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Yıl 2023, Cilt: 44 Sayı: 2, 258 - 262, 30.06.2023

Hayrani Eren Bostancı , Ulviye Acar Çevik

https://doi.org/10.17776/csj.1225497

Öz

Anahtar Kelimeler

Thiadiazole Hydrazone Anticancer Carbonic anhydrase.

Kaynakça

  • [1] Tapera M., Kekeçmuhammed H., Tüzün B., Sarıpınar E., Koçyiğit Ü. M., Yıldırım E., Doğen M., Zorlu Y., Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular docking studies of new imidazolyl hydrazone derivatives, J. Mol. Struct., 1269 (2022) 133816.
  • [2] Bilginer S., Bardaweel S. K., Demir Y., Gulcin I., & Kazaz C., Synthesis, cytotoxicities, and carbonic anhydrase inhibition activities of pyrazoline–benzenesulfonamide derivatives harboring phenol/polyphenol moieties, Med. Chem. Res., (2022) 1-11.
  • [3] Bonardi A., Bua S., Combs J., Lomelino C., Andring J., Osman S. M., Toti A., Mannelli L.D.C., Gratteri P., Ghelardini C., McKennac R., Nocentini A., The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII, J. Enzyme Inhib. Med. Chem., 37(2022) 930-939.
  • [4] Arrighi G., Puerta A., Petrini A., Hicke F. J., Nocentini A., Fernandes M. X., Padron J.M., Supuran C.T., Fernandes-Bolanos J.M., López Ó., Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations, Int. J. Mol. Sci., 23 (2022) 7685.
  • [5] Tawfik H. O., Petreni A., Supuran C. T., & El-Hamamsy M. H., Discovery of new carbonic anhydrase IX inhibitors as anticancer agents by toning the hydrophobic and hydrophilic rims of the active site to encounter the dual-tail approach, Eur. J. Med. Chem., 232 (2022) 114190.
  • [6] Al-Warhi T., Elbadawi M. M., Bonardi A., Nocentini A., Al-Karmalawy A. A., Aljaeed N., Alotaibi O.J., Abdel-Aziz H.A., Supuran C.T., Eldehna W. M., Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII, J. Enzyme inhib. Med. Chem., 37(2022) 2635-2643.
  • [7] Elimam D. M., Eldehna W. M., Salem R., Bonardi A., Nocentini A., Al-Rashood S. T., Elaasser M.M., Gratteri P., Supuran C.T., Allam H. A., Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors, Eur. J. Med. Chem., 228 (2022) 114008.
  • [8] Vanjare B. D., Choi N. G., Eom Y. S., Raza H., Hassan M., Lee K. H., & Kim S. J., Synthesis, carbonic anhydrase inhibition, anticancer activity, and molecular docking studies of 1, 3, 4-oxadiazole derivatives, Mol. Diver. (2022) 1-16.
  • [9] Hagras M., Saleh M. A., Ezz Eldin R. R., Abuelkhir A. A., Khidr E. G., El-Husseiny A. A., El-Mahdy H.A., Elkaeed E.B., Eissa I. H., 1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies. J. Enzyme inhib. Med. Chem., 37 (2022) 386-402.
  • [10] Abdelgawad M. A., Bukhari S. N., Musa A., Elmowafy M., Elkomy M. H., Nayl A. A., ... & Elshemy, H. A., New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling, Pharmaceuticals., 15 (2022) 1134.
  • [11] Elkamhawy A., Woo J., Nada H., Angeli A., Bedair T. M., Supuran C. T., & Lee K., Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies, Int. J. Mol. Sci., 23 (2022) 2540.
  • [12] Abdel‐Mohsen H. T., Omar M. A., Petreni A., & Supuran C. T., Novel 2‐substituted thioquinazoline‐benzenesulfonamide derivatives as carbonic anhydrase inhibitors with potential anticancer activity, Arch. Pharm., (2022) e2200180.
