Doğal Antidiyabetiklerin İnsan Karbonik Anhidraz İzoenzimleri Üzerine Etkilerinin Araştırılması

Yıl 2025, Cilt: 29 Sayı: 3, 502 - 508, 25.12.2025

Rahmah Al-nuaimi , Ekrem Tunca

https://doi.org/10.19113/sdufenbed.1511196

Öz

Solunum, pH homeostazisi, elektrolit salınımı, kemik resorpsiyonu ve bazı biyosentez reaksiyonlarında önemli roller üstlenen karbonik anhidrazlar (CA’lar), uzun yıllardır farmakolojik açıdan önemli hedefler arasında yer almaktadırlar. Günümüze kadar başta sülfonamitler olmak üzere pek çok CA inhibitörü rapor edilmiştir. Ancak bu alandaki temel sorun, CA izoenzimleri arasında yüksek seçiciliğe sahip olan inhibitörlerin rapor edildiği çalışmaların nispeten az sayıda olmasıdır. Özellikle, retina ve beyin ödemi başta olmak üzere birtakım hastalıklarla ilişkisi ortaya konulmuş olan hCA I izoenzimine karşı seçici olan inhibitörlerin rapor edildiği çalışma sayısı yok denilecek kadar azdır. Çalışmamızda, doğal kaynaklı antidiyabetik ajanlar olan andrografolid, vildagliptin ve buformin bileşiklerinin hCA I ve hCA II izoenzimlerinin esteraz aktiviteleri üzerindeki inhibisyon etkileri in vitro olarak incelenmiştir. Bileşiklerin tamamı sadece hCA I izoenzimini inhibe etmiş, hCA II üzerinde hiçbir etki göstermemiştir. Elde ettiğimiz sonuçlar, doğal kaynaklı ve izoenzim seçici CA inhibitörlerinin keşfi açısından kayda değerdir.

Anahtar Kelimeler

Andrografolid , Vildagliptin , Buformin , Karbonik Anhidraz

Etik Beyan

Bu çalışmada, “Yükseköğretim Kurumları Bilimsel Araştırma ve Yayın Etiği Yönergesi” kapsamında uyulması gerekli tüm kurallara uyulduğunu, bahsi geçen yönergenin “Bilimsel Araştırma ve Yayın Etiğine Aykırı Eylemler” başlığı altında belirtilen eylemlerden hiçbirinin gerçekleştirilmediğini taahhüt ederiz.

Destekleyen Kurum

TÜBİTAK

Proje Numarası

1919B012222800

Teşekkür

Çalışmamızı, 2022 yılı ikinci dönem 2209-A Üniversite Öğrencileri Araştırma Projeleri kapsamında destekleyen TÜBİTAK’a teşekkürlerimizi sunarız. (Proje No: 1919B012222800)

Investigation of the Effects of Natural Antidiabetics on Human Carbonic Anhydrase Isoenzymes

Öz

Carbonic anhydrases (CAs), which play important roles in respiration, pH homeostasis, electrolyte secretion, bone resorption and some biosynthesis reactions, have been among the pharmacologically important targets for many years. To date, many CA inhibitors, especially sulfonamides, have been reported. However, the main problem in this field is the relatively small number of studies reporting inhibitors with high selectivity between CA isoenzymes. In particular, the number of studies reporting inhibitors that are selective against the hCA I isoenzyme, which has been shown to be associated with some diseases, especially retinal and brain edema, is almost non-existent. In our study, the inhibition effects of andrographolide, vildagliptin and buformin compounds, which are natural antidiabetic agents, on the esterase activities of hCA I and hCA II isoenzymes were examined in vitro. All of the compounds inhibited only the hCA I isoenzyme and had no effect on hCA II. Our results are noteworthy for the discovery of natural origin and isoenzyme selective CA inhibitors.

