Ayşe ÇİÇEK KAYA, Hilal ÖZBEK, Hafize YUCA, Gülderen YILMAZ, Zeynebe BİNGÖL, Cavit KAZAZ, İlhami GÜLÇİN, Zuhal GÜVENALP

Phytochemical Analysis and Screening of Acetylcholinesterase and Carbonic Anhydrase I and II Isoenzymes Inhibitory Effect of Heptaptera triquetra (Vent.) Tutin Root

Alzheimer's disease (AD) is characterized by progressive memory loss, deterioration of other cognitive functions, and inability to perform activities of daily living. Inhibiting the AChE enzyme causes Ach accumulation in cholinergic synapses and is expected to increase cognitive functions. Carbonic anhydrase enzymes (CAs) are ubiquitous in all living organisms. They have crucial physiological and pathological roles. CA inhibitors bind to catalytic zinc ion in the active site of CA isoenzymes and block their activity. The clinical use of CAIs had been established as antiglaucoma, anticonvulsant agents, diuretics, and anti-obesity drugs, in the management of mountain sickness, gastric and duodenal ulcers, neurological disorders, osteoporosis, and tumors. To evaluate the bioactive profile of dichloromethane extract prepared from Heptaptera triquetra root, isolation studies, AChE, and hCA I and II inhibitory activities were performed. According to isolation studies, one fatty acid, coniferyl palmitate (1); four sesquiterpene coumarins, umbelliprenin (2), badrakemin acetate (4), colladonin (5), karatavicinol (6); and two sterols, stigmasterol (3a), β-sitosterol (3b) were isolated. The dichloromethane extract and all isolated compounds showed high potency against all enzymes (except badrakemin acetate for AChE) when compared to standards. Umbelliprenin (2) with IC50 value of 31.500 nM against hCA I, colladonin (5) with IC50 value of 36.473 nM against hCA II and stigmasterol (3a), and β-sitosterol (3b) mixture with IC50 value 9.000 nM against AChE demonstrated the best activity.

Keywords:

Heptaptera triquetra, Apiaceae, enzyme inhibition, acetylcholinesterase, carbonic anhydrase, isolation,

