Tetrahedron 71 (2015) 1815e1821 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 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 gold 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) sodium aurothiomalate (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 rheumatoid arthritis, 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 glucose, 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 , - À a b þ b À 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 À3 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-gÀ’ 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-gÀ’ has been predicted the molecule in vacuo.