Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion

Aug 26, 2016 - Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion Transfer Voltammetry and DFT Calculations. Jan Langmaier†, Martin Pižl...
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Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion Transfer Voltammetry and DFT Calculations Jan Langmaier,† Martin Pižl,†,‡ Zdeněk Samec,*,† and Stanislav Záliš*,† †

J. Phys. Chem. A 2016.120:7344-7350. Downloaded from pubs.acs.org by UNIV OF ALABAMA BIRMINGHAM on 11/27/18. For personal use only.

J. Heyrovský Institute of Physical Chemistry, v.v.i., Academy of Sciences of the Czech Republic, Dolejškova 3, 182 23 Prague 8, Czech Republic ‡ Department of Inorganic Chemistry, University of Chemistry and Technology, Prague 6, Technická 5, 166 28, Czech Republic S Supporting Information *

ABSTRACT: Ion transfer voltammetry is used to estimate the acid dissociation constants Ka1 and Ka2 of the mono- and diprotonated forms of the biguanide drugs metformin (MF), phenformin (PF), and 1-phenylbiguanide (PB) in an aqueous solution. Measurements gave the pKa1 values for MFH+, PFH+, and PBH+ characterizing the basicity of MF, PF, and PB, which are significantly higher than those reported in the literature. As a result, the monoprotonated forms of these biguanides should prevail in a considerably broader range of pH 1−15 (MFH+, PFH+) and 2−13 (PBH+). DFT calculations with solvent correction were performed for possible tautomeric forms of neutral, monoprotonated, and diprotonated species. Extreme basicity of all drugs is confirmed by DFT calculations of pKa1 for the most stable tautomers of the neutral and protonated forms with explicit water molecules in the first solvation sphere included.

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INTRODUCTION The biguanides metformin (MF, N,N-dimethylimidodicarbonimidic diamide) and phenformin (PF, N-(2-phenylethyl)imidodicarbonimidic diamide) have been widely used for the treatment of type 2 diabetes mellitus.1 MF has become one of the most commonly prescribed drugs worldwide.2 Recently, its role in scavenging of methylglyoxal in humans has been recognized.3 On the other hand, PF has been withdrawn from clinical practice in many countries due to the high incidence of lactic acidosis.4 At physiological pH, the MF and PF studied exist as the cationic species MFH+ and PFH+ (Chart 1), respectively, which are distributed into body tissues (intestine, liver, kidney) by organic cation transporters, while their passive diffusion through the cell membranes is very limited.2,5 1-

Phenylbiguanide (PB, 1-(diaminomethylidene)-2-phenylguanidine) is a 5-HT3 (serotonin) receptor agonist.6 The acid−base properties of MF, PF, and PB are characterized by the acid dissociation constants Ka1 and Ka2 for the mono- and diprotonated biguanide, respectively. In the case of MF, the most frequently cited values pKa1 = 11.5 and pKa2 = 2.85,7−11 are rarely7 referred to the original work by Sarma12 but often to the compilations and reviews.5,13 The pKa values above were obtained by the classical pH measurements of the aqueous solutions containing MF and various amounts of NaOH and HCl at 32 °C, with the mixture being eventually incubated for 48 h.12 More recently, the acid dissociation constants of mono- and diprotonated MF and PF have been determined by the 1H NMR-pH titration method.14 The pH dependence of the chemical shift provided a remarkably higher value of pKa1 = 13.85 and a comparable value of pKa2 = 3.14 for MFH+ and MFH22+, respectively.14 Similar values pKa1 = 13.27 and pKa2 = 3.26 were obtained for PFH+ and PFH22+, respectively.14 Strong basicity of MF was confirmed by the combined DFT and Raman scattering methods showing that Raman markers of the neutral MF species do not dominate even at very high pH values (>13), while the diprotonated form appears as the major population at very low pH ( 14 yields an estimate of pKa2 < 0.7 and pKa1 > 15.3 for MFH22+ and MFH+, respectively; cf. the solid line in Figure 2a. Analogous consideration based on the data shown in Figure 2b leads to the slightly different estimates of pKa2 < 1.1 and pKa1 > 14.9 for PFH22+ and PFH+, respectively; cf. the solid line in Figure 2b. The basicity of PB and PBH+ is somewhat less pronounced, as it can be seen from the dependence of Ip/Ip0 vs pH in Figure 3. In this case, the model calculations suggest that pKa2 = 2 and pKa1 = 13 for PBH22+ and PBH+, respectively.

