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Progress in the Enantioseparation of -Blockers by Chromatographic Methods

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molecules Review Progress in the Enantioseparation of β-Blockers by Chromatographic Methods Yiwen Yang 1,2,*, Yehui Wang 1, Zongbi Bao 1,2, Qiwei Yang 1,2, Zhiguo Zhang 1,2 and Qilong Ren 1,2 1 Institute of Pharmaceutical Engineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China; [email protected] (Y.W.); [email protected] (Z.B.); [email protected] (Q.Y.); [email protected] (Z.Z.); [email protected] (Q.R.) 2 Institute of Zhejiang University-Quzhou, Quzhou 324000, China * Correspondence: [email protected] Abstract: β-adrenergic antagonists (β-blockers) with at least one chiral center are an exceedingly important class of drugs used mostly to treat cardiovascular diseases. At least 70 β-blockers have been investigated in history. However, only a few β-blockers, e.g., timolol, are clinically marketed as an optically pure enantiomer. Therefore, the separation of racemates of β-blockers is essential both in the laboratory and industry. Many approaches have been explored to obtain the single enantiomeric β-blocker, including high performance liquid chromatography, supercritical fluid chromatography and simulated moving bed chromatography. In this article, a review is presented on different chromatographic methods applied for the enantioseparation of β-blockers, covering high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC) and simulated moving bed chromatography (SMB). Keywords: β-blockers; chromatography; enantioseparation; SFC; SMB; HPLC Citation: Yang, Y.; Wang, Y.; Bao, Z.; Yang, Q.; Zhang, Z.; Ren, Q. Progress in the Enantioseparation of 1. Introduction β-Blockers by Chromatographic β-adrenergic antagonists, usually termed as β-blockers, are competitive antagonists Methods. Molecules 2021, 26, 468. of the sympathetic effects of catecholamines on beta-adrenergic receptors [1,2] with an https://doi.org/10.3390/ amino-, hydroxyalkyl- side chain and at least one chiral center. Chemical structures of molecules26020468 typical β-blockers are presented in Table1. β-blockers are an exceedingly important class of cardiovascular medication used Academic Editor: Alessandra Gentili mostly to treat arterial hypertension, chronic heart failure, and coronary artery disease, Received: 9 December 2020 representing the cornerstone therapy in these cases for a long time [3]. In fact, four people Accepted: 12 January 2021 Published: 17 January 2021 at three times were awarded Noble prize in the adrenergic receptor research area, i.e., Sir Henry H. Dale being awarded Nobel prize for medicine in 1936, Sir James Black being awarded Nobel prize for medicine in 1988, Profs. Brian Kobilka and Robert Lefkowitz Publisher’s Note: MDPI stays neutral β with regard to jurisdictional claims in being awarded Nobel prize for Chemistry in 2012 [2]. Among chiral drugs, -adrenergic published maps and institutional affil- blocking agents are one of the most investigated pharmaceuticals for their stereochemical iations. impact on pharmacodynamics and pharmacokinetics [4]. Although β-blockers have been excluded from guidelines as the first-line therapy in essential hypertension, they remain the first choice in patients with heart failure, coronary artery disease, and atrial fibrillation [3]. At least 70 β-blockers have been investigated in history, as presented in Table2, according to the literatures, most of which have only one chiral center. Recently, researches about their Copyright: © 2021 by the authors. potential anticancer efficacy have been carried out that β-blockers can inhibit angiogenesis Licensee MDPI, Basel, Switzerland. This article is an