Generic placeholder image

Current Bioactive Compounds

Author(s): Huseyin Aksit*, Azhar Rasul, Şevki Adem, Çağlar Güler and İbrahim Demirtas

DOI: 10.2174/1573407219666230619110205

DownloadDownload PDF Flyer Cite As
Activation Effect of 2-β-hydroxy Manoyl Oxide Isolated from Sideritis perfoliata on Carbonic Anhydrase Isoenzymes I and II

Article ID: e190623218067 Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: Sideritis species were used for the treatment of mental disorders such as Alzheimer’s and dementia traditionally in Turkey. Several in vivo studies report that the mid-polar extract of Sideritis species can develop the brain functions of mice. 2-β-hydroxy manoyl oxide, isolated from ethyl acetate extract of Sideritis perfoliata, was assayed in vitro and in silico on human erythrocytes CA I and CA II. The compound was found to be an activator on two isoenzymes. It has been reported that activators of carbonic anhydrases may be used as a novel approach to treating disorders such as Alzheimer’s and age-related diseases. This study aimed to investigate the activity effect of 2-β-hydroxy manoyl oxide in vitro and in silico on human erythrocytes CA I and CA II (hCA I and hCA II) and to elucidate its pharmacokinetic and physicochemical characteristics.

Methods: The test compound was isolated from ethyl acetate extract of Sideritis perfoliata using chromatographic techniques and identified with spectroscopic evidence. Carbonic anhydrase activities were assayed using CO2 substrates. Docking studies were carried out with Molegro Virtual Docker. The compound underwent ADME-Tox prediction by using AdmetSAR and SwissADME software.

Results: 2-β-hydroxy manoyl oxide was found to increase the hCA-l and hCAII activity with AC50 values 9 and 19 μM, respectively. These results were further confirmed in silico molecular modeling. It showed favorable pharmacokinetic and physicochemical characteristics as a new drug candidate.

Conclusion: These findings demonstrated that 2-β-hydroxy manoyl oxide activated the hCA-l and hCA II. These results provide a novel and alternative activator for the carbonic anhydrase and confirm the traditional usage of the Sideritis perfoliata.

