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Article Cite This: ACS Omega 2018, 3, 17842−17852
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Biguanide Antidiabetic Drugs: Imeglimin Exhibits Higher Proton Basicity but Smaller Lithium-Cation Basicity than Metformin in Vacuo Ewa D. Raczyńska,*,† Jean-François Gal,*,‡ Pierre-Charles Maria,‡ and Fabien Fontaine-Vive‡ †
Department of Chemistry, Warsaw University of Life Science (SGGW), ul. Nowoursynowska 159c, 02-776 Warszawa, Poland Université Côte d’Azur, CNRS, Institut de Chimie de Nice, UMR 7272, 06108 NICE, France
‡
ACS Omega 2018.3:17842-17852. Downloaded from pubs.acs.org by 193.93.192.235 on 01/01/19. For personal use only.
S Supporting Information *
ABSTRACT: Compounds containing biguanide moiety, such as buformin, phenformin, and metformin are well recognized for their antihyperglycaemic action. Imeglimin is a dihydro1,3,5-triazine that can be considered as a cyclic metformin derivative, which has been tested as a promising new antidiabetic drug. Quantum-chemical calculations have been carried out to examine its structure and its gas-phase basicity toward the proton and the lithium cation. Owing to various structural isomeric rearrangements possible for imeglimin, 23 isomers have been considered for the neutral molecule in vacuo at the B3LYP/6-311+G(d,p) level. Four isomers (two major and two minor) have been selected and their exceptional energetic stabilities additionally confirmed by the G2, G2MP2, and G4 methods. The major isomers (>95%) correspond to the push−pull biguanide systems, which are similar to those for neutral metformin. The minor isomers (CH−CH3 group. The cyclic form of imeglimin precludes the possibility of chelation effect by two imino groups as it occurs for metformin. Consequently, imeglimin has a lower lithium-cation affinity than that of metformin by ca. 30 kJ mol−1. The lithium cation seems however to be weakly chelated by the neighboring imino and amino N atoms of imeglimin, an effect that is weaker than that of the two terminal imino N atoms of metformin. Gas-phase proton basicity of imeglimin falls between that of bicyclic amidine DBU and guanidine TBD, whereas lithium-cation basicity is situated between that of bicyclic guanidine MTBD and tricyclic vinamidine TTT. Electron delocalization in the biguanide moiety of imeglimin is analogously related to isomerism as that in the parent biguanide and metformin.
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promising molecule.9−18 Clinical trials on imeglimin are in progress.19,20 Imeglimin possesses a cyclic 1,3,5-triazine structure. Containing a biguanide substructure, it bears a similarity with metformin (Figure 1). At least three possible prototropic tautomers can be proposed for derivatives with the biguanide moiety. These isomers are a consequence of amino−imino tautomeric conversions. For metformin, we found recently that two tautomers possessing a central imino N atom are pivotal in determining the stable structures.6 Metformin (C4N5H11) is an acyclic dimethyl derivative of the parent biguanide (C2N5H7), whereas imeglimin (C6N5H13) possesses two additional C
INTRODUCTION
Diabetes constitutes a worldwide public health problem that affected 382 million people (8.3% of the world’s population) in 2013, and recent projections suggest that this prevalence is likely to increase in the next 20 years, affecting 592 million people (10.1%) in 2035.1 An increase of occurrence of diabetes from environmental effects is anticipated.2 The first-line treatment of type 2 diabetes is metformin, a biguanidic oral drug still used for its mechanism of action3−5 and for its structure and basicity properties.6 It also reduces cardiovascular and cancer risks.7,8 Because of lactic acidosis risk as a secondary effect, the other oral antidiabetic biguanidic drugs, phenformin and buformin, were withdrawn from most markets. A new class of dihydro-1,3,5-triazine derivatives, glimins, has the advantage of avoiding lactic acidosis risk.7 From experiments in vitro and in vivo, imeglimin emerges as a © 2018 American Chemical Society
Received: September 25, 2018 Accepted: December 6, 2018 Published: December 19, 2018 17842
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reported previously for metformin gives insights on the following phenomena: effect of cyclization (Figure 1), tautomeric equilibria, and intrinsic Brønsted and Lewis basicity.