Anahtar Kelimeler

Andrographolide , Vildagliptin , Buformin , Carbonic Anhydrase

Proje Numarası

1919B012222800

Kaynakça

• [1] Supuran, C. T. 2016. Structure and function of carbonic anhydrases. Biochemical Journal, 473(14), 2023-2032.
• [2] Khalifah, R. G. 1973. Carbon dioxide hydration activity of carbonic anhydrase: paradoxical consequences of the unusually rapid catalysis. Proceedings of the National Academy of Sci-ences, 70(7), 1986-1989.
• [3] Aggul, A. G., Uzun, N., Kuzu, M., Taslimi, P., Gulcin, I. 2022. Some phenolic natural com-pounds as carbonic anhydrase inhibitors: An in vitro and in silico study. Archiv der Pharmazie, 355(6), e2100476.
• [4] Emameh, R. Z., Kuuslahti, M., Nosrati, H., Lohi, H., Parkkila, S. 2020. Assessment of databases to determine the validity of β- and γ-carbonic anhydrase sequences from vertebrates. BMC Genomics, 21, 352.
• [5] Hirkawa, Y., Senda, M., Fukuda, K., Yu, H. Y., Ishida, M., Taira, M., Kinbara, K., Senda T. 2021. Characterization of a novel type carbonic an-hydrase that acts without metal cofactors. BMC Biology, 19, 105.
• [6] Al-Matarneh, C. M., Pinteala, M. Nicolescu, A., Silion, M., Mocci, F., Puf, R., Angeli, A., Ferraro-ni, M., Supuran, C. T., Zara, S., Carradori, S., Pao-letti, N., Bonardi, A., Gratteri, P. 2024. Synthetic approaches to novel human carbonic anhydrase isoform inhibitors based on pyrrol-2-one moie-ty. Journal of Medicinal Chemistry, 67(4), 3018-3038.
• [7] Aggarwal, M., Kondeti, B., McKenna, R. 2013. Insights towards sulfonamide drug specifity in α-carbonic anhydrases. Bioorganic & Medicinal Chemistry, 21(6), 1526-1533.
• [8] Alterio, V., Di Fiore, A., D’Ambrosio, K., Supu-ran, C. T., De Simone, G. 2012. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 differ-ent isoforms? Chemical Reviews, 112(8), 4421-4468.
• [9] De Simone, G., Alterio, V., Supuran, C. T. 2013. Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors. Expert Opinion on Drug Discovery, 8(7), 793-810.
• [10] García-Llorca, A., Carta, F., Supuran, C. T., Eysteinsson, T. 2024. Carbonic anhydrase, its inhibitors and vascular function. Frontiers in Molecular Biosciences, 11, 1338528.
• [11] Adeva-Andany, M. M., Fernández- Fernández, C., Sánchez-Bello, R., Donapetry-García, C., Martínez-Rodríguez, J. 2015. The role of car-bonic anhydrase in the pathogenesis of vascular calcification in humans. Atherosclerosis, 241(1), 183-191.
• [12] Chang, X., Han, J., Zhao, Y., Yan, X., Sun, S., Cui, Y. 2010. Increased expression of carbonic an-hydrase I in the synovium of patients with an-kylosing spondylitis. BMC Musculoskeletal Dis-orders, 11(1), 279.
• [13] Zheng, Y., Xu, B., Zhao, Y., Gu, H., Li, C., Wang, Y., Chang, X. 2015. CA1 contributes to micro-calcification and tumourigenesis in breast can-cer. BMC Cancer, 15, 679.
• [14] Yuan, L., Wang, M., Liu, T., Lei, Y., Miao, Q., Li, Q., Wang, H., Zhang, G., Hou, Y., Chang, X. 2019. Carbonic anhydrase 1-mediated calcification is associated with atherosclerosis, and methazo-lamide alleviates its pathogenesis. Frontiers in Pharmacology, 10, 766.
• [15] Gao, B. B., Clermont, A., Rook, S., Fonda, S. J., Srinivasan, V. J., Wojtkowski, M., Fujimoto, J. G., Avery, R. L., Arrigg, P. G., Bursell, S. E., Aiello, L. P., Feener, E. P. 2007. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekal-likrein activation. Nature Medicine, 13(2), 181-188.
• [16] Supuran, C. T. 2023. A simple yet multifaceted 90 years old, evergreen enzyme: carbonic an-hydrase, its inhibition and activation. Bioor-ganic & Medicinal Chemistry Letters, 93, 129411.
• [17] Dai, Y., Chen, S. R., Chai, L., Zhao, J., Wang, Y., Wang, Y. 2019. Overview of pharmacological activities of Andrographis paniculata and its major compound andrographolide. Critical Re-views in Food Science and Nutrition, 59(S1), S17-S29.
• [18] Lu, J., Ma, Y., Wu, J., Huang, H., Wang, X., Chen, Z., Chen, J. He, H., Huang, C. 2019. A review for the neuroprotective effects of andrographolide in the central nervous system. Biomedicine & Pharmacotherapy, 117, 109078.
• [19] Zhang, Z., Lai, D., Wang, L., Yu, P., Zhu, L., Guo, B., Xu, L., Zhou, L., Sun, Y., Lee, S. M. Y., Wang, Y. 2014. Neuroprotective effects of the andro-grapholide analogue AL-1 in the MPP+/MPTP-induced Parkinson’s disease model in vitro and in mice. Pharmacology Biochemistry and Be-havior, 122, 191-202.
