Exploring Novel Modified Vitamin B12 as a Drug Carrier: Forecast

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Exploring Novel Modified Vitamin B as a Drug Carrier: Forecast from DFT Modeling Dorota Rutkowska-Zbik, Gabriela Mazur, Agnieszka Drzewiecka-Matuszek, #ukasz Orze#, and Grazyna Stochel J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/jp405821k • Publication Date (Web): 26 Jul 2013 Downloaded from http://pubs.acs.org on August 1, 2013

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The Journal of Physical Chemistry

Exploring Novel Modified Vitamin B12 as a Drug Carrier: Forecast from DFT Modeling Dorota Rutkowska-Zbik,†* Gabriela Mazur,‡ Agnieszka Drzewiecka-Matuszek,† Łukasz Orzeł,‡ GraŜyna Stochel‡ †

Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, ul. Niezapominajek 8, 30-239 Kraków, Poland ‡

Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland

*corresponding author: Dorota Rutkowska-Zbik, e-mail: [email protected]

KEYWORDS cobalamin, cisplatin, DFT modeling, drug carriers, bridging ligand

Three non-native derivatives of vitamin B12 were characterized: with imidazole, ethylenediamine and pyrazine as cobalt(III) β ligands applying BP/def2-TZVP Density Functional Method. The binding of all tree ligands is thermodynamically favourable. It is proposed that their synthesis might be able from aquacobalamin as a starting form of vitamin B12, as has already been done in

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case of imidazole derivative of B12 (Inorg. Chem. 46 (2007) 3613-3618). Further, the possibility of the formation of their conjugates with cisplatin is investigated. The proposed β ligands may serve as bridging ligands, binding to the platin ion as N-donors. In parallel, the calculations are done for already synthetized B12-cisplatin adduct with CN- as a bridging ligand and confronted with available experimental data, allowing to assess the applied computational protocol. A good agreement of the computed and experimental structural parameters is obtained. In each of the studied structures the Co-β ligand is weaker than the Pt-β ligand bond.

Introduction

Cobalamin (Vitamin B12) is the coenzyme that affects the metabolism of every cell of a human body. Its primary role is related to the methylation reactions, the key steps in such processes as homocysteine conversion to methionine or synthesis of the succinyl-CoA, a metabolite of the Krebs cycle.1 Vitamin B12 participates in regulation of the brain and nervous system functioning, as well as in blood and nucleic acids formation. For these reasons there is a large demand on cobalamin uptake by highly proliferating cells.2 This fact entails extensive consequences in terms of the applicability of vitamin B12 in the diagnosis and treatment of tumours. Attaching the respective fluorescent markers to cobalamin molecule makes it useful in the imaging of malignant cells.3 Above all, the possibility to bind a drug makes vitamin B12 a kind of the Trojan horse in cancer therapy. Therefore, designing of the cobalamin-drug arrangement which ensures both biological activity and selective accumulation in the affected cells should be based on the


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analysis of stability of such combination and on the predictions of its influence on the B12 structure.

Cobalamin is a complex of cobalt ion with the corrin ligand, derived from the tetrapyrrolic framework. Displacement of one carbon atom from the methine bridge and the presence of dimethylbenzimidazole group in the peripheral substituent of the macrocycle which binds Co at its so-called α axial position determine complex stability and significantly affect the coordination properties of the central ion at the opposite β position. In native vitamin B12 it is occupied by cyanide or water molecule that are then enzymatically substituted by a methyl or adenosyl group inside the cells.4 Six other peripheral hydrocarbon chains in the structure of cobalamin are ended with the amide groups. They pose the potential sites of modifications that allow attachment of a therapeutic or diagnostic agent.5 There are numerous reports revealing, that modifications in the region of selected amide groups enabled to use B12 as a carrier in both radiotherapy6 and radiodiagnostics7,8 as well as NMR imaging of malignant tissues.9

The

diagnostic or therapeutic agent may also be attached to central cobalt ion by through a bridging ligand at β axial position. So far, the complexes of B12 with Fe(III), Pt(II), Re(I) and Tc(I) with native cyanic bridges have been synthesized.10-14 The conjugates with Pt(II), Re(I) and Tc(I) were found to reveal considerable cytostatic and radiochemical activity, respectively. Recently the inactive analogues of Pt(II)-B12 were reported.15,16 Such a class of pro-drugs introduces requirement for additional trigger thus lowering toxic side-effects.