Graphical Abstract

[1]
Supuran, C.T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov., 2008, 7(2), 168-181.
[http://dx.doi.org/10.1038/nrd2467] [PMID: 18167490]
[2]
Innocenti, A.; Gülçin, I.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Antioxidant polyphenols effectively inhibit mammalian isoforms I–XV. Bioorg. Med. Chem. Lett., 2010, 20(17), 5050-5053.
[http://dx.doi.org/10.1016/j.bmcl.2010.07.038] [PMID: 20674354]
[3]
Provensi, G.; Carta, F.; Nocentini, A.; Supuran, C.T.; Casamenti, F.; Passani, M.B.; Fossati, S. A new kid on the block? Carbonic anhydrases as possible new targets in Alzheimer’s disease. Int. J. Mol. Sci., 2019, 20(19), 4724.
[http://dx.doi.org/10.3390/ijms20194724] [PMID: 31554165]
[4]
Ruusuvuori, E.; Kaila, K. Carbonic anhydrases and brain ph in the control of neuronal excitability.In: Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications; Frost, S.C.; McKenna, R., Eds.; Springer Netherlands: Dordrecht, 2014, pp. 271-290.
[http://dx.doi.org/10.1007/978-94-007-7359-2_14]
[5]
Meier-Ruge, W.; Iwangoff, P.; Reichlmeier, K. Neurochemical enzyme changes in Alzheimer’s and Pick’s disease. Arch. Gerontol. Geriatr., 1984, 3(2), 161-165.
[http://dx.doi.org/10.1016/0167-4943(84)90007-4] [PMID: 6089677]
[6]
Sun, M.K.; Alkon, D.L. Carbonic anhydrase gating of attention: Memory therapy and enhancement. Trends Pharmacol. Sci., 2002, 23(2), 83-89.
[http://dx.doi.org/10.1016/S0165-6147(02)01899-0] [PMID: 11830265]
[7]
Adem, S.; Akkemik, E.; Aksit, H.; Guller, P.; Tüfekci, A.R.; Demirtas, I.; Ciftci, M. Activation and inhibition effects of some natural products on human cytosolic CAI and CAII. Med. Chem. Res., 2019, 28(5), 711-722.
[http://dx.doi.org/10.1007/s00044-019-02329-1]
[8]
Blandina, P.; Provensi, G.; Passani, M.B.; Capasso, C.; Supuran, C.T. Carbonic anhydrase modulation of emotional memory. Implications for the treatment of cognitive disorders. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 1206-1214.
[http://dx.doi.org/10.1080/14756366.2020.1766455] [PMID: 32401069]
[9]
Tutin, T.G.; Heywood, V.H.; Burges, N.A.; Valentine, D.H.; Walters, S.M.; Webb, D.A. Flora Europaea: Plantaginaceae to Compositae (and Rubiaceae); Cambridge University Press, 1964, p. 4.
[10]
Halfon, B.; Ciftci, E.; Topcu, G. Flavonoid constituents of Sideritis caesarea. Turk. J. Chem., 2013, 37(3), 464-472.
[11]
Aneva, I.; Zhelev, P.; Kozuharova, E.; Danova, K.; Nabavi, S.F.; Behzad, S. Genus Sideritis, section Empedoclia in Southeastern Europe and Turkey - studies in ethnopharmacology and recent progress of biological activities. Daru, 2019, 27(1), 407-421.
[http://dx.doi.org/10.1007/s40199-019-00261-8] [PMID: 30927208]
[12]
Żyżelewicz, D.; Kulbat-Warycha, K.; Oracz, J.; Żyżelewicz, K. Polyphenols and other bioactive compounds of sideritis plants and their potential biological activity. Molecules, 2020, 25(16), 3763.
[http://dx.doi.org/10.3390/molecules25163763] [PMID: 32824863]
[13]
Hofrichter, J.; Krohn, M.; Schumacher, T.; Lange, C.; Feistel, B.; Walbroel, B.; Pahnke, J. Sideritis spp. extracts enhance memory and learning in Alzheimer’s β-amyloidosis mouse models and aged C57Bl/6 mice. J. Alzheimers Dis., 2016, 53(3), 967-980.
[http://dx.doi.org/10.3233/JAD-160301] [PMID: 27258424]
[14]
Çelik, Í.; Atioğlu, Z.; Aksit, H.; Demirtas, I.; Erenler, R.; Akkurt, M. Crystal structure and Hirshfeld surface analysis of 2-oxo-13-epi-manoyl oxide isolated from Sideritis perfoliata. Acta Crystallogr. E Crystallogr. Commun., 2018, 74(5), 713-717.
[http://dx.doi.org/10.1107/S2056989018005807] [PMID: 29850098]
[15]
Çelik, Í.; Ersanlı, C.C.; Köseoğlu, R.; Akşit, H.; Erenler, R.; Demirtaş, I.; Akkurt, M. Crystal structure of 3,4a,7,7,10a-pentamethyl-3-vinyldodecahydro-1 H -benzo[ f]chromen-9-ol isolated from Sideritis perfoliata. Acta Crystallogr. E Crystallogr. Commun., 2016, 72(10), 1380-1382.
[http://dx.doi.org/10.1107/S2056989016013864] [PMID: 27746923]
[16]
Sezik, E.; Ezer, N.; Hueso-Rodríguez, J.A.; Rodríguez, B. Ent-2α-hydroxy-13-epi-manoyl oxide from Sideritis perfoliata. Phytochemistry, 1985, 24(11), 2739-2740.
[http://dx.doi.org/10.1016/S0031-9422(00)80713-X]
[17]
Anderson, N.G.; Wilbur, K.M. Electrometric and colorimetric determination of carbonic anhydrase. Anat. Rec., 1948, 101(4), 685.
