Letter to the Editor pubs.acs.org/journal/ascecg
Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Comment on “In Situ Derivatization of (RS)‑Mexiletine and Enantioseparation Using Micellar Liquid Chromatography: A Green Approach” Giovanni Lentini,*,† Gualtiero Milani,† and Solomon Habtemariam‡ †
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, via E. Orabona 4, 70126 Bari, Italy Pharmacognosy Research Laboratories, Medway School of Science, University of Greenwich, Chatham-Maritime, Kent ME4 4TB, United Kingdom
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‡
ACS Sustainable Chem. Eng. 2018, 6 (9), 11653−11661. DOI: 10.1021/acssuschemeng.8b01869 ACS Sustainable Chem. Eng. 2019, 7 (3). DOI: 10.1021/acssuschemeng.9b00896
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ecently, Alwera1 presented a micellar liquid chromatography system as a novel green method for enantioseparation of (±)-mexiletine diastereomers. The paper described in situ derivatization of (RS)-mexiletine with chirally pure drugs (e.g., levofloxacin) followed by separation of the diastereomers using surfactant-based aqueous solvent RPHPLC. The mexiletine enantiomers were finally recovered by acid hydrolysis. In principle, the proposed method might be useful to prepare both mexiletine enantiomers and to evaluate their enantiomeric purity (ep). Several points, both theoretically and experimentally, should be addressed, however, before adopting it for the claimed purpose. (1) Prediction of Elution Order. In order to predict the diastereomer elution order, the lowest-energy-optimized structures for both diastereomers were developed through hybrid density functional theory (DFT) B3LYP calculations with the 6-31G* basis set. Significant differences in spatial arrangements of the two diastereomer lowest-energy models were found. In particular, the longest molecular axes (that is, the distances between the two furthest carbon atoms in each derivative) were 17.21 and 14.34 Å for (S,R)- and (S,S)diastereomers, respectively. The folded (S,S)-diastereomer (LM-2) should display higher elution time than the extended (S,R)-diastereomer (LM-1). We were intrigued by such a dramatic difference which should be caused by simply exchanging the placement of the hydrogen atom with that of the methyl group at the asymmetric carbon atom of the mexiletine moiety (that is, epimerization at the carbon atom alpha to the NHCO group). Following the previously developed procedure,2 we generated seven and nine conformers in a window of 5 kcal/mol from the global minimum conformation (HF/6-31G*//HF/6-31G*) for LM-1 and LM2, respectively. Each conformer of the so-obtained conformer populations underwent geometry optimization at the DFT B3LYP/6-31G* level.3 The longest molecular axes for LM-1 and LM-2 conformer populations fell in the ranges of 16.7 ± 0.9 and 17.3 ± 2.1 Å, respectively. The most stable LM-1 and LM-2 conformers were true conformers (no IR imaginary frequencies) and did not display any significant difference in size with their corresponding longest axes being equal to 16.8 Å. Thus, the proposed molecular modeling analysis in Alwera’s method1 should not be used to predict the order of elution of levofloxacin derivatives of mexiletine. © XXXX American Chemical Society
(2) Obtained Mexiletine Enantiomers. The obtained mexiletine enantiomers were fully characterized as the corresponding free base forms. Surprisingly, a relatively high mp was reported for both enantiomers (198−200 °C), but both mexiletine enantiomers were previously reported as colorless oils.4 We wonder if the author rather obtained mexiletine enantiomer salts, and if so, which ones? (3) Enantiomeric Purity Analysis. Based on high optical purity (op) values, Alwera’s paper1 asserts that good ep was obtained for both mexiletine enantiomers. However, op values should not be considered as reliable succedanea of ep values, since the difference between op and ep can be large (see the Horeau effect).5 In fact, op is now mostly considered as a rough, obsolete approximation of ep, and its use is best avoided. Given that high ep values are mandatory for evaluating the stereoselectivity of drugs,6 credible ep data are needed before accepting the proposed method for preparativescale applications. On the other hand, the overlapping chromatographic peaks reported for the diastereomeric derivatives (Figure 6) cast doubts on the possibility of using Alwera’s method even for analytical assays. In conclusion, we think that the Alwera’s method would be effective as a green preparative procedure to obtain mexiletine enantiomers provided the above points of criticism are addressed.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Telephone: +39 0805442744. Fax: +39 080-5442050. ORCID
Giovanni Lentini: 0000-0001-7079-5994 Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Alwera, S. In situ derivatization of (RS)-mexiletine and enantioseparation using micellar liquid chromatography: a green approach. ACS Sustainable Chem. Eng. 2018, 6 (9), 11653−11661.
Received: December 20, 2018
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DOI: 10.1021/acssuschemeng.8b06684 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
ACS Sustainable Chemistry & Engineering
Letter to the Editor
(2) De Bellis, M.; De Luca, A.; Desaphy, J. F.; Carbonara, R.; Heiny, J. A.; Kennedy, A.; Carocci, A.; Cavalluzzi, M. M.; Lentini, G.; Franchini, C.; Conte Camerino, D. Combined modifications of mexiletine pharmacophores for new lead blockers of Nav1.4 channels. Biophys. J. 2013, 104 (2), 344−354. (3) Gualdani, R.; Tadini-Buoninsegni, F.; Roselli, M.; Defrenza, I.; Contino, M.; Colabufo, N. A.; Lentini, G. Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine. Pharmacol. Res. Perspect. 2015, 3 (5), No. e00160. (4) Sasikumar, M.; Nikalje, M. D.; Muthukrishnan, M. A convenient synthesis of enantiomerically pure (R)-mexiletine using hydrolytic kinetic resolution method. Tetrahedron: Asymmetry 2009, 20 (24), 2814−2817. (5) Covington, C. L.; Polavarapu, P. L. Specific optical rotations and the Horeau effect. Chirality 2016, 28 (3), 181−185. (6) Lentini, G. Shouldn’t enantiomeric purity be included in the “Minimum Information about a Bioactive Entity”? Nat. Rev. Drug Discovery 2012, 11 (9), 730.
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DOI: 10.1021/acssuschemeng.8b06684 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
