Tetrahedron 71 (2015) 1815e1821

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Tetrahedron

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Molecular structure of aurothioglucose: a comprehensive computational study

Sedat Karabulut a,*, Jerzy Leszczynski b a Balikesir University Faculty of Literature and Science Department of Chemistry, Balikesir, Turkey b Interdisciplinary Center for Nanotoxicity, Department of Chemistry and Biochemistry, Jackson State University, 1400 J. R. Lynch Street, Jackson, MS 39217, USA article info abstract

Article history: In order to investigate the molecular structure of aurothioglucose (ATG), six stable, well-known con- Received 7 November 2014 formations of glucopyranose (Gp) have been computed and compared with Gp, thioglucopyranose (TGp), Received in revised form 14 January 2015 monomeric aurothioglucose (MATG), and dimeric aurothioglucose (DATG) models. The study has been Accepted 2 February 2015 performed using two DFT approaches. It has been concluded that the ‘b’ anomer of ATG is more stable Available online 7 February 2015 than the ‘a’ anomer for TGp, MATG, and DATG models. M06 and B3LYP levels molecular geometries have been compared for the TGp species. Though both methods provided similar results, B3LYP is slightly Keywords: better than M06 for optimization of TGp, especially for accurate description of bond lengths and dihedral Aurothioglucose Molecular structure angles. Ó Anomer 2015 Elsevier Ltd. All rights reserved. Molecular modeling Medicinal chemistry

1. Introduction for organometallic oligomeric polymers, which may serve as optical non-linear, electrical conductive, and liquid crystalline materials.23 The treatment of diseases with complexes (chrysotherapy) The mechanism of action of the modifying gold antiarthritis e started in China in w2500 BC.1,2 Over the centuries various gold drugs has been a matter of discussion over the years.6,24 32 These compounds have been tested and applied for patients’ treatment. drugs, which all represent linear gold(I) thiolates, may have mul- Today it is possible to find many medical applications of gold(I) tiple effects on the immune response. It is likely they trigger broad thiolate complexes, especially as therapeutic agents against rheu- inhibitory effects, rather than exhibit a specific mechanism. Several e matoid arthritis (RA).1,3 9 theories have been suggested, including interaction with gene The most important gold(I) thiolate compounds, which aims at transcription, inhibition of reactive oxygen species, modulation of reducing inflammation and disease progression in patients, are cytokine levels, modification of the sulfhydryl (SH)-disulfide (SeS) (Myochrysine, gold sodium thiomalate), exchange, inhibition of lysosomal hydrolases, inhibition of some of aurothioglucose (Solganal, gold thioglucose), aurothiosulfate the selenoenzymes by formation of gold selenolate complexes, and (sanocrysin), sodium aurothiopropanol sulfonate (Allochrysine), inhibition of bone resorption.5,6,32,33 and auranofin (Ridaura) (Fig. 1). They are included in the class of One of the main reasons that the mechanism of interaction is e disease modifying antirheumatic drugs (DMARDs).2,3,10 13 In ad- unknown for most gold based drugs the fact that their complete, dition to the treatment of , some of the gold(I) structural characterization has not been done yet. There are limited thiolate compounds are also effective for HIV, cancer, psoriasis, experimental data (X-ray techniques such as WAXS and EXAFS but e pemphigus, asthma, urticarial, and obesity treatments.2,7,12,14 22 no single crystal for some of the gold I drugs) that suggest their Although the drug applications are the most common, gold(I) oligomeric or polymeric structures in solution and in the solid derivatives also have other important functions. These compounds state.3,10,11,28,34 Despite the importance of these compounds, crys- are especially interesting due to their luminescence properties. tallographic evidences for their structures are scarce, especially for Alkynylgold(I) complexes can be transformed into building blocks the polymeric species, owing to the difficulty of synthesizing single crystals for X-ray analysis.35 Most of the gold coordination compounds are in the I and III oxidation states.36 Gold(I) has a d10 configuration, which enables

* Corresponding author. E-mail address: [email protected] (S. Karabulut). three different coordination geometries: linear two-coordinated, http://dx.doi.org/10.1016/j.tet.2015.02.007 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved. 1816 S. Karabulut, J. Leszczynski / Tetrahedron 71 (2015) 1815e1821