open access article and tumor cell proliferation in breast cancer, multiple myeloma, pancreatic cancer, and distributed under the terms and neuroblastoma cell lines by decreasing catecholamine-driven proliferation [1,5,6], making conditions of the Creative Commons β-blockers jump out of the conventional field of cardiovascular disease. Therefore, there Attribution (CC BY) license (https:// would be a large and expanding market for β-blockers, considering the high incidence of creativecommons.org/licenses/by/ various cancer cases worldwide and that cardiovascular disease remains the most common 4.0/). cause of death in industrialized countries. Molecules 2021, 26, 468. https://doi.org/10.3390/molecules26020468 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 468 2 of 24 Molecules 2021,, 2626,, 468468 2 of 24 Molecules 2021, 26, 468 2 of 24 Molecules 2021, 26, 468 2 of 24 Molecules 2021, 26, 468 2 of 24 Molecules 2021, 26, 468 2 of 24 Molecules 2021, 26, 468 2 of 24 Molecules 2021, 26, 468 high incidence of various cancer cases worldwide and that cardiovascular disease remains2 of 24 high incidence of various cancer cases worldwide and that cardiovascular disease remains thehigh most incidence common of various cause of cancer death cases in industrialized worldwide and countries. that cardiovascular disease remains thehigh most incidence common of various cause of cancer death cases in industrialized worldwide and countries. that cardiovascular disease remains thehigh most incidence common of various cause of cancer death cases in industrialized worldwide and countries. that cardiovascular disease remains highthe most incidence common of various cause of cancer death cases in industrialized worldwide and countries. that cardiovascular disease remains Molecules 2021, 26, 468 highTablethe most incidence 1. Chemical common of structuresvarious cause ofcancer of death typical cases in β industrialized-blockers worldw withideide andand different countries. thatthat cardiovascularcardiovascularchiral centers. diseasedisease remainsremains2 of 23 Tablethehigh most incidence 1. Chemical common of structures various cause of cancer of death typical cases in β industrialized-blockers worldw withide anddifferent countries. that cardiovascularchiral centers. disease remains thetheTable mostmost 1. Chemical commoncommon structures causecause ofof of deathdeath typical inin β industrializedindustrialized-blockers with different countries.countries. chiral centers. theTable most 1. Chemical common Namestructures cause of of death typical in βindustrialized-blockers with differentcountries.Chemical chiral centers.Structure Table 1. Chemical Namestructures of typical β-blockers with differentChemical chiral centers.Structure Table 1. Chemical Namestructures of typical β-blockers with differentChemical chiral centers. Structure Table 1. Chemical structuresName of typical β-blockers-blockers withwith differentdifferentChemicalO chiralchiral centers.centers. Structure TableTable 1. Chemical 1. Chemical structures Namestructures of typicalof typicalβ-blockers β-blockers with with different differentChemical chiralO chiral centers. centers. Structure Name H N ChemicalO Structure Name H2N ChemicalO Structure AtenolName H2N ChemicalO StructureO AtenolName H2N Chemical Structure NH AtenolName 2 ChemicalO StructureO * NH Atenol H N O * NH Atenol H2N O O * NH H2N O O * OH NH Atenol H2N O O OH Atenol H 2N * OH NH Atenol H2 N O * OH NH Atenol 2 O * NH Atenol O * OHNH Atenol O * OH NH * OH OH OH NH OH Carvedilol NH Carvedilol NH Carvedilol O HO O NH Carvedilol O HO O NH Carvedilol HO O NH O O NH Carvedilol O O HO * NH Carvedilol O HN HO * O NH Carvedilol O O HN HO * O Carvedilol O O HN * O Carvedilol O HN HO O O O HO * O O O