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RESULTS AND DISCUSSION Major and Minor Isomers for Neutral, Monoprotonated, and Monolithiated Imeglimin. Looking for the composition of the isomeric mixture of neutral imeglimin, all reasonable types of isomerism have been considered, including prototropic conversions between conjugated sites and geometric isomerism about CN double bond. Enantiomers were not considered because R and S isomers have the same thermochemistry. Particular attention must be paid to prototropy,31−34 a particular kind of tautomerism in which tautomeric forms differ only in the position of protons and π bonds. Various prototropic rearrangements are possible for imeglimin (Figure 1). For example, labile protons at the endo and exo amino N atoms can move to the endo imino N atoms (and vice versa) according to amino−imino rearrangements. These proton transfers are analogous to those possible for the parent biguanide and its dimethyl derivative, metformin.6 Imeglimin has additionally a labile proton at the endo C atom. This proton can move to the other endo C atoms. After the 1,3- or 1,5-proton shift, the formed isomers have a labile proton at the exo C atom in the NC−Me group. This proton can move to the imino N atom according to imino− enamino tautomerism. Since tautomeric sites (N and C atoms) are conjugated, intramolecular proton transfers are always accompanied by changes of π-electron positions. Prototropic conversions lead to isomers, called tautomers, without separation of charge. None of the tautomers is zwitterionic. For tautomers possessing the exo NH group, two geometric isomers are possible. Taking all types of isomerism into account, DFT calculations have been carried out for 23 imeglimin isomers (Figure S1 in the Supporting Information). Each of them has been found to correspond to an energy minimum exhibiting real vibrational frequencies (Tables S1 and S2 in the Supporting Information). The lowest electronic energy (E at 0 K) at the DFT level has been found for the isomer I3 (Figure 2 and Table S1 in the Supporting Information). The E value of I1 is higher than that of I3 by only 0.4 kJ mol−1. When zero point energies are taken into account, the difference between the electronic energies of I1 and I3 is even smaller (0.2 kJ mol−1). Their enthalpies are almost equal, but the Gibbs energy is slightly higher by 1.0 kJ mol−1 for I1 (Table S2 in the Supporting Information), due to a small difference between their entropies. Similar conclusions can be derived on the basis of results found at the G2, G2MP2, and G4 levels (Tables 1 and S5 in the Supporting Information). The relative Gibbs energy between I1 and I3 remains close to 2 kJ mol−1 at all levels of theory. The two imeglimin isomers (I1 and I3) are favored in the gas phase (>95%). Their structures resemble those of the favored isomers of acyclic metformin (M3a and M1a, respectively, in Figure 2).6 The major isomer, I3 and M1a, contains the labile proton at the amino N atom placed near the C atom with the NMe2 group. The isomeric mixture of neutral imeglimin includes also two minor isomers, I6 and I13 (80%). The same structure is favored (>90%) at the G2, G2MP2, and G4 levels (Tables 2 and S5 in the Supporting Information). The amounts of three other selected adducts (I1Li+1b, I3Li+3, and I6Li+3) are also significant (CH− CH3 group, which closes the six-membered cycle of imeglimin. Additionally, the biguanide moiety in the cyclic imeglimin monoprotonated form is less twisted than in the protonated metformin, favoring the n−π conjugation and the push−pull effect. The estimated GB and PA for imeglimin appear to be close to those for bicyclic push−pull N bases, bicyclic amidine DBU and bicyclic guanidine TBD, for which experimental data are available.26 GB and PA experimental determination may be foreseen using DBU and TBD as reference bases. Lithium Gas-Phase Basicity of Imeglimin. For monoand polycyclic push−pull imines containing the amidine (>N− C(R)N−) or guanidine {(H2N)2CN−} group and also for vinamidines, the lithium cation is supposed to interact with the most basic N-imino site and to form monodentate adducts in the gas phase analogously, as for unsubstituted formamidine (H 2 NCHNH···Li + ) and unsubstituted guanidine {(H2N)2CNH···Li+}.29,30,41 Indeed, our DFT calculations
Figure 5. Favored structures for selected monodentate lithium-cation adducts of mono- and polycyclic push−pull imines and for bidentate adducts of biguanides found at the DFT level.
Generally, the distances between the lithium cation and the imino N atom in monodentate adducts of selected push−pull imines correlate well with gas-phase lithium-cation basicity data (Table S7 in the Supporting Information). Stronger imine−Li+ interaction leads to higher basicity parameters and to smaller N···Li+ distance. Figure 6 shows a linear trend 17846
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of a cyclic adduct), but these unfavorable effects are overcompensated by Li+ chelation. For the cyclic imeglimin, both the change of the tautomeric and conformational preferences and the chelation of the lithium cation by two imino N atoms are not possible. The only possible Li+ chelation in imeglimin adducts is by proximate N-imino and N-amino atoms, as shown in Chart 2. This chart shows the structures of selected mono- and Chart 2. DFT-Calculated Microscopic LiCAs (in kJ mol−1) for Selected Imeglimin−Li+ Adducts
Figure 6. Linear trend between lithium-cation basicities (LiCBs in kJ mol−1) and N···Li+ distances (in Å) for selected monodentate imines, both calculated at the DFT level.
