Levetiracetam analogs: chemoenzymatic synthesis, absolute configuration assignment and evaluation of cholinesterase inhibitory activities
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Abstract
A chemoenzymatic approach for the synthesis of α-N-heterocyclic ethyl- and phenylacetamides, levetiracetam analogs, is described. Eight nitrile substrates were prepared through the N-alkylation of heterocycles (2-pyrrolidinone, 2-piperidinone, 2-oxopiperazine and 1-methylpiperazine) directly from hydroxyl group of ethyl and phenyl α-hydroxynitriles with yield of 35−71% after 12 h. Twenty nitrile hydratases (NHases) were screened and showed that the N-derivatives lactam substrates led to their correspondent amides by Co-type NHase with conversion and enantiomeric excess of up to 47.5 and 52.3% for (S)-enantiomer, while the piperazine substrates underwent spontaneous decomposition by retro-Strecker reaction. In order to avoid a retro-Strecker reaction of α-aminonitriles, ionic liquids and polyethylene glycol (PEG400) were evaluated as alternative green solvents to aqueous buffered solutions in different proportions. Temperature was another parameter investigated during reaction-medium engineering for process optimization. However, unconventional reaction media and low temperature significantly reduced the NHase activity. The absolute configuration of α-N-heterocyclic ethyl- and phenylacetamides, some of which were new compounds, was determined using electronic circular dichroism (ECD) spectroscopy. Additionally, their potential as cholinesterase’s inhibitors was evaluated.
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Fundação de Amparo à Pesquisa do Estado de São Paulo
Grant numbers 2014/50249-8; 2010/02305-5; 2013/16636-1; 2014/50926-0; 2014/25222-9; 2019/22319-5; 2019/15230-8 -
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Grant numbers 465637/2014-0 -
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Grant numbers Finance Code 001 -
GlaxoSmithKline
References
Ahmad, G.; Rasool, N.; Rizwan, K.; Imran, I.; Zahoor, A. F.; Zubair, M.; Sadiq, A.; Rashid, U. Synthesis, in-Vitro Cholinesterase Inhibition, In-Vivo Anticonvulsant Activity And In-Silico Exploration of N-(4-methylpyridin-2-yl)thiophene-2-carboxamide analogs. Bioorg. Chem. 2019, 92, 103216. https://doi.org/10.1016/j.bioorg.2019.103216
Altenkämper, M.; Bechem, B.; Perruchon, J.; Heinrich, S.; Mädel, A.; Ortmann, R.; Dahse, H.-M.; Freunscht, E.; Wang, Y.; Rath, J.; Stich, A.; Hitzler, M.; Chiba, P.; Lanzer, M.; Schlitzer, M. Antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone. Bioorg. Med. Chem. 2009, 17 (22), 7690–7697. https://doi.org/10.1016/j.bmc.2009.09.043
Anuradha, S.; Preeti, K. Levetiracetam with its therapeutic potentials. Int. J. Univers. Pharm. Bio Sci. 2013, 2 (5), 45–58.
Bhalla, T. C.; Kumar, V.; Kumar, V.; Thakur, N.; Savitri. Nitrile metabolizing enzymes in biocatalysis and biotransformation. Appl. Biochem. Biotechnol. 2018, 185 (4), 925–946. https://doi.org/10.1007/s12010-018-2705-7
Bisogno, F. R.; López-Vidal, M. G.; de Gonzalo, G. Organocatalysis and biocatalysis hand in hand: Combining catalysts in one-pot procedures. Adv. Synth. Catal. 2017, 359 (12), 2026–2049. https://doi.org/10.1002/adsc.201700158
Brazil. Ministério da Saúde. Portaria nº 56, de 1 de dezembro de 2017. Fica incorporado o levetiracetam para o tratamento da epilepsia, no âmbito do Sistema Único de Saúde – SUS. Brasília: Diário Oficial da União, 2017. https://bvsms.saude.gov.br/bvs/saudelegis/sctie/2017/prt0056_05_12_2017.html (accessed 2021-07-19).