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Ahmed, A. A. (1999). Sesquiterpene coumarins and sesquiterpenes from Ferula sinaica. Phytochemistry, 50(1), 109-112.
Akbaba, Y., Akıncıoğlu, A., Göçer, H., Göksu, S., Gülçin, İ., & Supuran, C. T. (2014). Carbonic anhydrase inhibitory properties of novel sulfonamide derivatives of aminoindanes and aminotetralins. Journal of enzyme inhibition and medicinal chemistry, 29(1), 35-42.
Akdağ, M., Ergün, M., Özçelik, A.B., Uysal, M. (2019). Alzheimer hastalığının tedavisinde kullanılan ilaçlar ve yeni yaklaşımlar. Erzincan Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 12(2), 1149-1159.
Akıncıoğlu, A., Topal, M., Gülçin, İ., Göksu, S. (2014). Novel sulfamides and sulfonamides incorporating tetralin scaffold as carbonic anhydrase and acetylcholine esterase inhibitors. Archiv der Pharmazie, 347 (1), 68-76.
Appendino, G., Özen, H. Ç., Tagliapietra, S., & Cisero, M. (1992a). Coumarins from Heptaptera anisoptera. Phytochemistry, 31(9), 3211-3213.
Appendino, G., Özen, H. C., Nano, G. M., & Cisero, M. (1992b). Sesquiterpene coumarin ethers from the genus Heptaptera. Phytochemistry, 31(12), 4223-4226.
Appendino, G., Özen, H. C., & Jakupovic, J. (1993). A sesquiterpene coumarin ether and a coniferyl ester from Heptaptera anisoptera. Fitoterapia-Milano, 64, 505-505.
Appendino G, Tagliapietra S, Nano GM, Jakupovic J. (1994). Sesquiterpene coumarin eters from Asafetida. Phytochemistry, 35, 183-186.
Aydın, T., Yurtvermez, B., Şentürk, M., Kazaz, C., & Çakır, A. (2019). Inhibitory effects of metabolites isolated from Artemisia dracunculus L. against the human carbonic anhydrase I (hCA I) and II (hCA II). Records of Natural Products, 13(3), 225.
Aydin, T. (2020). Secondary metabolites of Helichrysum plicatum DC. subsp. plicatum flowers as strong carbonic anhydrase, cholinesterase and α-glycosidase inhibitors. Zeitschrift für Naturforschung C, 75(5-6), 153-159.
Bahadori, M. B., Dinparast, L., Valizadeh, H., Farimani, M. M., & Ebrahimi, S. N. (2016). Bioactive constituents from roots of Salvia syriaca L.: Acetylcholinesterase inhibitory activity and molecular docking studies. South African Journal of Botany, 106, 1-4.
Bayrak, Ç., Taslimi, P., Kahraman, H.S., Gülçin, İ., Menzek, A., (2019). The first synthesis, carbonic anhydrase inhibition and anticholinergic activities of some bromophenol derivatives with S including natural products. Bioorganic Chemistry, 85, 128-139.
Biçer, A., Taslimi, P., Yakali, G., Gülçin, İ., Gültekin, M.S., Turgut Cin, G. (2019). Synthesis, characterization, crystal structure of novel bis-thiomethylcyclohexanone derivatives and their inhibitory properties against some metabolic enzymes. Bioorganic Chemistry, 82, 393-404.
Burmaoğlu, S., Yılmaz, A.O., Polat, M.F., Kaya, R., Gülçin, İ., Algül, Ö., (2019). Synthesis and biological evaluation of novel tris-chalcones as potent carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase inhibitors. Bioorganic Chemistry, 85, 191-197.
Coban, T.A., Beydemir, S., Gücin, İ., Ekinci, D., Innocenti, A., Vullo, D., Supuran, C.T. (2009). Sildenafil is a strong activator of mammalian carbonic anhydrase isoforms I-XIV. Bioorganic and Medicinal Chemistry, 17 (16), 5791-5795.
Dall'Acqua, S., Maggi, F., Minesso, P., Salvagno, M., Papa, F., Vittori, S., & Innocenti, G. (2010). Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae). Fitoterapia, 81(8), 1208-1212.
Ellman, G. L., Courtney, K. D., Andres Jr, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology, 7(2), 88-95.
Eshbakova, K. A., Saidkhodzhaev, A. I., Vdovin, A. D., & Abdullaev, N. D. (2009). Terpenoid coumarins from Ferula feruloides. Chemistry of natural compounds, 45(5), 708-709.
Erdemir, F., Barut Celepci, D., Aktaş, A., Gök, Y., Kaya, R., Taslimi, P., Demir, Y., Gülçin, İ., (2019). Novel 2-aminopyridine liganded Pd(II) N-heterocyclic carbene complexes: synthesis, characterization, crystal structure and bioactivity properties. Bioorganic Chemistry, 91, (2019), 103134.
Eruygur, N., Koçyiğit, U. M., Taslimi, P., Ataş, M. E. H. M. E. T., Tekin, M., & Gülçin, İ. (2019). Screening the in vitro antioxidant, antimicrobial, anticholinesterase, antidiabetic activities of endemic Achillea cucullata (Asteraceae) ethanol extract. South African Journal of Botany, 120, 141-145.
Fois, B., Distinto, S., Meleddu, R., Deplano, S., Maccioni, E., Floris, C., Rosa, A., Nieddu, M., Caboni, P., Sissi, C., Angeli, A., Supuran C. T. & Cottiglia, F. (2020). Coumarins from Magydaris pastinacea as inhibitors of the tumour-associated carbonic anhydrases IX and XII: isolation, biological studies and in silico evaluation. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), 539-548.
Göçer, H., Akıncıoğlu, A., Öztaşkın, N., Göksu, S., & Gülçin, İ. (2013). Synthesis, Antioxidant, and Antiacetylcholinesterase Activities of Sulfonamide Derivatives of Dopamine‐R elated Compounds. Archiv der pharmazie, 346(11), 783-792.
Göçer, H., Topal, F., Topal, M., Küçük, M., Teke, D., Gülçin, İ., Alwasel, S. H. & Supuran, C. T. (2016). Acetylcholinesterase and carbonic anhydrase isoenzymes I and II inhibition profiles of taxifolin. Journal of enzyme inhibition and medicinal chemistry, 31(3), 441-447.
Gökcen, T., Al, M., Topal, M., Gulcin, I., Ozturk T., Goren A.C. (2017). Synthesis of some natural sulphonamide derivatives as carbonic anhydrase inhibitors. Organic Communication, 10(1), 15-23.