between DFT-calculated lithium-cation basicities (LiCBs) and N···Li+ distances for monocyclic (imidazole, imidazoline, and HP), bicyclic (DBN, DBD, DBU, TBD, and MTBD), tricyclic (TTT), as well as acyclic bases (Z-formamidine and guanidine). It should be also noted here that for monodentate push−pull imines, the lithium-cation basicity data, LiCBs and lithiumcation affinities (LiCAs), are almost parallel to the proton basicity data, GBs and PAs, respectively, all estimated at the same level of theory (Table S7 in the Supporting Information). For a set of 10 selected push−pull bases (Table S7), both LiCBs and LiCAs correlate well with PAs and GBs, respectively. Figure 7 presents the linear relationship between
bidentate imeglimin−Li+ adducts and the microscopic LiCAs calculated at the DFT level. According to DFT calculations performed for selected isomers of lithium-cation adducts, monodentate imeglimin displays considerably smaller LiCA and LiCB than imeglimin acting as a bidentate base. To the best of our knowledge, no systematic studies of rotational barriers for the NR2 (R = H, Me) groups in imeglimin were found. Only a few mentions of rotational barriers in open-chain biguanides and metformin may be found in the study of Bharatam and co-workers.27 Although this dynamic effect is partly related to chelation, we have not included this reactivity aspect in our thermochemical study. The interaction of the lithium cation with the imino and amino N atoms in imeglimin, forming a formally fourmembered ring chelate, is much less efficient than a 5- or 6membered ring chelation by two imino N atoms in open-chain biguanides.6 Consequently, imeglimin has a smaller lithium gas-phase basicity than metformin (Table 4). The presence of a >C−Me group in imeglimin is not sufficient to counteract the weaker chelation effect. Deviation (ca. 20 kJ mol−1) of its macroscopic (weighted average) LiCB from the linear relationship found for cyclic monodentate imines is smaller than that for open-chain biguanides (Figure 7). The macroscopic lithium-cation basicity data have been estimated as the enthalpy and Gibbs energy changes of reaction 2.
Figure 7. Strong deviations of biguanide and metformin from the linear relationship between lithium and proton basicity data (LiCB and GB in kJ mol−1) for monodentate push−pull imines calculated at the DFT level.
LiCBs and GBs for monodentate push−pull imines. Calculated gas-phase basicity data for unsubstituted formamidine and guanidine (acyclic bases) fit well this relationship. Quite a different situation takes place for open-chain biguanides.4 For the parent biguanide and its dimethyl derivative, metformin (Figure 5), the lithium cation, interacting with two terminal N atoms, changes the tautomeric preferences in biguanides by forming very stable bidentate adducts. This interaction reveals their exceptionally strong lithium-cation basicities (Table 4) in comparison to their proton basicities (Table 3), both computed at the DFT level. Hence, the two points in Figure 7 corresponding to biguanide and metformin deviate from the linear relationship found for monodentate imines. The large increase of lithium-cation basicity for open-chain biguanides when compared to that in monodentate bases (ca. 50−60 kJ mol−1) gives an indication of the chelation effect of Li+ by the open-chain biguanides. The adduct formation involves a less favored tautomer and additional destabilization by geometry constraint (formation
[I1Li+1b F I3Li+1 F I3Li+3 F I6Li+3] → [I1 F I3 F I6 F I13] + Li+
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Although the estimated macroscopic LiCB and LiCA for bidentate imeglimin (Table 4) are smaller than those for metformin, they seem to be higher than those for monodentate bicyclic guanidine MTBD. The higher range of the LiCB 17847
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Table 4. Comparison of the Calculated Macroscopic Lithium Gas-Phase Basicity Data (LiCB and LiCA at 298.15 K in kJ mol−1) for Biguanides with Experimental and Computational Data for Selected Push−Pull N Bases
a B3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p) for 298 K. bThis work. cAveraged value calculated for reaction 2 taking the percentage contents of the neutral and lithiated isomeric mixtures of imeglimin into account at the DFT, G2, G2MP2, and G4 levels, respectively. dRef 6. eB3LYP/6311+G(d,p)//B3LYP/6-31G(d,p) for 298 K. fRef 43. Difference between Exp. and DFT LiCB was discussed in ref 6. gAveraged value for metformin calculated according to the procedure from ref 6, the percentage contents of the neutral isomeric mixture taken into account at the G2, G2MP2, and G4 levels, respectively.