Selection of drug binding sites must be based on both ensuring the proper stability and preservation of the native structure of cobalamin. The latter is necessary for efficient transport


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across the membranes. The specialized system for cellular uptake of B12 involves three binding proteins, namely haptocorrin, intrinsic factor, and transcobalamin (TC),1,17 which together with attached cobalamin molecule remain recognizable by the membrane receptor protein, cubilin.18 The X-ray structure revealed that the TC tightly surrounds the entire cobalamin molecule.19 Although the histidine residue of the protein is able to displace a labile ligand at the β-axial position of the cobalamin20 a modification in this site does not influence much the cobalamin recognition by B12 transport proteins.19,21 The attachment of a drug molecule at β site is of particular interest, as it should not interfere much with B12 cellular transport pathways.

Therefore the aim of the present research was to characterize a) the possible modifications of vitamin B12 with various bridging species, which has not, as yet, been used for this purpose, namely: imidazole (im), pyrazine (pz), and ethylenediamine (en), and b) their conjugates with cisplatin. The selection of the bridging species follows from their use in similar systems and relatively small size, which is important to still fit into B12 transporting proteins. Imidazole is known as a bridging ligand especially in iron porphyrin conjugates.22 Pyrazine bridges e.g. Pt(II) ions in multinuclear Pt complexes, which are tested as analogues of cisplatin.23 Ethylenediamine is often employed as Pt(II) ligand in its mononuclear complexes.24

Methodology

Vitamin B12 was modelled by two geometries: a simplified structure, in which only the core structure of the corrin ring was taken into account with imidazole representing


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dimethylbenzimidazole axial ligand (DMB), in the manuscript referred to as Cob- – see Figure 1a, and the complete model, where all functional groups were retained, referred to as B12- – see Figure 1b. The first one is often employed for quantum chemical studies of cobalamins25-27, allowing for a considerable shortening of computational time. This model bears total charge of +1 for anionic and +2 for neutral ligands, because of +3 oxidation state of the cobalt ion and the total charge of -1 of the corrin ring. The second model, owing to the progress in computing facilities, recently becomes feasible,28-31 enabling for the full characterisation of this complex chemical entity and permitting to draw more founded conclusions on the influence of the new ligands on the structure of vitamin B12.

Quantum chemical method based on Density Functional Theory (DFT) with non-local BeckePerdew functional

32-36

was applied to obtain stable structures of the studied adducts of vitamin

B12 and selected bridging ligands. The selection of the functional resulted from the survey of literature data, which supports the use of non-hybrid functionals, especially BP, for obtaining correct geometries of cobalamin complexes and reliable binding energies

37,38

. Additionally, for

ligand binding energies, the influence of inclusion of dispersion interaction was checked by a single-point correction according to Grimme method (DFT-D2)39. This results from the recent theoretical reports indicating its importance for the correct prediction Co-C bond dissociation energy in the complete model of methylcobalamin28. Standard Grimme parameters were used, as listed in

39

, with c6 equals to 1409.1303505 a.u. and radius of 3.0443488 Bohr for Pt ion, as

implemented in Turbomole. Although earlier studies27 suggest that DFT-D3 dispersion correction together with other factors resulting from solute-solvent interactions might yield better results than DFT-D2, we have decided to conduct a comparative analysis of different ligands,


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which may be used as bridging ligands in further synthesis of bi-nuclear complexes within one, established method. All-electron Gaussian type orbitals of def2-TZVP quality were used to define atomic orbitals

40,41

. The solvation was accounted for by COSMO model

42

with default

radii for the elements (H = 1.30, C = 2.00, N = 1.83, O = 1.72) and 2.00 Å for cobalt and phosphorus, with permittivity ε = 80 representing the aqueous environment. The calculation consisted of geometry optimizations of the studied structures and was further confirmed with vibrational analysis. The reported electronic energies were corrected for zero-point vibrational energy. The Resolution-of-identity (RI) algorithm was applied in order to accelerate computation 43,44

. The electronic structures of the investigated species are additionally elucidated by means of

ESP population analysis. 45 The present results were obtained with Turbomole v. 6.3. 46

Results and Discussion

The discussion of the results starts with the characterization of the complexes of the vitamin B12 with the proposed bridging ligands (L = ImH/Im-, pz, en), as obtained within both reduced (Cob-) and full (B12-) models. Two forms of imidazole: protonated ImH and de-protonated Imare investigated following the bridging role of this ligand. It is expected that the stable form of imidazole derivative will contain protonated ligand, whereas in its adduct with cisplatin the nitrogen atom will be deprotonated and constitute the N-donor group, bound to Pt. The pKa value of imidazole coordinated to the cobalt ion being ca. 1020,47,48 and known stability of cisplatin at this pH should enable for the synthesis of this adduct.