Gulcin, I., & Beydemir, S. (2013). Phenolic compounds as antioxidants: carbonic anhydrase isoenzymes inhibitors. Mini reviews in medicinal chemistry, 13(3), 408-430.
Gülçin, İ., Scozzafava, A., Supuran, C.T., Akıncıoğlu, H., Koksal, Z., Turkan, F., Alwasel, S. (2016). The effect of caffeic acid phenethyl ester (CAPE) metabolic enzymes including acetylcholinesterase, butyrylcholinesterase, glutathione s-transferase, lactoperoxidase and carbonic anhydrase isoenzymes I, II, IX and XII. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(6), 1095-1101.
Güner, A., Aslan, S., Ekim, T., Vural, M., Babaç, M. T. (2012). Turkey Plants List (Vascular Plants). Nezahat Gökyiğit Botanical Garden and Flora Research Association Publication, İstanbul.
Güvenalp, Z., Özbek, H., Kuruüzüm-Uz, A., Kazaz, C., Demirezer, L. Ö. (2009). Secondary metabolites from Nepeta heliotropifolia. Turkish Journal of Chemistry, 33(5), 667-675.33:667-675.
Guvenalp, Z., Ozbek, H., Yerdelen, K. O., Yilmaz, G., Kazaz, C., & Demirezer, L. O. (2017). Cholinesterase inhibition and molecular docking studies of sesquiterpene coumarin ethers from Heptaptera cilicica. Records of Natural Products, 11, 462-467.
Hisar, O., Beydemir, Ş., Gülçin, İ., Küfrevioğlu, Ö.İ., Supuran, C.T., (2005). Effect of low molecular weight plasma inhibitors of rainbow trout (Oncorhyncytes mykiss) on human erythrocytes carbonic anhydrase-II isozyme activity in vitro and rat erythrocytes in vivo. Journal of Enzyme Inhibition and Medicinal Chemistry, 20(1), 35-39.
International Plant Names Index (IPNI). Genus: Heptaptera. https://www.ipni.org/?q=heptaptera. Last access: 21.07.2022.
Jang, B. G., Yun, S. M., Ahn, K., Song, J. H., Jo, S. A., Kim, Y. Y., Kim, D. K., Park, M. H., Han, C. & Koh, Y. H. (2010). Plasma carbonic anhydrase II protein is elevated in Alzheimer's disease. Journal of Alzheimer's Disease, 21(3), 939-945.
Küçük, M., Gulcin, İ. (2016). Purification and characterization of carbonic anhydrase enzyme from black sea trout (Salmo trutta Labrax Coruhensis) kidney and inhibition effects of some metal ions on the enzyme activity. Environmental Toxicology and Pharmacology, 44,134-139.
Lee, J. Y., Yoon, J. W., Kim, C. T., & Lim, S. T. (2004). Antioxidant activity of phenylpropanoid esters isolated and identified from Platycodon grandiflorum A. DC. Phytochemistry, 65(22), 3033-3039.
Lolak, N., Akocak, S., Türkeş, C., Taslimi, P., Işık, M., Beydemir, Ş., Gülçin, İ. & Durgun, M. (2020). Synthesis, characterization, inhibition effects, and molecular docking studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors of novel benzenesulfonamides incorporating 1, 3, 5-triazine structural motifs. Bioorganic chemistry, 100, 103897.
Nar, M., Çetinkaya, Y., Gülçin, İ., Menzek, A. (2013). (3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 28(2), 402-406.
Orhan, I. E., Tosun, F., Deniz, F. S. S., Eren, G., Mıhoğlugil, F., Akalgan, D., & Miski, M. (2021). Butyrylcholinesterase-inhibiting natural coumarin molecules as potential leads. Phytochemistry Letters, 44, 48-54.
Özbek, H., Güvenalp, Z., Yılmaz, G., Yerdelen, K. Ö., Kazaz, C., & Demirezer, Ö. L. (2018). In vitro anticholinesterase activity and molecular docking studies of coumarin derivatives isolated from roots of Heptaptera cilicica. Medicinal Chemistry Research, 27(2), 538-545.
Öztürk, G.B., Karan, M.A. (2009). Alzheimer hastalığının fizyopatolojisi. Klinik gelişim, 22(3), 36-45.
Polat Köse, L., Gülcin, I., Gören, A. C., Namiesnik, J., Martinez-Ayala, A. L., & Gorinstein, S. (2015). LC–MS/MS analysis, antioxidant and anticholinergic properties of galanga (Alpinia officinarum Hance) rhizomes. Industrial crops and products, 74, 712-721.
Pereira, V. V., Silva, R. R., Duarte, L. P., & Takahashi, J. A. (2016). Chemical constituents of Jacaranda oxyphylla and their acetylcholinesterase inhibitory and antimicrobial activities. Records of Natural Products, 10(3), 392.
Saleem, M., Hareem, S., Khan, A., Naheed, S., Raza, M., Hussain, R., Hussain, R., Imran, M. & Choudhary, M. I. (2019). Dual inhibitors of urease and carbonic anhydrase-II from Iris species. Pure and Applied Chemistry, 91(10), 1695-1707.
Sepheri, N., Mohammadi-Khanaposhtani, M., Asemanipoor, N., Hosseini, S., Biglar, M., Larijani, B., Mahdavi, M., Hamedifar, H., Taslimi, P., Sadeghian, N., Gulçin, İ., (2020). Synthesis, characterization, molecular docking and biological activities of coumarin-1,2,3-triazole-acetamide hybrid derivatives. Archiv der Pharmazie, 353(10), (2020) e2000109.
Simova, M., Tomov, E., Pangarova, T., & Pavlova, N. (1986). Determination of phenolic compounds in Colladonia triquetra L. Journal of Chromatography A, 351, 379-382.
Supuran, C. T. (2020). Coumarin carbonic anhydrase inhibitors from natural sources. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), 1462-1470.
Şenol, F. S., Yilmaz, G., Şener, B., Koyuncu, M., & Orhan, I. (2010). Preliminary screening of acetylcholinesterase inhibitory and antioxidant activities of Anatolian Heptaptera species. Pharmaceutical Biology, 48(3), 337-341.
Verpoorte, J. A., Mehta, S., & Edsall, J. T. (1967). Esterase activities of human carbonic anhydrases B and C. Journal of biological chemistry, 242(18), 4221-4229.
Woldeyes, S., Adane, L., Tariku, Y., Muleta, D., & Begashaw, T. (2012). Evaluation of antibacterial activities of compounds isolated from Sida rhombifolia Linn.(Malvaceae). Natural Products Chemistry & Research, 2013.