Fig. 1. Structures of gold complexes. trigonal three-coordinated, and tetrahedral four-coordinated. The the molecular structure of ATG, the optimization has started from 6se6p energy gap of gold increases because of the relativistic ef- the six stable conformers of Gp, which represents the most stable fects and makes the linear two-coordinated geometry more anomer of , and TGp, its sulfur analog. Monomeric and di- stable.13 meric gold complexes of stable TGp conformations have been The gold compounds used to treat arthritis are all linear, two- modeled and optimized. Relative energies of the different con- coordinated gold(I) thiolates.28 One of the most important mem- formers of ATG have been compared. In addition to selection of the bers of this group is aurothioglucose (ATG). ATG (Fig. 1) is a gold most stable configuration of ATG, this study also evaluated the derivative of glucose, in which the saccharide to metal linkage is via performance of the B3LYP and M06 functionals for the optimization a sulfur atom. It has been known for a long time in the pharma- of TGp. ceutical industry.9,37 Besides drug properties, ATG also displays important toxic side effects like skin rashes, diarrhea, proteinuria, and thrombocytope- 2. Materials and methods nia.1 Generally, side effects occur after excessive gold administra- tion and can affect skin, blood, kidneys, or other organs. Other The optimization process has been executed in three steps: major reported side effects include proteinuria, thrombocytopenia, First step: Optimization of Gp, which represents predominantly 39 or nephropathy.8,20,38 Excess side effects result in discontinuation the most stable anomer of glucose in water. Since optimization of of the treatment for some patients. Because of these side effects the all possible conformations of glucopyranose at high calculation a þ a some of the countries have stopped to use the ATG. levels are too expensive, the most stable six conformers ( -g , - a b þ b b 39 ATG is one of the gold(I) compounds, which has never been g , -t, -g , -g , and -t) (Fig. 2) have been selected. Full crystallized for a complete X-ray analysis. The uncertain molecular standard optimizations have been performed for the six Gp con- þþ structure makes it difficult to understand its biochemical mecha- formers at the MP2/6-311 G (2d,2p) level in vacuo. In all calcu- ‘ ’ nism of action and also possible side effects. The detection of the lations standard option was used for the optimization thresholds. molecular structure of glucose is a difficult task because of the In addition, single point calculations have been carried out at the 40e44 existence of several molecular conformations, which are energeti- MP2 (cc-pVDZ, cc-pVTZ, and cc-pVQZ basis sets ) and CCSD(T) 45 cally close.39 ATG is a derivative of glucose and it is possible to have aug cc-pVDZ levels, applying GAUSSIAN09 suite of programs. fi more than one stable conformer for ATG. The lack of experimental Calculated energies have been extrapolated to the in nite basis structural information makes this situation even more complex and set by using two largest basis sets (cc-pVTZ and cc-pVQZ) for the 46 computational methods are very useful to solve this structural MP2 method based on Eq. 1. puzzle. ð Þ¼ þ 3 Due to the direct relationship between the molecular structure Y x YCBS Ax (1) and reactivity, ATG has been studied by molecular modeling tech- In this equation Y(x) is the calculated energy at related basis set niques, in order to provide more information that might assist in level, YCBS is the complete basis set limit, A is fitted parameter, x is 3 the development of a biomolecular mechanism of ATG. To identify for cc-pVTZ and 4 for cc-pVQZ. S. Karabulut, J. Leszczynski / Tetrahedron 71 (2015) 1815e1821 1817

Fig. 2. Six stable conformers of Gp.

A scaling factor that accounts for the relative energy differences b anomer is more stable than the a in water. Although these studies between cc-pVDZ basis set calculations using CCSD(T) and MP2 suggest a more stable b anomer, there are several quantum e methods for each considered species have been calculated. The pro- mechanics52 54 studies, which suggest the a anomer to be more portion between the calculated energy values is then used as a scaling stable. The main reason for this difference is the solvent effect, factor that was applied to the MP2 extrapolation results in order to which stabilizes the b anomer. provide a more accurate relative energy value for each isomer. All six stable conformers of TGp have been optimized and the Second step: In order to compare the most stable conformer of TGp single point energy has been calculated at different calculation and Gp, the optimizations and single point energy calculations of TGp levels, the same way as previously was described for Gp. The main have been performed with the same methodology as in the step 1. purpose for these calculations is to understand how the relative Third step: Modeling the MATG and DATG complexes of stable stabilities of TGp conformers are linked to Gp species. TGp conformers. Lanl2-dz47 has been chosen for the standard op- While the ‘a-g’ conformer has been calculated as the most timization of gold and the 6-31þg(d,p) basis set48,49 for the rest of stable one at all calculation levels for Gp, ‘b-g’ has been predicted the molecule in vacuo. The calculations were carried out using the as the most stable conformer for TGp (Table 1). This difference can B3LYP functional. be explained by the different atom sizes of oxygen and sulfur; the Vibrational frequencies of all considered species have been sulfur atom is bigger than oxygen (covalent radii of O¼0.73 pm, calculated and no imaginary frequencies have been detected. All S¼1.02 pm). The equatorial position contributes to the stability of

Table 1 Calculated relative energies and relative Gibbs free energies (kcal/mol) of Gp and TGp at different levels

