-diazabicyclo[3.3.1]nonane, an analogue of cisplatin and a new anticancer drug with promising properties, to clarify the reactivity and the mechanism of action of this compound. We calculated both the thermodynamics and kinetics of the first and second aquation steps and of the reaction of the generated mono- and diaqua species with guanine, the main target of the platinum based antitumor compounds. An activation free energy of 25.1 kcal mol−1 was calculated for the first hydrolysis step, significantly higher than that calculated for cisplatin, ca. 1 kcal mol−1, so to lead to a kinetic constant (through the Eyring equation) almost 5 times smaller than for cisplatin, consistent with the experimental evidence. On the other hand, the activation free energies calculated for the binding of guanine to the mono- and diaqua complex of the bispidine analogue are very close to those for the corresponding aqua complexes of cisplatin, 20.8 vs 20.4 kcal mol−1 and 21.3 vs 20.9 kcal mol−1, respectively, indicating similar reactivity for these aqua species. In conclusion, in agreement with the experimental evidence, our calculations indicate that the bispidine analogue is significantly less reactive than cisplatin toward aquation, but the K


Article

The Journal of Physical Chemistry A (15) Herman, F.; Kozelka, J.; Stoven, V.; Guittet, E.; Girault, J.-P.; Huynh-Dinh, T.; Igolen, J.; Lallemand, J.-Y.; Chottard, J.-C. A d(GpG)platinated decanucleotide duplex is kinked. An extended NMR and molecular mechanics study. Eur. J. Biochem. 1990, 194, 119−133. (16) Coe, J. S. In MTP International Review of Science; Tobe, M. L., Ed.; Inorganic Chemistry, Series Two; Butterworths: London, 1974, Vol. 9, 45−62. (17) Perumareddi, J. R.; Adamson, A. W. Photochemistry of complex ions. V. The photochemistry of some square-planar platinum(II) complexes. J. Phys. Chem. 1968, 72, 414−420. (18) Bose, R. N.; Cornelius, R. D.; Viola, R. E. Phosphorus-31 NMR and kinetic studies of the formation of ortho-, pyro-, and triphosphato complexes of cis-dichlorodiammineplatinum(II). J. Am. Chem. Soc. 1984, 106, 3336−3343. (19) Arpalahti, J.; Mikola, M.; Mauristo, S. Kinetics and mechanism of the complexation of cis-diamminedichloroplatinum(II) with the purine nucleoside inosine in aqueous solution. Inorg. Chem. 1993, 32, 3327− 3332. (20) Hindmarsch, K.; House, D. A.; Turnbull, M. M. The hydrolysis product of cis-diamminedichloroplatinum(II) 9. Chloride and bromide anation kinetics for some [PtII(N)2(OH2)2]2+ complexes and the structures of [PtIVBr4(N)2] ((N)2= en, tn)1. Inorg. Chim. Acta 1997, 257, 11−18. (21) Jestin, J.-L.; Lambert, B.; Chottard, J.-C. Kinetic study of DNA binding of cisplatin and of a bicycloalkyl-substituted(ethylenediamine)dichloroplatinum(II) complex. JBIC, J. Biol. Inorg. Chem. 1998, 3, 515− 519. (22) Baik, M.-H.; Friesner, R. A.; Lippard, S. J. Theoretical study on the stability of N-glycosyl bonds: why does N7-platination not promote depurination? J. Am. Chem. Soc. 2002, 124, 4495−4503. (23) Raber, J.; Zhu, C.; Eriksson, L. A. Activation of anti-cancer drug cisplatin - is the activated complex fully aquated? Mol. Phys. 2004, 102, 2537−2544. (24) Burda, J. V.; Zeizinger, M.; Leszczynski, J. Hydration process as an activation of trans- and cisplatin complexes in anticancer treatment. DFT and ab initio computational study of thermodynamic and kinetic parameters. J. Comput. Chem. 2005, 26, 907−914. (25) Zimmermann, T.; Chval, Z.; Burda, J. V. Cisplatin Interaction with Cysteine and Methionine in Aqueous Solution: Computational DFT/PCM Study. J. Phys. Chem. B 2009, 113, 3139−3150. (26) Zimmermann, T.; Burda, J. V. Reactions of cisplatin with cysteine and methionine at constant pH; a computational study. Dalton Trans 2010, 39, 1295−1301. (27) Lau, J. K. C.; Deubel, D. V. Hydrolysis of the anticancer drug cisplatin: Pitfalls in the interpretation of quantum chemical calculations. J. Chem. Theory Comput. 2006, 2, 103−106. (28) Pavelka, M.; Lucas, M. A. F.; Russo, N. On the hydrolysis mechanism of the second-generation anticancer drug carboplatin. Chem. - Eur. J. 2007, 13, 10108−10116. (29) Lucas, M. F. A.; Pavelka, M.; Alberto, M. E.; Russo, N. Neutral and acidic hydrolysis reactions of the third generation anticancer drug oxaliplatin. J. Phys. Chem. B 2009, 113, 831−838. (30) Alberto, M. E.; Lucas, M. F. A.; Pavelka, M.; Russo, N. The second-generation anticancer drug nedaplatin: a theoretical investigation on the hydrolysis mechanism. J. Phys. Chem. B 2009, 113, 14473−14479. (31) Alberto, M. E.; Butera, V.; Russo, N. Which one among the Ptcontaining anticancer drugs more easily forms monoadducts with G and A DNA bases? A comparative study among oxaliplatin, nedaplatin, and carboplatin. Inorg. Chem. 2011, 50, 6965−6971. (32) Ciancetta, A.; Coletti, C.; Marrone, A.; Re, N. Activation of carboplatin by chloride ions: a theoretical investigation. Theor. Chem. Acc. 2011, 129, 757−769. (33) Ciancetta, A.; Coletti, C.; Marrone, A.; Re, N. Activation of Carboplatin by Carbonate: A Theoretical Investigation. Dalton Trans. 2012, 41, 12960−12969. (34) Ranaldo, R.; Margiotta, N.; Intini, F. P.; Pacifico, C.; Natile, G. Conformer distribution in (cis-1,4-DACH)bis(guanosine-5′-