Figure 3. Plot of y = Ip/Ip0 vs pH, where Ip and Ip0 represent the peak currents measured at the given pH and at pH 7.41, respectively, for PB. The solid line represents a model dependence calculated assuming pKa1 = 13 and pKa2 = 2.

The experimentally determined pKa1 and pKa2 are supported by the DFT calculations. Prior to calculating the pKa values, the structures of all possible tautomers of the neutral and protonated forms of MF, PF, and PB were optimized including the PCM correction. The structures of the lowest energy tautomers of MF, MFH+, and MFH22+ are depicted in Figure 4; analogous tautomers of PF, PFH+, PFH22+, PB, PBH+, and PBH22+ are depicted in Figures S2 and S3 (Supporting Information). Calculations on the neutral forms of all biguaninides suggest that the tautomer (a) with the nonprotonated bridging nitrogen N4 has the highest stability in the case of systems studied. Calculated Gibbs free energy differences between the most stable MF tautomer (a) with the nonprotonated bridging nitrogen N4 and the tautomer (b), (c), or (d) are given in Table S1, together with energy differences of individual MFH+ tautomers. These differences are quite appreciable and make 2.9−3.0 kcal/mol for the neutral forms and 10.0−14.1 kcal/mol for the protonated form. Analogous results were found for PF and PB (Tables S2 and S3). Geometry optimization of the MFH+ tautomer (a) and the complex formed between MF and HCl (MFH+Cl−) well reproduces the experimental struc7347

DOI: 10.1021/acs.jpca.6b04786 J. Phys. Chem. A 2016, 120, 7344−7350

Article

The Journal of Physical Chemistry A

Figure 5. DFT/M06-2X/G3/PCM optimized structure of (a) {(MF)·(H2O)20}, (b) {(MFH)·(H2O)20}+, and (c) {(MFH2)·(H2O)20}2+ systems. The shortest hydrogen bond distance drawn as a dashed line was calculated to be 1.838 and 1.754 Å for the systems shown in parts b and c, respectively. The circles indicate the groups including protons in the mono- and diprotonated MF forms.

Figure 6. DFT/M06-2X/G3/PCM optimized structure of (a) {(PF)·(H2O)20}, (b) {(PFH)·(H2O)20}+, and (c) {(PFH)·(H2O)20}2+. The circles indicate the groups including protons in the mono- and diprotonated PF forms. The shortest hydrogen bond distances were calculated to be of 1.884 Å for system b and 1.732 and 1.857 Å for system c.

range of pH 1−15 (MFH+, PFH+) and 2−13 (PBH+). Strong basicity of the neutral biguanides should be emphasized by DFT calculations of pKa1 for the most stable tautomers of the neutral and protonated biguanide forms with explicit water molecules in the first solvation sphere. Calculations also well describe the second dissociation constant Ka2. Both experimental and computational results emphasize the extraordinary stability of monoprotonated forms of all drugs, which should play a key role in their chemical transformations in aqueous solutions.

Table 1. Comparison of the Experimental pKa1 and pKa2 Values with Those Calculated for MF, PF, and PB Surrounded by 20 Water Molecules MF pKa1

pKa2

a

PF

PB

Exp.

Calc.

Exp.

Calc.

Exp.

Calc.

>15.3a 11.5b 13.85c >13d PBH+ is reasonably reproduced. Differences between pKa1 and pKa2 are also well reproduced by calculations.