scale30 is currently limited to about 200 kJ mol−1 and potentially up to 230 kJ mol−1 using diaminoalkanes as chelating ligands,42 including 2-(β-aminoethyl)-pyridine (AEP) and histamine (HA).43 The development of the LiCB scale by relative basicity determinations may benefit from the close relative basicities estimated for monodentate and bidentate ligands listed in Table 4. Electron Delocalization in the Biguanide Moiety for Selected Isomers of Neutral, Protonated, and Lithiated Imeglimin. Only five imeglimin tautomers (I1−I5) possess the conjugated biguanide moiety −HN−C(NH2)N−C(NMe2)N−, which is also present in open-chain metformin tautomers. The isomers I1−I5 (Figure S1 in the Supporting Information) contain a 10-electron system, i.e., three pairs of n-electrons at the amino N atoms and two pairs of π-electrons in the imino CN group, which are conjugated in a different way; I1, I3, and I5 are doubly n-π-cross-conjugated system, whereas I2 and I4 possess two differently bonded Yconjugated fragments. Various resonance structures (Scheme S1 in the Supporting Information) can be proposed for the biguanide moiety to illustrate its high electron delocalization. The transfer of the labile proton from the C atom bonded with Me to the C atom bearing NH2 (I6−I10) or NMe2 (I11−I18) excludes the NH2 or NMe2 group (and their n-electrons) from the conjugated system. These isomers do not belong to the biguanide family. They are singly n−π-cross-conjugated (I6, I7, I12, I13, and I15) or Y-conjugated compounds (I8−I11, I14, and I16−I18). Analogous n−π conjugation in the biguanidinium moiety takes place for monoprotonated forms, for which the positive charge is additionally delocalized. For the lithium-cation adducts, the strength of n−π conjugation strongly depends of the type of interaction. For monodentate adducts, it may be seen as similar to that for monoprotonated isomers, but the participation of N-amino electron pairs in bidentate adducts may alter the conjugation by changing the out-of-plane twist angle of the amino group. All of these changes in electron
delocalization for neutral, protonated, and lithiated imeglimin isomers are well illustrated by variation of the CN bond lengths that vary from 1.27 to 1.48 Å. The geometry-based harmonic oscillator model of electron delocalization (HOMED) index44,45 takes into account quantitatively all changes in the bond lengths and consequently in electron delocalization of the system. This index is based on computed bond lengths and mathematically compared to reference bond lengths computed at the DFT level of theory, B3LYP/6-311+G(d,p), as described in the Supporting Information. The impact of resonance energies on basicities may be estimated by considering the thermochemistry of isodesmic reactions, which may be deduced from the H and G data reported in the Supporting Information data, and indirectly from the PA and LiCA values of the isomers in Charts 1 and 2. We chose the geometric descriptor (HOMED) as a complementary approach for the quantitative analysis of resonance stabilization in biguanides, because the geometric parameters of all structures examined for basicity in the gas phase were available. The HOMED indices have been estimated for the biguanide moiety (six bonds, HOMED6) in selected neutral (I1−I5), protonated (I1/I3H+, I1/I2H+, and I2/I3H+), and lithiated (I1Li+1−I1Li+3 and I3Li+1−I3Li+3) imeglimin isomers (Table S8 in the Supporting Information). The estimated HOMED6 indices were also previously estimated for unsubstituted biguanide and metformin at the same DFT level. In Figure 8, trend plots between HOMED indices and the relative stabilities of individual isomers are shown. There is a clear tendency that a high delocalization (large HOMED) favors a high stability (low ΔG). An exception is the neutral isomer I2 (HOMED6 = 0.579), which deviates from the linear tendency found for other neutral biguanides isomers. There are no stable isomers for unsubstituted biguanide and metformin similar to I2, and it is difficult to propose some general explanation. 17848
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adducts. Electron delocalization does not seem to dictate the isomeric preferences for Li+ adducts, and the plot of HOMED6 vs ΔG shows a large scatter for cyclic imeglimin, analogously, as that for open-chain biguanides. The chelating power of two N atoms appears to strongly affect the stability of biguanide-Li+ adducts.
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CONCLUSIONS Despite advanced clinical tests on imeglimin, very little is known about its structure and properties. Imeglimin prototropy and its Brønsted−Lowry and Lewis basicity were not documented. For the neutral molecule, we identified 18 tautomers, including geometric isomerism about CN bond; the isomeric mixture consists of 23 isomers for which the gasphase thermochemistry was investigated computationally at the B3LYP/6-311+G(d,p) level. From the calculated Gibbs energies, it appears that four isomers dominate the equilibrium mixture at 298.15 K, a trend confirmed at the G2 and G4 levels. The push−pull electronic structure of the two most stable tautomers indicates that imeglimin is expected to be a very strong Brønsted−Lowry base. Quantum-chemical calculations were carried out on the gas-phase basicity of imeglimin toward the proton and the lithium cation. The proton affinity of imeglimin is even larger than that for the similar antidiabetic drug metformin, and imeglimin can be designated as a superbase. Comparative calculations on bases known to be very strong in the gas phase support this conclusion. The thermochemistry of bonding to the lithium cation was examined for comparison with metformin. The imeglimin affinity for Li+ was found to be weaker than that for metformin. This difference can be attributed to a strong chelation of the cation in metformin, this effect being much less efficient with imeglimin. Our exploration of the intrinsic properties of imeglimin is a necessary first step to the understanding of the behavior of this promising drug under physiological conditions. After completion of this work, we became aware of two publications relevant to our study. Metformin protonation, its solvation by water, and interactions with DNA were investigated from the experimental (NMR, IR, UV−vis) and theoretical (DFT, molecular dynamics) point of views.50 The basicities in the gas phase and in acetonitrile solution of seven substituted biguanides have been measured using mass spectrometric methods, and DFT calculations at a simple level were used for comparison with previous studies.51
Figure 8. Comparison of the plots between electron delocalization in the biguanide moiety (measured by the HOMED6 index, Table S8) and relative Gibbs energies (ΔG, Tables S2 and S4), both estimated at the DFT level for neutral, monoprotonated, and monolithiated isomers of unsubstituted biguanide, metformin, and imeglimin. Data for biguanide and metformin taken from ref 6.