phosphate)platinum(II) adducts: a reliable model for DNA adducts of antitumoral cisplatin. Inorg. Chem. 2008, 47, 2820−2830. (35) Margiotta, N.; Marzano, C.; Gandin, V.; Osella, D.; Ravera, M.; Gabano, E.; Platts, J. A.; Petruzzella, E.; Hoeschele, J. D.; Natile, G. Revisiting [PtCl2(cis-1,4-DACH)]: an underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer. J. Med. Chem. 2012, 55, 7182−7192. (36) Mukhopadhyay, U.; Thurston, J. H.; Whitmire, K. H.; Khokhar, A. R. Synthesis and characterization of cis-bis-heptamethyleneimine platinum(II) dicarboxylate complexes: crystal structure of cis-[Pt(heptamethyleneimine)2(malonate)]·H2O. Polyhedron 2002, 21, 2369−2374. (37) Luzyanin, K. V.; Gushchin, P. V.; Pombeiro, A. J. L.; Haukka, M.; Ovcharenko, V. I.; Kukushkin, V. Y. Oxidation of Pt-bound bishydroxylamine as a novel route to unexplored dinitrosoalkane ligated species. Inorg. Chem. 2008, 47, 6919−6930. (38) Ali, M. S.; Powers, C. A.; Whitmire, K. H.; Guzman-Jimenez, I.; Khokhar, A. R. Synthesis, characterization, and representative crystal structure of lipophilic platinumII (homopiperazine)carboxylate complexes. J. Coord. Chem. 2001, 52, 273−287. (39) Cui, H.; Goddard, R.; Pörschke, K.-R.; Hamacher, A.; Kassack, R. U. Bispidine analogues of cisplatin, carboplatin, and oxaliplatin. Synthesis, structures, and cytotoxicity. Inorg. Chem. 2014, 53, 3371− 3384. (40) Jaguar, version 7.7; Schrodinger, LLC: New York, 2010. (41) Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648−5652. (42) Becke, A. D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098−3100. (43) Niu, S.; Hall, B. M. Theoretical studies on reactions of transitionmetal complexes. Chem. Rev. 2000, 100, 353−405. (44) Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A., III A computational model relating structure and reactivity in enantioselective oxidations of secondary alcohols by (−)-sparteina-PdII complexes. J. Am. Chem. Soc. 2004, 126, 7967−7974. (45) Hariharan, P. C.; Pople, J. A. The effect of d-functions on molecular orbital energies for hydrocarbons. Chem. Phys. Lett. 1972, 16, 217−219. (46) Hay, P. J.; Wadt, W. R. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys. 1985, 82, 299−310. (47) Tannor, D. J.; Marten, B.; Murphy, R.; Friesner, R. A.; Sitkoff, D.; Nicholls, A.; Ringnalda, M.; Goddard, W. A., III; Honig, B. Accurate first principles calculation of molecular charge distributions and solvation energies from ab initio quantum mechanics and continuum dielectric theory. J. Am. Chem. Soc. 1994, 116, 11875−11882. (48) Wertz, D. H. Relationship between the gas-phase entropies of molecules and their entropies of solvation in water and 1-octanol. J. Am. Chem. Soc. 1980, 102, 5316−5322. (49) Cooper, J.; Ziegler, T. A density functional study of SN2 substitution at square-planar platinum(II) complexes. Inorg. Chem. 2002, 41, 6614−6622. (50) Ahlquist, M.; Nielsen, R. J.; Periana, R. A.; Goddard, W. A., III Product protection, the key to developing high performance methane selective oxidation catalysts. J. Am. Chem. Soc. 2009, 131, 17110−17115. (51) Zhu, H.; Ziegler, T. Probing the influence of trans and leaving ligands on the ability of square-planar platinum(II) complexes to activate methane. A theoretical study. Organometallics 2009, 28, 2773− 2777. (52) Bercaw, J. E.; Chen, G. S.; Labinger, J. A.; Lin, B. L. Protonolysis of platinum(II) and palladium(II) methyl complexes: a combined experimental and theoretical investigation. Organometallics 2010, 29, 4354−4359. (53) Corinti, D.; Coletti, C.; Re, N.; Chiavarino, B.; Crestoni, M. E.; Fornarini, S. Cisplatin binding to biological ligands revealed at the encounter complex level by IR action spectroscopy. Chem. - Eur. J. 2016, 22, 3794−3803.

L


Activation and Reactivity of a Bispidine Analogue of Cisplatin: A

Recommend Documents