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Next, geometric and electronic parameters of their adducts with cisplatin derivative [Pt(NH3)2Cl]+ complex will be discussed. The selection of the form of a drug to be attached to the B12 core follows from the experimental work of Mundwiler et al.11, where the coordination of this moiety to the vitamin through cyano- bridge had been confirmed with x-ray diffraction. Owing to the size of the system, the bi-metallic complexes were calculated employing the reduced model of the B12 vitamin: Cob-L-[Pt(NH3)2Cl]. The computed parameters of the proposed adducts with Im, pz, and en as bridging ligands, are also compared with data computed for CN- ion as a bridge.

Geometry of Cob-L complexes (L = ethylenediamine, imidazole, and pyrazine)

The geometry structures of the studied B12 derivatives are depicted in Figure 2 and their main structural parameters are collected in Table 1.

The comparison of the computed structural parameters with those obtained with X-ray diffraction method is possible only for cobalamins with imidazole and cyano ligands. The cobalt – axial ligand bonds computed for Cob-Im-/B12-Im- systems show smaller differences with the experimentally determined bond lengths than in Cob-ImH/B12-ImH systems, which may indicate that in experiment20 Co(III)-Im- is prevalent. For cyanocobalamin models, the geometry is well reproduced, once again confirming the appropriateness of the chosen theoretical model and methodology.


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In each of the studied complexes with tested bridging ligands, both axial bonds of cobalt ion are of different lengths. Neutral β ligands are further from the cobalt center than the α ligands (DMB or imidazole) for both theoretical models. This does not hold true for the Cob-ImH system, where both imidazole species are practically equidistant from the Co ion owing to the symmetry and the construction of the employed small model. In complexes with anionic ligands (CN-, Im-) the Co-β ligand bonds are shorter than the Co-α ligand bonds, which results from the electrostatic attraction between the opposite charges of the central metal and the ligand.

Ligand binding energies of Cob-L complexes

The binding energies of the non-native B12 ligands are computed according to the reaction scheme: Cob + L → Cob-L as total energy difference between the product and a sum of the substrates. The reported energies, EbL, computed with COSMO in water as a reaction medium and corrected by ZPVE, are reported in Table 2. As stated in Methodology section, the values were obtained with BP and with BP with D2 dispersion correction.

All studied non-native ligands form stable bonds with cobalt ion, as indicated by the computed binding energies, irrespectively of the model and computational method chosen.

The bond between Co and pyrazine is the weakest, and the bonds with imidazole and ethylenediamine are characterized by comparable binding energies (see Table 2, results for Cob


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model at BP/def2-TZVP level). The deprotonated form of imidazole is the most strongly bound, owing probably to the negative charge of the ligand, which is electrostatically attracted by a positively charged cobalt ion. While the theoretical model is enlarged to full B12 model, the changes in the computed values of all ligand binding energies indicate weaker binding, but their order is not changed. The inclusion of dispersion correction results in stronger ligand binding, without altering their order. The Co - pyrazine bond becomes stronger and is now comparable to Co - en binding in terms of EbL. This result might be explained by the fact, that pz is an electronricher ligand than en and it contains more atoms that are brought in close contact with corrin ring and the α-ligand by the binding, enabling larger dispersion interaction with the rest of the complex. Interestingly, when dispersion is included, there are no significant differences in EbL computed for both, Cob and B12, models. The comparison of the values of dispersion energy between two models reveal that there is a substantial contribution resulting from the corrin peripheral groups interacting with the rest of the system.

Possible synthesis route of Cob-L complexes

The above reported findings regarding cobalt – L ligands binding energies reveal that all postulated Co-bridging ligand bonds are weaker than Co-CN- bond. As a result, their synthesis from cyanocobalamin by simple ligand exchange would probably not be successful. Aquacobalamin is yet another available form of cobalamin, which may serve as a starting material for cobalamin – cisplatin adduct. Water binding by cobalt in H2O-B12 is much weaker


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than cyano ion in CN-B12. In order to explore the possibility of water replacement by imidazole, pyrazine, and ethylenediamine, the free energies accompanying the ligand exchange reaction: Cob-H2O + L → Cob-L + H2O (L = ImH, Im-, pz, en) were computed.