Cantone, S.; Hanefeld, U.; Basso, A. Biocatalysis in non-conventional media—ionic liquids, supercritical fluids and the gas phase. Green Chem. 2007, 9 (9), 954–971. https://doi.org/10.1039/b618893a
Carmona, A. T.; Fialová, P.; Křen, V.; Ettrich, R.; Martínková, L.; Moreno-Vargas, A. J.; González, C.; Robina, I. Cyanodeoxy-glycosyl derivatives as substrates for enzymatic reactions. Eur. J. Org. Chem. 2006, 2006 (8), 1876–1885. https://doi.org/10.1002/ejoc.200500755
Casey, M.; Leonard, J.; Lygo, B.; Procter, G. Working up the reaction. In Advanced practical organic chemistry; Springer, 1990; pp 141–187. https://doi.org/10.1007/978-1-4899-6643-8
Chaudhry, S. A.; Jong, G.; Koren, G. The fetal safety of Levetiracetam: A systematic review. Reprod. Toxicol. 2014, 46, 40–45. https://doi.org/10.1016/j.reprotox.2014.02.004
Chen, Z.; Meng, L.; Ding, Z.; Hu, J. Construction of versatile N-heterocycles from in situ generated 1,2-Diaza-1,3-dienes. Curr. Org. Chem. 2019, 23 (2), 164–187. https://doi.org/10.2174/1385272823666190227162840
Choi, I.; Chung, H.; Park, J. W.; Chung, Y. K. Active and recyclable catalytic synthesis of indoles by reductive cyclization of 2-(2-Nitroaryl)acetonitriles in the presence of Co-Rh heterobimetallic nanoparticles with atmospheric hydrogen under mild conditions. Org. Lett. 2016, 18 (21), 5508–5511. https://doi.org/10.1021/acs.orglett.6b02659
D’Antona, N.; Morrone, R. Biocatalysis: Green transformations of nitrile function. In Green chemistry for environmental sustainability; Sanjay, K., Sharma, A. M., Eds.; CRC Press - Taylor and Francis, 2010.
Dupont, J.; Consorti, C. S.; Suarez, P. A. Z.; Souza, R. F. Preparation of 1-Butyl-3-Methyl Imidazolium-Based room temperature ionic liquids. Org. Synth. 2002, 79, 236. https://doi.org/10.15227/orgsyn.079.0236
Gaussian 09. Revision A.02; Gaussian, Inc.: Wallingford, 2016.
Giorgi, F. S.; Guida, M.; Vergallo, A.; Bonuccelli, U.; Zaccara, G. Treatment of epilepsy in patients with Alzheimer’s disease. Expert Rev. Neurother. 2017, 17 (3), 309–318. https://doi.org/10.1080/14737175.2017.1243469
Gong, J.-S.; Shi, J.-S.; Lu, Z.-M.; Li, H.; Zhou, Z.-M.; Xu, Z.-H. Nitrile-converting enzymes as a tool to improve biocatalysis in organic synthesis: Recent insights and promises. Crit. Rev. Biotechnol. 2017, 37 (1), 69–81. https://doi.org/10.3109/07388551.2015.1120704
González-Vera, J. A.; García-López, M. T.; Herranz, R. Molecular diversity via amino acid derived α-amino nitriles: Synthesis of spirocyclic 2,6-Dioxopiperazine Derivatives. J. Org. Chem. 2005, 70 (9), 3660–3666. https://doi.org/10.1021/jo050146m
Hong, F.; Xia, Z.; Zhu, D.; Wu, H.; Liu, J.; Zeng, Z. N-terminal strategy (N1-N4) toward high performance liquid crystal materials. Tetrahedron 2016, 72 (10), 1285–1292. https://doi.org/10.1016/j.tet.2015.11.013
Hönig, M.; Sondermann, P.; Turner, N. J.; Carreira, E. M. Enantioselective chemo- and biocatalysis: Partners in retrosynthesis. Angew. Chem. Int. Ed. 2017, 56 (31), 8942–8973. https://doi.org/10.1002/anie.201612462
Jenner, G. Homogeneous ruthenium catalysis of N-alkylation of amides and lactams. J. Mol. Catal. 1989, 55 (1), 241–246. https://doi.org/10.1016/0304-5102(89)80257-3
Jiao, S.; Li, F.; Yu, H.; Shen, Z. Advances in acrylamide bioproduction catalyzed with Rhodococcus cells harboring nitrile hydratase. Appl. Microbiol. Biotechnol. 2020, 104, 1001–1012. https://doi.org/10.1007/s00253-019-10284-5
Kenda, B. M.; Matagne, A. C.; Talaga, P. E.; Pasau, P. M.; Differding, E.; Lallemand, B. I.; Frycia, A. M.; Moureau, F. G.; Klitgaard, H. V.; Gillard, M. R.; Fuks, B.; Michel, P. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J. Med. Chem. 2004, 47 (3), 530–549. https://doi.org/10.1021/jm030913e
Krasowski, M. D.; McMillin, G. A. Advances in anti-epileptic drug testing. Clin. Chim. Acta 2014, 436, 224–236. https://doi.org/10.1016/j.cca.2014.06.002
Kuca, K.; Soukup, O.; Maresova, P.; Korabecny, J.; Nepovimova, E.; Klimova, B.; Honegr, J.; Ramalho, T. C.; França, T. C. C. Current approaches against Alzheimer’s disease in clinical trials. J. Braz. Chem. Soc. 2016, 27 (4), 641–649. https://doi.org/10.5935/0103-5053.20160048
Kumar, D.; Grapperhaus, C. A. Sulfur-oxygenation and functionalmodels of nitrile hydratase. In Bioinspired catalysis; Weigand, W., Schollhammer, P., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA, 2014. https://doi.org/10.1002/9783527664160.ch12
Li, L.; Si, Y.-K. Study on the absolute configuration of Levetiracetam via density functional theory calculations of electronic circular dichroism and optical rotatory dispersion. J. Pharm. Biomed. Anal. 2011, 56 (3), 465–470. https://doi.org/10.1016/j.jpba.2011.07.002
Liu, S.; Zhao, Z.; Wang, Y. Construction of N‐heterocycles through cyclization of tertiary amines. Chem. Eur. J. 2019, 25 (10), 2423–2441 https://doi.org/10.1002/chem.201803960
Lyseng-Williamson, K. A. Spotlight on Levetiracetam in epilepsy. CNS Drugs 2011a, 25, 901–905. https://doi.org/10.2165/11208340-000000000-00000
Lyseng-Williamson, K. A. Levetiracetam: A review of its use in epilepsy. Drugs 2011b, 71 (4), 489–514.