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METHODOLOGY
Quantum-chemical calculations at the B3LYP/6-311+G(d,p) level have been performed for all possible isomers of isolated neutral imeglimin and for selected isomers of its monoprotonated and monolithiated forms (Figures S1 and S2 in the Supporting Information), as described previously.6 Additional calculations have been carried out at the G2, G2MP2, and G4 levels for major and minor isomers selected on the basis of the DFT results. Toomsalu et al.46 made an extensive study regarding the performances of DFT and Gn methods for calculations of gas-phase basicities and acidities defined from Gibbs energies of deprotonation (reaction 3). The B3LYP/6311+G(d,p) is one of the most widely used method for structural and thermochemical studies. Although a few other DFT methods perform better in general,46 this level of DFT was chosen for the present study to enable comparisons. For basicities, the B3LYP, G2, and G4 methods are reported to
Generally, monoprotonated biguanides display a stronger electron delocalization of the biguanide moiety than the neutral forms. For the most stable monoprotonated isomers, the HOMED6 indices (0.983 for biguanide, 0.972 for metformin, and 0.984 for imeglimin) are close to unity whereas they are slightly smaller for the most stable neutral isomers (0.851 for biguanide, 0.868 for metformin, and 0.856 for imeglimin). In the case of the lithium-cation adducts, the HOMED6 indices depend on the type of imeglimin−Li+ interaction. For the monodentate adduct I1Li+1a, the HOMED6 index is close to unity (0.963) similar to that for the major isomer of monoprotonated imeglimin (0.984 for I1/ I3H+), whereas the HOMED6 values are considerably smaller (0.764 for I1Li+1b and 0.791 for I3Li+1) for bidentate 17849
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produce average absolute errors of 10, 7.5, and 8.4 kJ mol−1, respectively. In fact, a closer examination of the results obtained for the strongest bases, i.e., the basicity region actually investigated, shows that Gn methods perform much better than DFT. The calculated Gn basicities of the strong bases examined in this work are therefore expected to be the closest to the current experimental gas-phase basicity scale and useful for selecting reference bases for future experimental measurements. All computational details and procedures for estimations of thermochemical quantities, proton and lithium-cation basicities, and geometry-based indices are given in the Supporting Information. The DFT-optimized structures and electronic energies for all possible (23) neutral isomers of imeglimin, as well as their relative thermochemical quantities (298.15 K, 1 atm), are included in Tables S1 and S2 (Supporting Information), respectively. The DFT-optimized structures and electronic energies for the selected monoprotonated and monolithiated forms of imeglimin and their thermochemical quantities are summarized separately in Tables S3 and S4 (Supporting Information), respectively. Thermochemical quantities calculated at the Gn levels for selected isomers are given in Table S5 (Supporting Information). The DFTestimated “microscopic” proton affinities and lithium-cation affinities for selected imeglimin isomers are listed in Table S6 (Supporting Information). Microscopic affinities are defined as the thermochemistry of the hypothetical protonation or lithiation of a given neutral isomer. Note that this definition is valid either in the gas phase (in vacuo) or in solution. Conversely, a macroscopic affinity corresponds to the result of a measurement (or a calculation) on a mixture of neutral isomers present in a sample under given experimental conditions of temperature and pressure. The DFT-estimated proton and lithium-cation basicity data for selected push−pull imines, which form monodentate adducts with the lithium cation, are given in Table S7 (Supporting Information). Note that four or five significant figures in tables are not representative of the expected accuracy on absolute basicities but are considered useful for comparison of relative basicities. The geometry-based indices that describe electron delocalization in the biguanide moiety of selected neutral, monoprotonated, and monolithiated isomers of imeglimin are summarized in Table S8 (Supporting Information). Owing to the small number of isomers with Gibbs energies less than 1 kcal mol−1 (4.184 kJ mol−1) above the most stable form (Tables S2 and S4 in the Supporting Information), the entropy of mixing6,47,48 of neutral and protonated or lithiated imeglimin contributes weakly (TΔmixS < 1.7 kJ mol−1) to the Gibbs energy of protonation and lithiation. This entropy contribution is not considered in the estimation of gas-phase basicities. The Gaussian values of the H and S at 298.15 K for imeglimin I and for its conjugate acid IH+ have been used for calculating the enthalpy and Gibbs energy of reaction 3. The calculated quantities correspond to the proton affinity (PA) and the gas-phase basicity (GB), respectively.24−26,49 IH+ → I + H+
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ILi+ → I + Li+
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02507.