• [20] Serrano, F. G., Tapia-Rojas, C., Carvajal, F. J., Hancke, J., Cerpa, W., Inestrosa, N. C. 2014. An-drographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice. Molec-ular Neurodegeneration, 9, 61.
• [21] Polyakova, E. B., Sabirzyanov, D. R., Prozorova, N. A., Foteeva, A. V. 2022. Physicochemical properties and methods of analysis of vildag-liptin. Pharmaceutical Chemistry Journal, 56(1), 110-117.
• [22] Banerjee, M., Younis, N., Soran, H. 2009. Vildag-liptin in clinical practice: a review of literature. Expert Opinion on Pharmacotherapy, 10(16), 2745-2757.
• [23] Khan, S., Khan, S., Imran, M., Pillai, K. K., Akh-tar, M., Najmi, A. K. 2013. Effects of pioglita-zone and vildagliptin on coagulation cascade in diabetes mellitus – targeting thrombogenesis. Expert Opinion on Therapeutic Targets, 17(6), 627-639.
• [24] Chou, C. H., Cheng, C. L., Huang, C. C. 2004. A validated HPLC method with ultraviolet detec-tion for the determination of buformin in plas-ma. Biomedical Chromatography, 18(4), 254-258.
• [25] Chen, L., Zhang, T., Liu, Q., Tang, M., Yang, Y., Wang, Y., Qiu, H., Yu, J. 2018. Buformin increas-es radiosensitivity in cervical cancer cells via cell-cycle arrest and delayed DNA-damage re-pair. Experimental Biology and Medicine, 243(4), 1133-1140.
• [26] Alkan Alkaya, Z., İlkimen H., Yenikaya C., Tun-ca, E., Bülbül, M., Tunç, T., Sarı M. 2018. Syn-thesis and characterization of Cu(II) complexes of 2-amino-6-sulfamoylbenzothiazole and their inhibition studies on carbonic anhydrase iso-enzymes. Polyhedron, 151, 199-205.
• [27] Okumuş, A., Elmas, G., Binici, A., Tunca, E., Hökelek, T., Kılıç, Z. 2023. Phosphorus‒nitrogen compounds: part 70. Syntheses of tetraaminomono/bis(4-fluorobenzyl)spiro(N/N)cyclotriphosphazenes: structural characterization, Hirshfeld surface analysis and comparative evaluation of esterase activities of hCA I and hCA II isoenzymes. New Journal of Chemistry, 47(18), 8578-8588.
• [28] Tunca, E., Bülbül, M., İlkimen, H., Saygılı Canlıdinç, R., Yenikaya, C. 2020. Investigation of the effects of proton transfer salts of 2-aminopyridine derivatives with 5-sulfosalicylic acid and their Cu(II) complexes on cancer-related carbonic anhydrases: CA IX and CA XII. Chemical Papers, 74, 2365-2374.
• [29] Al-Dhrub, A. H. A., Sahin, S., Ozmen, I., Tunca, E., Bulbul, M. 2017. Immobilization and charac-terization of human carbonic anhydrase I on amine functionalized magnetic nanoparticles. Process Biochemistry, 57, 95-104.
• [30] İlkimen H., Yenikaya, C., Sarı, M., Bülbül, M., Tunca, E., Dal, H. 2014. Synthesis and charac-terization of a proton transfer salt between 2,6-pyridinedicarboxylic acid and 2-aminobenzothiazole, and its complexes and their inhibition studies on carbonic anhydrase isoenzymes. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(3), 353-361.
• [31] Verpoorte, J. A., Mehta, S., Edsall, J. T. 1967. Esterase activities of human carbonic anhy-drases B and C. Journal of Biological Chemistry, 242(18), 4221-4229.
• [32] Bhatt, A., Mahon, B. P., Cruzerio, V. W. D., Cor-nelio, B., Laronze-Cochard, M., Ceruso, M., Sapi, J., Rance, G. A., Khlobystov, A. N., Fontana, A., Roitberg, A., Supuran, C. T., McKenna, R. 2017. Structure-activity relationships of benzenesul-fonamide-based inhibitors towards carbonic anhydrase isoform specifity. ChemBioChem, 18(2), 213-222.
• [33] National Center for Biotechnology Information, 2024. PubChem Compound Summary for CID 5318517, Andrographolide. https://pubchem.ncbi.nlm.nih.gov/compound/Andrographolide (Erişim Tarihi: 08.10.2024).
• [34] National Center for Biotechnology Information, 2024. PubChem Compound Summary for CID 6918537, Vildagliptin. https://pubchem.ncbi.nlm.nih.gov/compound/Vildagliptin (Erişim Tarihi: 08.10.2024).
• [35] National Center for Biotechnology Information, 2024. PubChem Compound Summary for CID 2468, Buformin. https://pubchem.ncbi.nlm.nih.gov/compound/Buformin (Erişim Tarihi: 08.10.2024).
• [36] Kuznetsov, M. A., Shestakov, A. N., Zibinsky, M., Krasavin, M., Supuran, C. T., Kalinin, S., Tanç, M. 2017. Synthesis, structure and properties of N-aminosaccharin – A selective inhibitor of human carbonic anhydrase I. Tetrahedron Let-ters, 58(2), 172-174.
• [37] Berrino, E., Bua, S., Mori, M., Botta, M., Murthy, V. S., Vijayakumar, V., Tamboli, Y., Bartolucci, G., Mugelli, A., Cerbai, E., Supuran, C. T., Carta, F. 2017. Novel sulfamide-containing com-pounds as selective carbonic anhydrase I inhib-itors. Molecules, 22(7), 1049.