Opt MP2/6-311þþg(2d,2p) ZPE Relative Gibbs free SPE MP2/aug SPE MP2/aug SPE MP2/aug CCSD(T)/aug Extrapolation CCSD(T) scaling energies 6-311þþg(2d,2p) cc-pVDZ cc-pVTZ cc-pVQZ cc-pVDZ Glucose a-gt 0.52 0.12 0.48 0.29 0.25 0.35 0.23 0.10 a-g 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 a-gþ 0.11 0.32 0.24 0.13 0.11 0.21 0.09 0.06 b-gt 2.45 2.72 2.79 2.42 2.35 2.60 2.29 2.10 b-g 1.90 2.38 2.30 2.13 2.08 2.24 2.04 1.97 b-gþ 1.70 2.14 2.19 1.89 1.82 2.12 1.76 1.69

Thioglucose t-a-gt 1.58 1.23 0.93 1.03 1.13 0.97 1.21 1.25 t-a-g 0.81 0.64 0.22 0.49 0.64 0.40 0.75 0.92 t-a-gþ 1.04 0.90 0.59 0.73 0.84 0.74 0.92 1.08 t-b-gt 0.94 0.76 0.79 0.70 0.71 0.66 0.72 0.59 t-b-g 0.23 0.26 0.12 0.23 0.26 0.13 0.29 0.30 t-b-gþ 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

structures are characterized as minima on the respective potential TGp more than Gp because of the more effective 1e3 diaxial in- energy surfaces. teractions at axial position (Fig. 3). According to the data from Table 1 the a anomer of glucose is approximately 2 kcal/mol more stable than b. Interestingly, when 3. Result and discussions Gibbs Free Energy is compared the relative stability of the second and third most stable conformers a-gt and a-gþ reverses. However, The stable Gp anomer (or conformer), which represents the the predicted changes are very small, within 0.4 kcal/mol. The re- global minimum structure is an ongoing discussion. According to placement of the oxygen with sulfur raises stability of the b anomer, recent experimental50 and molecular dynamic51 studies the 1818 S. Karabulut, J. Leszczynski / Tetrahedron 71 (2015) 1815e1821

Fig. 3. Top view of optimized geometries of a Gp (a) and a TGp (b) with van der Waals radii. resulting in its relative energy to be 1 kcal/mol lower than the The studies published in the literature suggest a polymeric, a form. Thus such substitution changes the stability of Gp versus generally oligomeric, structure for ATG and similar metal com- TGp structure by 3 kcal/mol (Table 1). plexes, which are used for RA treatment.3,10,11,28,34 However, there The TGp isomers have been optimized at the M06/6-31gþ(d,p) is no X-ray crystallographic data, which exactly proves the poly- and B3LYP/6-31þg(d,p) levels. Both results have been compared meric structure for ATG. Only identified structures of similar metal with MP2/6-311þþg(2d,2p) results as a reference. It has been complexes provide clue for the molecular structure of ATG. This concluded that while B3LYP is better for calculation of bond lengths suggests that a monomeric gold complex is not a sufficient model and dihedral angles, M06 better approximates MP2 level bond for the reliable prediction of stable conformer of ATG. angles. To provide more reliable models, a number of structures in- The energy difference between the most and least stable con- volving two TGp units were investigated. The DATG models were formers of TGp is 1.25 kcal/mol. This is not a significant energy prepared for three stable b anomers and optimized at the same difference, so all six TGp conformers have been considered while calculation level (using lanl2-dz for Au and 6-31þG(d,p) basis set modeling the MATG complex (Fig. 4). It has been concluded that for for the rest of the molecule) with MATG. The dimeric gold com- such complexes the b anomers are more stable than the a anomers plexes were modeled assuming the linear eSeAueSe fragment, as and the ‘t-b-gþ’ conformer is still the most stable one as in TGp suggested in the literature.6,32 According to the calculation results (Table 2). the ‘t-b-gþ’ conformer is predicted as the most stable one, similar to the MATG and TGp results (Table 3). The energy difference

Fig. 4. MATG models.