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Possible isomers for neutral imeglimin (Figure S1); selected isomers for its monoprotonated and monolithiated forms (Figure S2); DFT structures, atom coordinates, electronic energies, and relative thermochemical quantities for neutral, protonated, and lithiated isomers of imeglimin (Tables S1−S4); Gn-calculated thermochemical quantities (Table S5); microscopic basicity data (Table S6); basicity data for reference bases (Table S7); resonance structures (Scheme S1), and HOMED indices (Table S8) for selected imeglimin isomers (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. Tel: +48 22 5937623. Fax: +48 22 5937635 (E.D.R.). *E-mail:
[email protected]. Tel: +33 492076361. Fax: +33 492076189 (J.-F.G.). ORCID
Jean-François Gal: 0000-0002-5500-5461 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Support from Université Cô te d’Azur (UCA) and the computational services of the ICN Technical Platform (PFTC) for calculations with Gaussian 16 program are gratefully acknowledged.
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REFERENCES
(1) Baena-Díez, J. M.; Peñafiel, J.; Subirana, I.; Ramos, R.; Elosua, R.; Marín-Ibañez, A.; Guembe, M. J.; Rigo, F.; Tormo-Díaz, M. J.; Moreno-Iribas, C.; Cabré, J. J.; Segura, A.; García-Lareo, M.; Gómez de la Cámara, A.; Lapetra, J.; Quesada, M.; Marrugat, J.; Medrano, M. J.; Berjón, J.; Frontera, G.; Gavrila, D.; Barricarte, A.; Basora, J.; García, J. M.; Pavone, N. C.; Lora-Pablos, D.; Mayoral, E.; Franch, J.; Mata, M.; Castell, C.; Frances, A.; Grau, M. Risk of cause-specific death in individuals with diabetes: a competing risks analysis. Diabetes Care 2016, 39, 1987−1995. (2) Bowe, B.; Xie, Y.; Li, T.; Yan, Y.; Xian, H.; Al-Aly, Z. The 2016 global and national burden of diabetes mellitus attributable to PM2.5 air pollution. Lancet Planet Health 2018, 2, e301−e312. (3) Madiraju, A. K.; Qiu, Y.; Perry, R. J.; Rahimi, Y.; Zhang, X. M.; Zhang, D.; Camporez, J. G.; Cline, G. W.; Butrico, G. M.; Kemp, B. E.; Casals, G.; Steinberg, G. R.; Vatner, D. F.; Petersen, K. F.; Shulman, G. I. Metformin inhibits gluconeogenesis via a redoxdependent mechanism in vivo. Nat. Med. 2018, 24, 1384−1394. (4) An, H.; He, L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol. 2016, 228, R97− R106. (5) Śliwińska, A.; Drzewoski, J. Molecular action of metformin in hepatocytes: an updated insight. Curr. Diabetes Rev. 2015, 11, 175− 181. (6) Raczyńska, E. D.; Gal, J.-F.; Maria, P.-C.; Michalec, P.; Zalewski, M. Exceptionally high proton and lithium cation gas-phase basicity of
(3)
In the same way, lithium-cation affinity (LiCA) and lithiumcation basicity (LiCB)29 for imeglimin I were deduced from the enthalpy and Gibbs energy for the Li+ adduct dissociation, reaction 4, calculated from the H and S quantities of I, ILi+, and Li+. 17850
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the anti-diabetic drug metformin. J. Phys. Chem. A 2017, 121, 8706− 8718. (7) Daniels, M. A.; Kan, C.; Willmes, D. M.; Ismail, K.; Pistrosch, F.; Hopkins, D.; Mingrone, G.; Bornstein, S. R.; Birkenfeld, A. L. Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs. Pharmacogenomics J. 2016, 16, 399−410. (8) Pernicova, I.; Korbonits, M. Metformin - mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol. 2014, 10, 143−156. (9) Pirags, V.; Lebovitz, H.; Fouqueray, P. In Imeglimin, a Novel Glimin Oral Antidiabetic, Exhibits Good Glycaemic Control in Type 2 Diabetes Mellitus Patients, 46th Annual Meeting of EASD, Stockholm, Sweden, 2010; Diabetologia, 2010, 53, Suppl. 1, Meeting Abstract 884. (10) Fouqueray, P.; Leverve, X.; Fontaine, E.; Baquié, M.; Wollheim, C.; Lebovitz, H.; Bozec, S. Imeglimin - a new oral anti-diabetic that targets the three key defects of type 2 diabetes. J. Diabetes Metab. 