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CONCLUSIONS In summary, we have demonstrated that ion transfer voltammetry can be used to estimate the acid dissociation constants Ka1 and Ka2 of the mono- and diprotonated biguanidines metformin, phenformin, and 1-phenylbiguanide in an aqueous solution. The pKa1 values for MFH+, PFH+, and PBH+, which characterize the basicity of MF, PF, and PB, are significantly higher than those reported in the literature. On the other hand, the pKa2 values for MFH22+ and PFH22+ are lower than literature data. As a result, the monoprotonated forms of the studied biguanides should prevail in a considerably broader

AUTHOR INFORMATION

Corresponding Authors

*Email: [email protected]. Phone: 00420266052017. *Email: [email protected]. Phone: 00420266053268. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Czech Science Foundation (project number 15-03139S). 7348

DOI: 10.1021/acs.jpca.6b04786 J. Phys. Chem. A 2016, 120, 7344−7350

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(24) Eckert, F.; Diedenhofen, M.; Klamt, A. Towards a First Principles Prediction of pK(a): COSMO-RS and the ClusterContinuum Approach. Mol. Phys. 2010, 108, 229−241. (25) Houari, Y.; Jacquemin, D.; Laurent, A. D. Methodological Keys for Accurate pK(a)* Simulations. Phys. Chem. Chem. Phys. 2013, 15, 11875−11882. (26) Houari, Y.; Jacquemin, D.; Laurent, A. D. Td-Dft Study of the pK(a)* for Coumarins. Chem. Phys. Lett. 2013, 583, 218−221. (27) Saracino, G. A. A.; Improta, R.; Barone, V. Absolute pK(a) Determination for Carboxylic Acids Using Density Functional Theory and the Polarizable Continuum Model. Chem. Phys. Lett. 2003, 373, 411−415. (28) Brown, T. N.; Mora-Diez, N. Computational Determination of Aqueous pKa Values of Protonated Benzimidazoles (Part 2). J. Phys. Chem. B 2006, 110, 20546−20554. (29) Casasnovas, R.; Fernandez, D.; Ortega-Castro, J.; Frau, J.; Donoso, J.; Munoz, F. Avoiding Gas-Phase Calculations in Theoretical pK(a) Predictions. Theor. Chem. Acc. 2011, 130, 1−13. (30) Schuurmann, G.; Cossi, M.; Barone, V.; Tomasi, J. Prediction of the Pk(a) of Carboxylic Acids Using the Ab Initio ContinuumSolvation Model PCM-UAHF. J. Phys. Chem. A 1998, 102, 6706− 6712. (31) Sutton, C. C. R.; Franks, G. V.; da Silva, G. First Principles pK(a) Calculations on Carboxylic Acids Using the Smd Solvation Model: Effect of Thermodynamic Cycle, Model Chemistry, and Explicit Solvent Molecules. J. Phys. Chem. B 2012, 116, 11999−12006. (32) Rebollar-Zepeda, A. M.; Campos-Hernandez, T.; Ramirez-Silva, M. T.; Rojas-Hernandez, A.; Galano, A. Searching for Computational Strategies to Accurately Predict pK(a)s of Large Phenolic Derivatives. J. Chem. Theory Comput. 2011, 7, 2528−2538. (33) Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. Adding Explicit Solvent Molecules to Continuum Solvent Calculations for the Calculation of Aqueous Acid Dissociation Constants. J. Phys. Chem. A 2006, 110, 2493−2499. (34) Rebollar-Zepeda, A. M.; Galano, A. First Principles Calculations of pKa Values of Amines in Aqueous Solution: Application to Neurotransmitters. Int. J. Quantum Chem. 2012, 112, 3449−3460. (35) Thapa, B.; Schlegel, H. B. Calculations of pK(a)’s and Redox Potentials of Nucleobases with Explicit Waters and Polarizable Continuum Solvation. J. Phys. Chem. A 2015, 119, 5134−5144. (36) Thapa, B.; Schlegel, H. B. Density Functional Theory Calculation of pKa’s of Thiols in Aqueous Solution Using Explicit Water Molecules and the Polarizable Continuum Model. J. Phys. Chem. A 2016, 120, 5726−5735. (37) Langmaier, J.; Samec, Z. Voltammetry of Ion Transfer across a Polarized Room-Temperature Ionic Liquid Membrane Facilitated by Valinomycin: Theoretical Aspects and Application. Anal. Chem. 2009, 81, 6382−6389. (38) Frisch, M. J.; et al. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009. (39) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−241. (40) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A Consistent and Accurate Ab Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu. J. Chem. Phys. 2010, 132, 154104. (41) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies, Structures, and Electronic Properties of Molecules in Solution with the C-PCM Solvation Model. J. Comput. Chem. 2003, 24, 669−681. (42) Munoz Frean, S.; Alcolea Palafox, M.; Rastogi, V. K. Effect of the Microhydration on the Tautomerism in the Anticarcinogenic Drug 5-Fluorouracil and Relationships with Other 5-Haloderivatives. J. Mol. Struct. 2013, 1054−1055, 32−45. (43) Tissandier, M. D.; Cowen, K. A.; Feng, W. Y.; Gundlach, E.; Cohen, M. H.; Earhart, A. D.; Coe, J. V.; Tuttle, T. R. The Proton’s