HNHO * O O HN HO * O HN O* OH O HN * O O HN O* OH Metoprolol O HN OH O O * OH Metoprolol O O OHNH * Metoprolol O O OH NH Metoprolol O O * OH O * OH NH Metoprolol O O OH NH Metoprolol O O * OH Metoprolol O * NH Metoprolol O * NH Metoprolol * NH * NH NH HO Oxprenolol HO Oxprenolol HO * O Oxprenolol HO * O Oxprenolol HO * O O HON * Oxprenolol O O Oxprenolol HOHN * O Oxprenolol HOH * O O Oxprenolol HOHN * O O OxprenololOxprenolol HOHN * O O Oxprenolol HN * O O NH * O HN O NH O Propranolol HN Propranolol H Propranolol * Propranolol O * N Propranolol O * HN Propranolol O * NH Propranolol O OH* HN Propranolol O OH* HN Propranolol O OH* NH Propranolol O * NH O *OH HN O *OH NH O OH HN OH H HN OH Sotalol HN OH Sotalol HN * NH O Sotalol HN * NH Sotalol * NH O HN HO * NH S Sotalol HN HO * S O Sotalol HN HO NH S O Sotalol HN HO * ONH S O Sotalol HN HO * ONH Sotalol HN * ONH S O Sotalol HO * NHO S O HO * ONH S OO HO S OO HO O O HO O S O S O Timolol O N O OH O N O Timolol OH N O Timolol H OH NO Timolol NH OH O O Timolol H NON Timolol NH *OH O N N NH *OH O NSN Timolol *OH N NSN Timolol HN *OH O NN SN Timolol HN OH* O N NS Timolol H OH O N N HN * OH O NO SN H H* OHO O SN N * OH NO N Labetalol N NH* OH O NO SN Labetalol HN* * N SNH Labetalol * NH *OH N OS 2 Labetalol * NH *OH NO SNH 2 Labetalol * * 2 Labetalol * HN OH OOHNH2 Labetalol HN OH* OOH NH * NH OH* OOH 2 Labetalol * H OH O NH2 Labetalol NH * OHNH Labetalol OH* N * OHNH2 Labetalol OH* N * NH 2 OH* * H OHNH2 HO OH** NH OH 2 HO * HN OH Nadolol HO * OH* NH OH Nadolol HO * OH* O * N OH Nadolol * O H Nadolol HO OH* O * OHHN HO * OH * OH Nadolol * OH* O * OHHN HO OH* NH Nadolol HO * * O * HNOH Nadolol HO * * O * NHOH Nadolol HO * * O N Nadolol * O * OH Nadolol F * O * OH F F O * OH F F * OH F Nebivolol F * *OH F Nebivolol O * * O Nebivolol F * * N * * F O* * HN * * O Nebivolol F O* NH * O F Nebivolol F O OH* HN OH* O F F * OH* OH* * F Nebivolol F O* OH HN OH * O F Nebivolol F O OH* H OH* O F Nebivolol * * N * * * indicates chiral center. O* *OH NH OH * O Nebivolol O* HN * * O Nebivolol O * *OH NH *OH * O O OH* N OH* O OH H OH OH H OH OH OH Molecules 2021, 26, 468 3 of 23 Table 2. List of β-blockers reported in the literature.
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    Supplementary material BMJ Open Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to September 16, 2019> # Searches Results 1 exp Hypertension/ 247434 2 hypertens*.tw,kf. 420857 3 ((high* or elevat* or greater* or control*) adj4 (blood or systolic or diastolic) adj4 68657 pressure*).tw,kf. 4 1 or 2 or 3 501365 5 Sex Characteristics/ 52287 6 Sex/ 7632 7 Sex ratio/ 9049 8 Sex Factors/ 254781 9 ((sex* or gender* or man or men or male* or woman or women or female*) adj3 336361 (difference* or different or characteristic* or ratio* or factor* or imbalanc* or issue* or specific* or disparit* or dependen* or dimorphism* or gap or gaps or influenc* or discrepan* or distribut* or composition*)).tw,kf. 10 or/5-9 559186 11 4 and 10 24653 12 exp Antihypertensive Agents/ 254343 13 (antihypertensiv* or anti-hypertensiv* or ((anti?hyperten* or anti-hyperten*) adj5 52111 (therap* or treat* or effective*))).tw,kf. 14 Calcium Channel Blockers/ 36287 15 (calcium adj2 (channel* or exogenous*) adj2 (block* or inhibitor* or 20534 antagonist*)).tw,kf. 16 (agatoxin or amlodipine or anipamil or aranidipine or atagabalin or azelnidipine or 86627 azidodiltiazem or azidopamil or azidopine or belfosdil or benidipine or bepridil or brinazarone or calciseptine or caroverine or cilnidipine or clentiazem or clevidipine or columbianadin or conotoxin or cronidipine or darodipine or deacetyl n nordiltiazem or deacetyl n o dinordiltiazem or deacetyl o nordiltiazem or deacetyldiltiazem or dealkylnorverapamil or dealkylverapamil