2011, 2, No. 126. (11) Pirags, V.; Lebovitz, H.; Fouqueray, P. Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients. Diabetes, Obes. Metab. 2012, 14, 852−858. (12) Idris, I. A combination therapy of sitaglitpin with a new class of antidiabetic therapy, imeglimin shown to be beneficial in people with type 2 diabetes. Diabetes, Obes. Metab. 2013, 15, 96. (13) Fouqueray, P.; Pirags, V.; Inzucchi, S. E.; Bailey, C. J.; Schernthaner, G.; Diamant, M.; Lebovitz, H. E. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care 2013, 36, 565−568. (14) Fouqueray, P.; Pirags, V.; Diamant, M.; Schernthaner, G.; Lebovitz, H. E.; Inzucchi, S. E.; Bailey, C. J. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. Diabetes Care 2014, 37, 1924−1930. (15) Vuylsteke, V.; Chastain, L. M.; Maggu, G. A.; Brown, C. Imeglimin: a potential new multi-target drug for type 2 diabetes. Drugs R&D 2015, 15, 227−232. (16) Pacini, G.; Mari, A.; Fouqueray, P.; Bolze, S.; Roden, M. Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes. Diabetes, Obes. Metab. 2015, 17, 541−545. (17) Vial, G.; Chauvin, M. A.; Bendridi, N.; Durand, A.; Meugnier, E.; Madec, A. M.; Bernoud-Hubac, N.; Pais de Barros, J.-P.; Fontaine, E.; Acquaviva, C.; Hallakou-Bozec, S.; Bolze, S.; Vidal, H.; Rieusset, J. Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. Diabetes 2015, 64, 2254−2264. (18) Detaille, D.; Vial, G.; Borel, A.-L.; Cottet-Rouselle, C.; Hallakou-Bozec, S.; Bolze, S.; Fouqueray, P.; Fontaine, E. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discovery 2016, 2, No. 15072. (19) Jarvis, L. Sumimoto licenses diabetes drug. Chem. Eng. News 2017, 95, 15. (20) McCoy, M. Roivant and Poxel join for imeglimin. Chem. Eng. News 2018, 96, 14. (21) Smith, M. B. Organic Chemistry: An Acid-Base Approach, 2nd ed; CRC Press, 2010. (22) The Chemistry of Amidines and Imidates; Patai, S., Ed.; Wiley: Chichester, UK, 1975. (23) The Chemistry of Amidines and Imidates; Patai, S., Rappoport, Z., Eds.; Wiley: London, UK, 1991; Vol. 2. (24) Maksić, Z. B.; Kovačević, B.; Vianello, R. Advances in determining the absolute proton affinities of neutral organic molecules in the gas phase and their interpretation: A theoretical account. Chem. Rev. 2012, 112, 5240−5270. (25) Leito, I.; Koppel, I. A.; Koppel, I.; Kaupmees, K.; Tshepelevitsh, S.; Saame, J. Basicity limits of neutral organic superbases. Angew. Chem., Int. Ed. 2015, 54, 9262−9265.
(26) Raczyńska, E. D.; Gal, J.-F; Maria, P.-C. Enhanced basicity of push-pull nitrogen bases in the gas phase. Chem. Rev. 2016, 116, 13454−13511. (27) Kathuria, D.; Bankar, A. A.; Bharatam, P. V. What’s in a structure? The story of biguanides. J. Mol. Struct. 2018, 1152, 61−78. (28) Charifson, P. S.; Walters, W. P. Acidic and basic drugs in medicinal chemistry: A perspective. J. Med. Chem. 2014, 57, 9701− 9717. (29) Burk, P.; Koppel, I. A.; Koppel, I.; Kurg, R.; Gal, J.-F.; Maria, P.C.; Herreros, M.; Notario, R.; Abboud, J.-L. M.; Anvia, F.; Taft, R. W. Revised and expanded scale of the gas-phase lithium-cation basicities an experimental and theoretical study. J. Phys. Chem. A 2000, 104, 2824−2833. (30) Mayeux, C.; Burk, P.; Gal, J.-F.; Kaljurand, I.; Koppel, I.; Leito, I.; Sikk, L. Gas-phase lithium cation basicity: Revisiting the high basicity range by experiment and theory. J. Am. Soc. Mass Spectrom. 2014, 25, 1962−1973. (31) Pauling, L. The Nature of the Chemical Bond, 3rd ed.; Cornel University Press: New York, 1960. (32) Müller, P. Glossary of terms used in physical organic chemistry (IUPAC Recommendations, 1994). Pure Appl. Chem. 1994, 66, 1077−1184. (33) IUPAC “Gold Book”: http://goldbook.iupac.org/ (accessed June 09, 2018). (34) Raczyńska, E. D.; Kosińska, W.; Ośmiałowski, B.; Gawinecki, R. Tautomeric equilibria in relations to pi-electron delocalization. Chem. Rev. 2005, 105, 3561−3612. (35) Wacharine-Antar, S.; Levilain, G.; Dupray, V.; Coquerel, G. Resolution of (±)-imeglimin-2,4-dichlorophenylacetate methanol solvate by preferential crystallization. Org. Process Res. Dev. 2010, 14, 1358−1363. (36) Rodgers, M. T.; Armentrout, P. B. A Critical evaluation of the experimental and theoretical determination of lithium cation affinities. Int. J. Mass Spectrom. 