REFERENCES

(1) Madiraju, A. K.; et al. Metformin Suppresses Gluconeogenesis by Inhibiting Mitochondrial Glycerophosphate Dehydrogenase. Nature 2014, 510, 542. (2) Gong, L.; Goswami, S.; Giacomini, K. M.; Altman, R. B.; Klein, T. E. Metformin Pathways: Pharmacokinetics and Pharmacodynamics. Pharmacogenet. Genomics 2012, 22, 820−827. (3) Kinsky, O. R.; Hargraves, T. L.; Anumol, T.; Jacobsen, N. E.; Dai, J.; Snyder, S. A.; Monks, T. J.; Lau, S. S. Metformin Scavenges Methylglyoxal to Form a Novel Imidazolinone Metabolite in Humans. Chem. Res. Toxicol. 2016, 29, 227−234. (4) Kwong, S. C.; Brubacher, J. Phenformin and Lactic Acidosis: A Case Report and Review. J. Emerg. Med. 1998, 16, 881. (5) Graham, G. G.; et al. Clinical Pharmacokinetics of Metformin. Clin. Pharmacokinet. 2011, 50, 81−98. (6) Higgins, G. A.; Joharchi, N.; Sellers, E. M. Behavioral Effects of the 5-Hydroxytryptamine3 Receptor Agonists 1-Phenylbiguanide and M-Chlorophenylbiguanide in Rats. J. Pharmacol. Exp. Ther. 1993, 264, 1440−1449. (7) Dutta, R. L.; Sengupta, N. R. J. Ind. Chem. Soc. 1961, 38, 741. (8) Hernández, B.; Pfluger, F.; Kruglik, S. G.; Cohen, R.; Ghomi, M. Protonation-Deprotonation and Structural Dynamics of Antidiabetic Drug Metformin. J. Pharm. Biomed. Anal. 2015, 114, 42−48. (9) Tao, C. A.; Wang, J. F.; Qin, S. Q.; Lv, Y. A.; Long, Y.; Zhu, H.; Jiang, Z. H. Fabrication of Ph-Sensitive Graphene Oxide-Drug Supramolecular Hydrogels as Controlled Release Systems. J. Mater. Chem. 2012, 22, 24856−24861. (10) Trouillas, P.; Marchetti, C.; Bonnefont-Rousselot, D.; Lazzaroni, R.; Jore, D.; Gardes-Albertd, M.; Collin, F. Mechanism of OneElectron Oxidation of Metformin in Aqueous Solution. Phys. Chem. Chem. Phys. 2013, 15, 9871−9878. (11) Clarke, G. S.; Bretnall, A. E. Metformin Hydrochloride. In Analytical Profiles of Drug Substances and Excipients; Brittain, H. G., Ed.; Academic Press: San Diego, CA, 1998; pp 243−293. (12) Sarma, B. D. Acid Dissotiation Constants and Basicity of Biguanides and Dibiguanides. J. Ind. Chem. Soc. 1952, 29, 217. (13) Craig, P. N. In Comprehensive Medicinal Chemistry; Hansch, C., Sammes, P. G., Taylor, J. B., Eds.; Pergamon Press: Oxford, U.K., 1990; p 658. (14) Orgovan, G.; Noszal, B. Electrodeless, Accurate pH Determination in Highly Basic Media Using a New Set of H-1 Nmr Ph Indicators. J. Pharm. Biomed. Anal. 2011, 54, 958−964. (15) Ernst, S. R.; Cagle, F. W., Jr Biguanide. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 235−237. (16) Ernst, S. Biguanide Hydrochloride. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 237−240. (17) Bharatam, P. V.; Patel, D. S.; Iqbal, P. Pharmacophoric Features of Biguanide Derivatives: An Electronic and Structural Analysis. J. Med. Chem. 2005, 48, 7615−7622. (18) Wei, X. D.; Fan, Y. H.; Bi, C. F.; Yan, X. C.; Zhang, X.; Li, X. Crystal Structure and Tautomerism Study of the Mono-Protonated Metformin Salt. Bull. Korean Chem. Soc. 2014, 35, 3495−3501. (19) Ruggiero-Lopez, D.; Lecomte, M.; Moinet, G.; Patereau, G.; Lagarde, M.; Wiernsperger, N. Reaction of Metformin with Dicarbonyl Compounds. Possible Implication in the Inhibition of Advanced Glycation End Product Formation. Biochem. Pharmacol. 1999, 58, 1765−1773. (20) Solis-Calero, C.; Ortega-Castro, J.; Frau, J.; Munoz, F. Scavenger Mechanism of Methylglyoxal by Metformin. A DFT Study. Theor. Chem. Acc. 2015, 134, 48. (21) Samec, Z.; Langmaier, J.; Kakiuchi, T. Charge-Transfer Processes at the Interface between Hydrophobic Ionic Liquid and Water. Pure Appl. Chem. 2009, 81, 1473−1488. (22) Samec, Z.; Trojánek, A.; Samcová, E. Ion and Pore Fluid Transport-Properties of a Nafion(R) Membrane Separating 2 Electrolyte-Solutions 0.1. Kinetics of the Proton and Alkali-Metal Cation-Transport. J. Electroanal. Chem. 1995, 389, 1−11. (23) Cramer, C. J.; Truhlar, D. G. A Universal Approach to Solvation Modeling. Acc. Chem. Res. 2008, 41, 760−768. 7349

DOI: 10.1021/acs.jpca.6b04786 J. Phys. Chem. A 2016, 120, 7344−7350

Article

The Journal of Physical Chemistry A Absolute Aqueous Enthalpy and Gibbs Free Energy of Solvation from Cluster-Ion Solvation Data. J. Phys. Chem. A 1998, 102, 7787−7794. (44) Albert, A.; Goldacre, R.; Phillips, J. The Strength of Heterocyclic Bases. J. Chem. Soc. 1948, 2240−2249. (45) Hariharan, M.; Rajan, S. S.; Srinivasan, R. Structure of Metformin Hydrochloride. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1989, 45, 911−913. (46) Hatanaka, M. Tautomerism in Polyguanide. Comput. Theor. Chem. 2011, 971, 58−64. (47) Hatanaka, M. Role of Topological Charge Stabilization in Protomeric Tautomerism. J. Phys. Chem. A 2015, 119, 1074−1086.

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DOI: 10.1021/acs.jpca.6b04786 J. Phys. Chem. A 2016, 120, 7344−7350