The obtained results, presented in Table 3, indicate that the proposed synthesis route through aquacobalamin should be feasible from the thermodynamic point of view. All ligand exchange processes are accompanied by the negative change of Gibbs free energies.

The kinetic aspect of the reaction is not studied in the present studies. Experimental data, however, indicate that water ligand in auqacobalamin is labile, what would additionally facilitate ligand substitution.49

Such an approach has already been tested in the synthesis of imidazole derivative of vitamin B12.20

Prerequisites of the Cob-L complexes as cis-plain carriers

For the investigated B12 derivatives, the ability to coordinate to platinum ion is important to be considered as potential cisplatin carriers. One of the parameters, which may indicate their usefulness, would be the accumulation of the electron density on an outer nitrogen atom of the β ligand. This atom, further denoted as Nout, will serve as a donor of the σ pair in coordinative bond with the platinum ion. The negative charge accumulated on Nout (see Table 1), being the


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simplest measure of the charge density, indicates that all postulated ligands would be suitable as coordination sites for Pt. The negative charge of the outer nitrogen atoms of Im- and pz is comparable to that of the cyanine ligand, and equals to ca. -0.5, confirming their high nucleophilicity. The largest negative charge (-1.03) is exposed by Nout of the en ligand. One should mention here again, that the deprotonation of imidazole ImH is possible at higher pH and would lead to the exposure of more nucleophilic nitrogen atom of Im-.

Another factor contributing to the possibility of Pt binding is the steric hindrance in the vicinity of the Nout. The geometries of the resulting complexes reveal that the Nout atoms are exposed outside of the complex, not involved in the intra-molecular hydrogen bonding, and thus not blocked against binding to the metal species present in solution.

Geometry of Cob-L-Pt(NH3)2Cl adducts

As a next step, the structures of B12 vitamin with cisplatin moiety: -[Pt(NH3)2Cl]+ are obtained: Cob-L-[Pt(NH3)2Cl] (the total charge of the systems vary depending on the bridging ligand and equals to +3 for en and pz, and +2 for Im- and CN-). The complexes are depicted in Figure 3, where also their main structural parameters are given.

The crystallographic data of only B12-CN-[Pt(NH3)2Cl] adduct are published,11 allowing for the validation of the computed structural data for the cyanine-bridged system. Table 4 compares the experimental and theoretical bond lengths in the immediate region of both metal ions. Good


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agreement between predicted and measured bond lengths is found (the differences do not exceed 0.02 Å), except for the platinum – ammonia bonds, where the discrepancies arise to 0.1 Å.

Platinum complex forms bonds of ca. 2.00 Å with the investigated bridging ligands through the coordination to the Nout atoms. The Pt-Nout bond lengths are varied, depending on the bridging ligand and increase in order: CN- < Im- < pz < en. The survey on the other Pt(II) complexes enables the comparison of the Pt-L bond lengths in the studied conjugates. Typical platinum - pyrazine bonds lengths are in the range 2.010 – 2.026 Å

23,50,51

, in comparison to

2.026 in the studied Cob-pz-[Pt(NH3)2Cl] adduct. Bond lengths in the Pt(II) complexes with en are slightly longer (2.039-2.046 Å)52, whereas in Cob-en-[Pt(NH3)2Cl] its length amounts to 2.093.

The attachment of the cisplatin moiety to the Cob-L complex leaves the Co-CN bond unchanged. By contrast, it results in the slight shortening of the Co–Im- and Co–pz bonds, and the elongation of the Co–en one, as compared to their values in the Cob-L systems respectively.

The axial Co-DMB bonds are also affected: in the cyano- and imidazole- systems these are elongated, while in the other two slightly shortened, however, all the reported changes do not exceed 0.06 Å. Such a small change in axial bond length is positive taking into account that a B12 modification at α position results in drastic lowering of the coenzyme recognition by membrane receptors.53

Ligand binding energies of Cob-L-Pt(NH3)2Cl adducts


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Table 5 collects the computed ligand binding energies (EbL) of Co-L and L-Pt bonds, according to the following processes: Cob + [Pt(NH3)2 (L)Cl] → Cob-L-[Pt(NH3)2Cl] (for Co-L bond) Cob-L + [Pt(NH3)2Cl] → Cob-L-[Pt(NH3)2Cl] (for Pt-L bond)

As is seen from the EbL values, all investigated metal – ligand L bonds are stable, irrespectively of the method used for computation.