Mashweu, A. R.; Chhiba-Govindjee, V. P.; Bode, M. L.; Brady, D. Substrate profiling of the cobalt nitrile hydratase from Rhodococcus rhodochrous ATCC BAA 870. Molecules 2020, 25 (1), 238. https://doi.org/10.3390/molecules25010238
Mitra, S.; Holz, R. C. Unraveling the catalytic mechanism of nitrile hydratases. J. Biol. Chem. 2007, 282 (10), 7397–7404. https://doi.org/10.1074/jbc.M604117200
Miyanaga, A.; Fushinobu, S.; Ito, K.; Shoun, H.; Wakagi, T. Mutational and structural analysis of cobalt-containing nitrile hydratase on substrate and metal binding. Eur. J. Biochem. 2004, 271 (2), 429–438. https://doi.org/10.1046/j.1432-1033.2003.03943.x
Narczyk, A.; Mrozowicz, M.; Stecko, S. Total synthesis of Levetiracetam. Org. Biomol. Chem. 2019, 17 (10), 2770–2775. https://doi.org/10.1039/C9OB00111E
Nelp, M. T.; Astashkin, A. V.; Breci, L. A.; McCarty, R. M.; Bandarian, V. The alpha subunit of nitrile hydratase is sufficient for catalytic activity and post-translational modification. Biochemistry 2014, 53 (24), 3990–3994. https://doi.org/10.1021/bi500260j
Prasad, S.; Bhalla, T. C. Nitrile hydratases (NHases): At the interface of academia and industry. Biotechnol. Adv. 2010, 28 (6), 725–741. https://doi.org/10.1016/j.biotechadv.2010.05.020
Prozomix. Enzyme Catalogue. 2020. http://www.prozomix.com/products/listing?searchby=name&searchby_name=Nitrile+hydratase&category=21&x=53&y=3 (accessed 2020-01-27).
Saini, M. S.; Kumar, A.; Dwivedi, J.; Singh, R. A review: Biological significances of heterocyclic compounds. Int. J. Pharm. Sci. Res. 2013, 4 (3), 66–77.