2007, 267, 167−182. (37) Rodgers, M. T.; Armentrout, P. B. Cationic noncovalent interactions: energetics and periodic trends. Chem. Rev. 2016, 116, 5642−5687. (38) Laurence, C.; Gal, J.-F. Lewis Basicity and Affinity Scales: Data and Measurements, Wiley: Chichester, 2010; Chapter 6. (39) Kaljurand, I.; Koppel, I. A.; Kütt, A.; Rõõm, E.-I.; Rodima, T.; Koppel, I.; Mishima, M.; Leito, I. Experimental gas-phase basicity scale of superbasic phosphazenes. J. Phys. Chem. A 2007, 111, 1245− 1250. (40) Raczyńska, E. D.; Decouzon, M.; Gal, J.-F.; Maria, P.-C.; Gelbard, G.; Vielfaure-Joly, F. Gas-phase structural (internal) effects in strong organic nitrogen bases. J. Phys. Org. Chem. 2001, 14, 25−34. (41) Tortajada, J.; Leon, E.; Luna, A.; Mó, O.; Yáñez, M. Ab initio calculations on formamidine-X+ (X = H, Li, Na, Mg, and Al) complexes. J. Phys. Chem. 1994, 98, 12919−12926. (42) Mayeux, C.; Burk, P.; Gal, J.-F.; Kaljurand, I.; Koppel, I.; Leito, I. In Revised and Expanded Scale of the Lithium Cation Basicities, 20th International Mass Spectrometry Conference; Geneva, Switzerland, Aug 24−29, 2014. (43) Hallmann, M.; Raczyńska, E. D.; Gal, J.-F.; Maria, P.-C. Gasphase lithium cation basicity of histamine and its agonist 2-(βaminoethyl)-pyridine. Experimental and theoretical studies (DFT) of chelation effect. Int. J. Mass Spectrom. 2007, 267, 315−323. (44) Raczyńska, E. D.; Krygowski, T. M.; Duczmal, K.; Hallmann, M. In On Geometry-Based HOMED (A Measure of Hyperconjugation, nπ, and π-π Conjugation) and HOMA Index (A Measure of Aromaticity), XVIII International Conference on Physical Organic Chemistry; Warsaw, Poland, 2006; Book of Abstracts p 31. (45) Raczyńska, E. D.; Hallmann, M.; Kolczyńska, K.; Stępniewski, T. M. On the harmonic oscillator model of electron delocalization (HOMED) index and its application to heteroatomic π-electron systems. Symmetry 2010, 2, 1485−1509. (46) Toomsalu, E.; Koppel, I. A.; Burk, P. Critical test of some computational chemistry methods for prediction of gas-phase acidities and basicities. J. Chem. Theory Comput. 2013, 9, 3947−3958. 17851
DOI: 10.1021/acsomega.8b02507 ACS Omega 2018, 3, 17842−17852
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(47) Guthrie, J. P. Use of DFT method for the calculation of the entropy of gas phase organic molecules: an examination of the quality of results from a simple approach. J. Phys. Chem. A 2001, 105, 8495− 8499. (48) Raczyńska, E. D.; Gal, J.-F.; Maria, P.-C. The guanylated bioamine agmatine − a theoretical investigation of its structure and exceptional high basicity in the gas phase. Comput. Theor. Chem. 2017, 1109, 10−18. (49) Hunter, E. P. L.; Lias, S. G. Evaluated gas phase basicities and proton affinities of molecules: an update. J. Phys. Chem. Ref. Data 1998, 27, 413−656. (50) Mondal, S.; Samajdar, R. N.; Mukherjee, S.; Bhattacharyya, A. J.; Bagchi, B. Unique features of metformin: A combined experimental, theoretical, and simulation study of its structure, dynamics, and interaction energetics with DNA grooves. J. Phys. Chem. B 2018, 122, 2227−2242. (51) Glasovac, Z.; Eckert-Maksić, M.; Kaljurand, I.; Saame, J.; Leito, I. Gas phase basicity of biguanides − Comparison of the equilibrium and the kinetic methods. Int. J. Mass Spectrom. 2019, 435, 61−68.
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DOI: 10.1021/acsomega.8b02507 ACS Omega 2018, 3, 17842−17852