The strongest Co-L is found for the cyano-bridged system, the respective bond in the imidazole-bridged one is weaker. This order is changed when dispersion correction is included, and both appear of comparable strength. The bond between cobalt ion and the bridging pz ligand is the weakest from the studied set. The relevant strengthening of the Co-pz bond is seen along with inclusion of D2 correction (pyrazine ligand is electron rich).

The strongest Pt-L bond is found in the system with imidazole as a bridging ligand. The strength of the of Pt-en bond is very close to that of Pt-NC. The bond with Cob-pz is the weakest. The inclusion of dispersion correction does not change the above-listed conclusions, and the obtained values of binding energies indicate stronger binding.

The comparison of the EbL values within each of the bi-metallic systems would allow for the prediction of the scission site when one of the bonds is broken and therapeutic molecule is released from the carrier. It would also facilitate the prediction which of the dissociation


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products: Pt(NH3)2Cl] + or [Pt(NH3)2(L)Cl]+/0 would be released. Last but not least, a preliminary statement on the stability of the proposed adducts might be made.

For the model of the experimentally tested B12-CN-[Pt(NH3)2Cl], higher stability of Pt-NCN than Co-CCN is found. This might indicate that this would be the Co-CN bond, which will be disrupted before the same happens to the Pt-NC bond. Similar pattern is found in all studied systems.

Finally, thermodynamic parameters (∆G, ∆H, -T∆S) of the studied processes were computed to judge the stability of the Co-L and Pt-L bonds – see Table 6. Due to the large destabilizing entropy effects, only Co-Im and Co-CN- are stable, Co-en is almost thermo-neutral and Co-pz is unstable when dispersion is not included in computation scheme. When calculations are corrected for dispersion interactions, all Co-L bonds become stable. By contrast, all Pt-L are stable independent of the method used. It is seen that the Pt-L bonds are stronger than the Co-L ones confirming our conclusions based on EbL values.

Conclusions

Three non-native derivatives of vitamin B12, in which a native cyano ligand was replaced by ethylenediamine, imidazole and pyrazine were described and their electronic and geometry structures were characterized. The computed geometry parameters of the imidazole derivative


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agree well with the available crystallographic data. A route for the new systems was proposed, taking aquacobalamin as a substrate.

The proposed bi-metallic systems of the general formula Cob-L-[Pt(NH3)2Cl] were then investigated with the focus on the structure prediction. It is found that the size of the vitamin B12 α side is not affected much by the introduction of the bulky complex on the β side of the corrole ring. The strength of the metal – bridging ligand bonds vary, but in each case Co-L bond is weaker than Pt-L. We may propose that the release of a cisplatin drug will occur through Co-L bond breaking and the [Pt(NH3)2(L)Cl] cisplatin moiety will probably be released prior to B12-L.

The synthesis of the other non-native derivatives, with ethylenediamine and pyrazine, is, as to the best of our knowledge, not reported in literature. We hope, that their characterisation and forecast applicability as drug carriers might stimulate experimental research to obtain and test their properties for this promising application.

ACKNOWLEDGEMENTS: This research received funding from the Marian Smoluchowski Krakow Research Consortium - a Leading National Research Center KNOW supported by the Ministry of Science and Higher Education.


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FIGURES

Figure 1. Models of vitamin B12 used in the manuscript: a) Cob model; b) B12 model.


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Figure 2. Structures of vitamin B12 adducts with investigated L ligands (L = ImH, Im-, pz, en, CN-).


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Figure 3. Structures of bi-metallic complexes of cisplatin linked through L ligand to vitamin B12 (L = ImH, Im-, pz, en, CN-).


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TABLES Table 1. Selected parameters of cobalamin derivatives modified in β axial position by L ligand (L = Im-, ImH, pz, en, CN-). Experimental data are given in italics. Nout denotes the outer nitrogen atom of the β ligand, able to coordinate to Pt.

model

Im-

ImH

pz

en

CN-

Co-L bond length Cob

1.982

1.939

2.020

2.037

1.853

B12

2.013

1.959

2.056

2.044

1.868

-

-

1.858

Exp.

1.94(1)20

Co-DMB bond length Cob

1.984

2.058

1.987

1.981

2.089

B12

1.984

2.033

2.004

1.977

2.071

-

-

2.011

Exp.