Table 2 Relative energies (kcal/mol) of MATG conformers

TGp conformers Relative energies Table 3 t-a-gt 2.01 Relative energies (kcal/mol) of DATG conformers t-a-g 1.73 Conformation of eCH2OH Relative energies Relative amounts t-a-gþ 1.73 b t-b-gt 0.70 t- -gt 1.53 0.05 b t-b-g 0.32 t- -g 0.59 0.26 b þ t-b-gþ 0.00 t- -g 0 0.69 S. Karabulut, J. Leszczynski / Tetrahedron 71 (2015) 1815e1821 1819 between the dimeric b ATG conformers increased from 0.32 to 0.59 substituted methanol rotation might be the driving factor for this and from 0.70 to 1.53 kcal/mol, when compared with the MATG phenomenon. results (Tables 2 and 3). The calculated vibrational frequencies and assignments of the To get additional insight into the characteristics of the in- most stable conformers (t-b-gþ) of TGp, MATG, and DATG have vestigated compounds, the electrostatic potential energy (ESP) been summarized in Table 4. It is possible to categorize all the vi- maps of DATG complexes have been generated (Fig. 5). One notices brations of three structures in five groups (Fig. 7). 200e500 cm 1 is

Fig. 5. ESP maps of DATG. that the glucose rings at both sides of the molecule are more the first region, which represents the OeH wagging vibrations. The negative than the center of the molecular surface. Oxygen is more second region ranges between 1000 and 1150 cm 1 and includes electronegative than all other atoms in the DATG and oxygen atoms symmetric and asymmetric stretching vibrations of CeC and CeO are all located on the glucose rings. The high electronegativity and bonds. A combination of CeH twisting and OeH bending vibrations close localization of oxygens are the main factors for the charge constitute the third region. CeH and OeH stretching vibrations are separation on the ATG surface. The ESP maps suggest that the linear the fourth and fifth regions. eSeAueSe unit, at the center of the molecule, might be the first As can be concluded from Fig. 7 the IR spectra of three structures target for a nucleophilic attack. are similar. There is a small frequency shift between the TGp and Although the three ESP maps look similar, there are notable gold complexes (MATG and DATG), which is expected between the differences among these maps. The only structural difference ligands and metal complexes. Another difference is related to in- among the considered conformers is the position of the methanol tensities; the DATG is characterized by a higher intensity of vibra- group (eCH2eOH), which is attached to the glucose ring. In the ‘t-b- tional bands than the MATG and TGp, except fourth region. The gt’ form the position of methanol increases the charge separation intensities are similar at the fourth region because all absorption when compared with other two species (Fig. 6). In the ‘t-b-gt’ bands represent stretching of a single OeH group for all structures.

Fig. 6. Polarization of ATG by the rotation of substituted methanol group. conformer the hydroxyl (eOH) group of the methanol is located as The other regions generally include a combination of more than far as possible from the relatively positive eSeAueSe unit, which is one vibration. The number of atoms in the considered molecules is at the center of the molecule. Charge separation is reduced at ‘t-b- 47, 24, and 24 for DATG, MATG, and TGp, respectively. So the g’ conformer due to rotation of the CeCH2OH bond and the ‘t-b- number of atoms involved in the combined vibrations is larger in gþ’ conformer provides the closest position of the hydroxyl to the DATG than the MATG and TGp. This difference may explain the center of the molecule. This position of the substituted methanol intensity variations at related regions. results in the least polarized DATG structure (Fig. 6). Based on the values of the relative energy, the relative amounts 4. Conclusions of ATG conformers are evaluated to be equal to 69%, 26%, and 5%, respectively (Table 3). Thus it can be concluded that the majority Gold represents one of the most commonly used metals in of ATG molecular structures exists as the ‘t-b-gþ’ conformer. Al- various drugs. The well-known medical application for gold com- though the ‘t-b-gþ’ species is the most stable for both MATG and pounds is the treatment of rheumatoid arthritis, and there is also TGp ligands, the energy difference between the conformers is not a growing interest in the application of gold complexes as anti- as large as in DATG model. The polarization of molecule by the cancer drugs. Its current use in modern medicine has resulted in 1820 S. Karabulut, J. Leszczynski / Tetrahedron 71 (2015) 1815e1821

Table 4 The calculated vibrational frequency assignment of TGp, MATG, and DATG (Selected frequencies are the most intense band of related region)

Frequency region (cm 1) Selected frequency (cm 1) Intensity (epsilon) Assignment TGp First region 200e500 423 661 OeH wagging Second region 1000e1150 1109 487 CeO and CeC stretching Third region 1200e1500 1355 175 CeH twisting and OeH bending Fourth region 3000e3100 3069 345 CeH stretchings Fifth region 3780e3840 3836 337 OeH stretchings

MATG First region 250e450 411 599 OeH wagging Second region 1000e1100 1062 692 CeO and CeC stretching Third region 1200e1450 1255 192 CeH twisting and OeH bending Fourth region 3000e3100 3021 347 CeH stretchings Fifth region 3700e3840 3811 332 OeH stretchings

DATG First region 250e400 393 810 OeH wagging Second region 1000e1100 1038 1646 CeO and CeC stretching Third region 1200e1500 1238 679 CeH twisting and OeH bending Fourth region 3000e3150 3022 397 CeH stretchings Fifth region 3800e3820 3812 708 OeH stretchings

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