Seidl, C.; Vilela, A. F. L.; Lima, J. M.; Leme, G. M.; Cardoso, C. L. A novel on-flow mass spectrometry-based dual enzyme assay. Anal. Chim. Acta 2019, 1072, 81–86. https://doi.org/10.1016/j.aca.2019.04.057
Sheldon, R. A.; Pereira, P. C. Biocatalysis engineering: The big picture. Chem. Soc. Rev. 2017, 46 (10), 2678–2691. https://doi.org/10.1039/C6CS00854B
Shen, Y.; Du, F.; Gao, W.; Wang, A.; Chen, C. Stereoselective nitrile hydratase. Afr. J. Microbiol. Res. 2012, 6 (32), 6114–6121. https://doi.org/10.5897/AJMR12.101
Siebel, A. M.; Rico, E. P.; Capiotti, K. M.; Piato, A. L.; Cusinato, C. T.; Franco, T. M. A.; Bogo, M. R.; Bonan, C. D. In vitro effects of antiepileptic drugs on acetylcholinesterase and ectonucleotidase activities in zebrafish (Danio rerio) brain. Toxicol. Vitro 2010, 24 (4), 1279–1284. https://doi.org/10.1016/j.tiv.2010.03.018
Sola, I.; Aso, E.; Frattini, D.; López-González, I.; Espargaró, A.; Sabaté, R.; Di Pietro, O.; Luque, F. J.; Clos, M. V.; Ferrer, I.; Muñoz-Torrero, D. Novel Levetiracetam derivatives that are effective against the alzheimer-like phenotype in mice: Synthesis, in vitro, ex vivo, and in vivo efficacy studies. J. Med. Chem. 2015, 58 (15), 6018–6032. https://doi.org/10.1021/acs.jmedchem.5b00624
Souza, R. O. M. A.; Miranda, L. S. M.; Bornscheuer, U. T. A retrosynthesis approach for biocatalysis in organic synthesis. Chem. Eur. J. 2017, 23 (50), 12040–12063. https://doi.org/10.1002/chem.201702235
Supreetha, K.; Rao, S. N.; Srividya, D.; Anil, H. S.; Kiran, S. Advances in cloning, structural and bioremediation aspects of nitrile hydratases. Mol. Biol. Rep. 2019, 46, 4661–4673. https://doi.org/10.1007/s11033-019-04811-w
Tao, J.; Liu, J.; Chen, Z. Some recent examples in developing biocatalytic pharmaceutical processes. In Asymmetric catalysis on industrial scale: Challenges, approaches and solutions; Hans‐Ulrich, B., Hans‐Jürgen, F., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA, 2010. https://doi.org/10.1002/9783527630639.ch1
Tucker, J. L.; Xu, L.; Yu, W.; Scott, R. W.; Zhao, L.; Ran, N. Chemoenzymatic processes for preparation of Levetiracetam. US WO2009009117, 2009.
U.S Department of Health and Human Services, 2014. Levetiracetam for Alzheimer’s disease-associated epileptiform activity. https://www.nia.nih.gov/alzheimers/clinical-trials/levetiracetam-alzheimers-disease-associated-epileptiform-activity (accessed 2020-04-29).
UCB. 2018 Full Year Results. UCB https://www.ucb.com/_up/ucb_com_ir/documents/2018_FY_results_presentation_-_final.pdf (accessed (accessed 2020-01-17).
Uges, J. W. F.; Vecht, C, J. Levetiracetam. In Atlas of Epilepsies; Panayiotopoulos, C. P., Ed.; Springer London, 2010. https://doi.org/10.1007/978-1-84882-128-6_271
van Pelt, S.; Zhang, M.; Otten, L. G.; Holt, J.; Sorokin, D. Y.; van Rantwijk, F.; Black, G. W.; Perry, J. J.; Sheldon, R. A. Probing the enantioselectivity of a diverse group of purified cobalt-centred nitrile hydratases. Org. Biomol. Chem. 2011, 9 (8), 3011–3019. https://doi.org/10.1039/c0ob01067g
Vilela, A. F. L.; Seidl, C.; Lima, J. M.; Cardoso, C. L. An improved immobilized enzyme reactor-mass spectrometry-based label free assay for butyrylcholinesterase ligand screening. Anal. Biochem. 2018, 549, 53–57. https://doi.org/10.1016/j.ab.2018.03.012
Wang, M.-X. Progress of enantioselective nitrile biotransformations in organic synthesis. CHIMIA International Journal for Chemistry 2009, 63 (6), 331–333. https://doi.org/10.2533/chimia.2009.331
Wang, M.-X. Enantioselective biotransformations of nitriles in organic synthesis. Acc. Chem. Res. 2015, 48 (3), 602–611. https://doi.org/10.1021/ar500406s
Wen, Y.; Liang, M.; Wang, Y.; Ren, W.; Lü, X. Perfectly green organocatalysis: Quaternary ammonium base triggered cyanosilylation of aldehydes. Chinese J. Chem. 2012, 30 (9), 2109–2114. https://doi.org/10.1002/cjoc.201200598
Yasukawa, K.; Hasemi, R.; Asano, Y. Dynamic kinetic resolution of α-aminonitriles to form chiral α-amino acids. Adv. Synth. Catal. 2011, 353 (13), 2328–2332. https://doi.org/10.1002/adsc.201100360.
Young, S. D.; Buse, C. T.; Heathcock, C. H. 2-Methyl-2-(Trimethylsiloxy)Pentan-3-one. In Organic Syntheses; John Wiley & Sons, 2003. https://doi.org/10.1002/0471264180.os063.09
Zhang, J.; Wang, H.; Ma, Y.; Wang, Y.; Zhou, Z.; Tang, C. CaF2 Catalyzed SN2 type chlorodehydroxylation of chiral secondary alcohols with thionyl chloride: A practical and convenient approach for the preparation of optically active chloroalkanes. Tetrahedron Lett. 2013, 54 (18), 2261–2263. https://doi.org/10.1016/j.tetlet.2013.02.079