2.01(1)20

ESP charge on Nout Cob

-0.25

-0.53

-0.56

-1.03

-0.59

B12

-0.18

-0.53

-0.64

-0.78

-0.64

Table 2. Ligand binding energies (EbL) of cobalamin derivatives modified in β axial position by L ligand (L = Im-, ImH, pz, en, CN-). Data are in kcal/mol.

model

ImH

Im-

pz

en

CN-


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EbL [ε = 80] at BP/def2-TZVP Cob

-18.1

-27.6

-12.3

-17.4

-35.5

B12

-10.1

-14.6

-3.1

-10.0

-33.0

EbL [ε = 80] at BP+D2/def2-TZVP// BP/def2-TZVP Cob

-35.7

-44.9

-31.6

-33.9

-42.4

B12

-33.5

-43.2

-28.3

-33.0

-42.1

Table 3. Thermodynamic parameters (BP/def2-TZVP) of water for ligand L exchange reaction (∆Gex, ∆Hex, -T∆Sex) computed for cobalamin derivatives modified in β axial position by L ligand (L = Im-, ImH, pz, en, CN-). Data are in kcal/mol.

Cob model

ImH

Im-

pz

en

BP/def2-TZVP (ε=80) ∆Gex

-8.8

-19.0

-3.5

-8.7

∆Hex

-11.8

-21.2

-6.1

-11.1

-T∆Sex

3.0

2.2

2.6

2.4

Table 4. Comparison of x-ray11 and computed bond lengths (in Å) in vitamin B12-CN[Pt(NH3)2Cl] adduct.


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Bond

This work

Exp.

Co-CCN

1.850

1.879

CCN-NCN

1.169

1.17

NCN-Pt

1.963

1.953

Pt-Cl

2.289

2.300

Pt-NNH3

2.072

1.982

Pt-NNH3

2.114

2.000

Table 5. Energies (BP/def2-TZVP and BP+D2/def2-TZVP) of cobalt-ligand and ligandplatinum bonds in the studied bi-metallic Cob-L-[Pt(NH3)2Cl] adducts.

L

Im-

pz

en

CN-

EbL [ε = 80] at BP/def2-TZVP Co-L

-20.1

-4.7

-10.0

-26.8

L-Pt

-49.0

-36.1

-39.6

-40.8

EbL [ε = 80] at BP+D2/def2-TZVP Co-L

-40.3

-24.7

-27.5

-39.3

L-Pt

-59.7

-45.1

-50.0

-49.4


21


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Page 22 of 31

Table 6. Thermodynamic properties (∆G, ∆H, -T∆S at BP/def2-TZVP and BP+D2/def2-TZVP) of cobalt-ligand and ligand-platinum bonds in the studied bi-metallic Cob-L-[Pt(NH3)2Cl] adducts.

Im-

L

pz

CN-

en

Cob + [Pt(NH3)2 (L)Cl] → Cob-L-[Pt(NH3)2Cl] BP/def2-TZVP (ε = 80) ∆G

-7.0

9.2

1.8

-15.2

∆H

-19.9

-4.6

-9.9

-26.5

-T∆S

12.9

13.8

11.7

11.3

BP+D2/def2-TZVP (ε = 80) ∆G

-27.1

-10.8

-15.7

-27.7

∆H

-40.0

-24.6

-27.4

-39.0

-T∆S

12.9

13.8

11.7

11.3

Cob-L + [Pt(NH3)2Cl] → Cob-L-[Pt(NH3)2Cl] BP/def2-TZVP (ε = 80) ∆G

-36.4

-24.3

-29.4

-29.2

∆H

-48.5

-35.4

-38.2

-40.3

-T∆S

12.1

11.1

9.8

11.1

BP+D2/def2-TZVP (ε = 80)


22

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


∆G

-47.2

-33.4

-39.8

-37.8

∆H

-59.3

-44.5

-49.6

-48.9

-T∆S

12.1

11.1

9.8

11.1

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TOC Figure


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Models of vitamin B12

used in the manuscript: a) Cob model; b) B12 model.

176x120mm (300 x 300 DPI)


Page 28 of 31

Page 29 of 31

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Structures of vitamin B12 adducts with investigated L ligands (L = ImH, Im-, pz, en, CN-). 134x269mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Structures of bi-metallic complexes of cis-platin linked through L ligand to vitamin B12 (L = ImH, Im-, pz, en, CN-). 169x171mm (300 x 300 DPI)


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Page 31 of 31

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50x50mm (300 x 300 DPI)


Exploring Novel Modified Vitamin B12 as a Drug Carrier: Forecast

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