[PMID: 18882470]
[18]
Alterio, V.; Monti, S.M.; Truppo, E.; Pedone, C.; Supuran, C.T.; De Simone, G. The first example of a significant active site conformational rearrangement in a carbonic anhydrase-inhibitor adduct: The carbonic anhydrase I–topiramate complex. Org. Biomol. Chem., 2010, 8(15), 3528-3533.
[http://dx.doi.org/10.1039/b926832d] [PMID: 20505865]
[19]
Bhatt, A.; Mondal, U.K.; Supuran, C.T.; Ilies, M.A.; McKenna, R. Crystal structure of carbonic anhydrase II in complex with an activating ligand: Implications in neuronal function. Mol. Neurobiol., 2018, 55(9), 7431-7437.
[http://dx.doi.org/10.1007/s12035-017-0854-2] [PMID: 29423818]
[20]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[21]
Yang, H.; Lou, C.; Sun, L.; Li, J.; Cai, Y.; Wang, Z.; Li, W.; Liu, G.; Tang, Y. admetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties. Bioinformatics, 2019, 35(6), 1067-1069.
[http://dx.doi.org/10.1093/bioinformatics/bty707] [PMID: 30165565]
[22]
Supuran, C.T. Carbonic anhydrase activators. Future Med. Chem., 2018, 10(5), 561-573.
[http://dx.doi.org/10.4155/fmc-2017-0223] [PMID: 29478330]
[23]
Domsic, J.F.; Avvaru, B.S.; Kim, C.U.; Gruner, S.M.; Agbandje-McKenna, M.; Silverman, D.N.; McKenna, R. Entrapment of carbon dioxide in the active site of carbonic anhydrase II. J. Biol. Chem., 2008, 283(45), 30766-30771.
[http://dx.doi.org/10.1074/jbc.M805353200] [PMID: 18768466]
[24]
Briganti, F.; Mangani, S.; Orioli, P.; Scozzafava, A.; Vernaglione, G.; Supuran, C.T. Carbonic anhydrase activators: X-ray crystallographic and spectroscopic investigations for the interaction of isozymes I and II with histamine. Biochemistry, 1997, 36(34), 10384-10392.
[http://dx.doi.org/10.1021/bi970760v] [PMID: 9265618]
[25]
Temperini, C.; Scozzafava, A.; Puccetti, L.; Supuran, C.T. Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with l-histidine as a platform for the design of stronger activators. Bioorg. Med. Chem. Lett., 2005, 15(23), 5136-5141.
[http://dx.doi.org/10.1016/j.bmcl.2005.08.069] [PMID: 16214338]
[26]
Temperini, C.; Scozzafava, A.; Vullo, D.; Supuran, C.T. Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII, and XIV with L- and D-phenylalanine and crystallographic analysis of their adducts with isozyme II: Stereospecific recognition within the active site of an enzyme and its consequences for the drug design. J. Med. Chem., 2006, 49(10), 3019-3027.
[http://dx.doi.org/10.1021/jm0603320] [PMID: 16686544]
[27]
Temperini, C.; Scozzafava, A.; Vullo, D.; Supuran, C.T. Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l- and d-histidine and crystallographic analysis of their adducts with isoform II: Engineering proton-transfer processes within the active site of an enzyme. Chemistry, 2006, 12(27), 7057-7066.
[http://dx.doi.org/10.1002/chem.200600159] [PMID: 16807956]
[28]
van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: Towards prediction paradise? Nat. Rev. Drug Discov., 2003, 2(3), 192-204.
[http://dx.doi.org/10.1038/nrd1032] [PMID: 12612645]
[29]
Wei, W.; Cherukupalli, S.; Jing, L.; Liu, X.; Zhan, P. Fsp3: A new parameter for drug-likeness. Drug Discov. Today, 2020, 25(10), 1839-1845.
[http://dx.doi.org/10.1016/j.drudis.2020.07.017] [PMID: 32712310]
[30]
Stratton, C.F.; Newman, D.J.; Tan, D.S. Cheminformatic comparison of approved drugs from natural product versus synthetic origins. Bioorg. Med. Chem. Lett., 2015, 25(21), 4802-4807.
[http://dx.doi.org/10.1016/j.bmcl.2015.07.014] [PMID: 26254944]
[31]
Pardridge, W.M. Alzheimer’s disease drug development and the problem of the blood-brain barrier. Alzheimers Dement., 2009, 5(5), 427-432.
[http://dx.doi.org/10.1016/j.jalz.2009.06.003] [PMID: 19751922]
[32]
Liu, X.; Lu, D.; Bowser, R.; Liu, J. Expression of carbonic anhydrase I in motor neurons and alterations in ALS. Int. J. Mol. Sci., 2016, 17(11), 1820.
[http://dx.doi.org/10.3390/ijms17111820] [PMID: 27809276]
[33]
Halmi, P.; Parkkila, S.; Honkaniemi, J. Expression of carbonic anhydrases II, IV, VII, VIII and XII in rat brain after kainic acid induced status epilepticus. Neurochem. Int., 2006, 48(1), 24-30.
[http://dx.doi.org/10.1016/j.neuint.2005.08.007] [PMID: 16271802]