  • [13] Nada H., Elkamhawy A., Abdellattif M. H., Angeli A., Lee C. H., Supuran C. T., & Lee K., 4-Anilinoquinazoline-based benzenesulfonamides as nanomolar inhibitors of carbonic anhydrase isoforms I, II, IX, and XII: design, synthesis, in-vitro, and in-silico biological studies, J. Enzyme Inhib. Med. Chem., 37 (2022) 994-1004.
  • [14] Janowska S., Khylyuk D., Gornowicz A., Bielawska A., Janowski M., Czarnomysy R., ... & Wujec M., Synthesis and Anticancer Activity of 1, 3, 4-Thiadiazoles with 3-Methoxyphenyl Substituent, Molecules., 27 (2022) 6977.
  • [15] Janowska S., Khylyuk D., Gornowicz A., Bielawska A., Janowski M., Czarnomysy R., ... & Wujec M., Synthesis and Anticancer Activity of 1, 3, 4-Thiadiazoles with 3-Methoxyphenyl Substituent. Molecules., 27 (2022) 6977.
  • [16] Janowska S., Khylyuk D., Bielawska A., Szymanowska A., Gornowicz A., Bielawski K., ... & Wujec M., New 1,3,4-Thiadiazole Derivatives with Anticancer Activity, Molecules., 27 (2022) 1814.
  • [17] Ibrahim S. A., Salem M. M., Abd Elsalam H. A., & Noser A. A., Design, synthesis, in-silico and biological evaluation of novel 2-Amino-1,3,4-thiadiazole based hydrides as B-cell lymphoma-2 inhibitors with potential anticancer effects, J. Mol. Struct., 1268 (2022) 133673.
  • [18] Vilková M., Hudáčová M., Palušeková N., Jendželovský R., Almáši M., Béres T., ... & Kožurková M., Acridine Based N-Acylhydrazone Derivatives as Potential Anticancer Agents: Synthesis, Characterization and ctDNA/HSA Spectroscopic Binding Properties, Molecules., 27 (2022) 2883.
  • [19] Tapera M., Kekeçmuhammed H., Tüzün B., Sarıpınar E., Koçyiğit Ü. M., Yıldırım E., ... & Zorlu Y., Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular docking studies of new imidazolyl hydrazone derivatives, J. Mol. Struct., 1269 (2022)133816.
  • [20] Ayşen I., Çevik U. A., Çelik I., Bostancı H. E., Karayel A., Gündoğdu G., ... & Kaplancıklı Z. A., Benzimidazole-hydrazone derivatives: Synthesis, in vitro anticancer, antimicrobial, antioxidant activities, in silico DFT and ADMET studies, J. Mol. Struct., 1270 (2022) 133946.
  • [21] Valkova N., Lépine F., Labrie L., Dupont M., & Beaudet R., Purification and Characterization of PrbA, a New Esterase fromEnterobacter cloacae Hydrolyzing the Esters of 4-Hydroxybenzoic Acid (Parabens), J. Biol. Chem., 278 (2003) 12779-12785.
  • [22] Henke E., & Bornscheuer U., Esterases from Bacillus subtilis and B. stearothermophilus share high sequence homology but differ substantially in their properties. Appl. Microbiol. Biotechnol, 60 (2002) 320-326.
  • [23] Ciccone L., Cerri C., Nencetti S., & Orlandini E., Carbonic anhydrase inhibitors and epilepsy: State of the art and future perspectives, Molecules, 26 (2021) 6380.
  • [24] Ragab M. A., Eldehna W. M., Nocentini A., Bonardi A., Okda H. E., Elgendy B., Ibrahim T.S., Abd-Alhaseeb M.M., Gratteri P., Supuran, C.T., Al-Karmalawy A.A., Elagawany M., 4-(5-Amino-pyrazol-1-yl) benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments, Eur. J. Med. Chem., 250 (2023) 115180.
  • [25] Küçükoğlu K., Acar Çevik U., Nadaroglu H., Celik I., Işık A., Bostancı H. E., Ozkay Y., Kaplancıklı Z. A., Design, synthesis and molecular docking studies of novel benzimidazole-1, 3, 4-oxadiazole hybrids for their carbonic anhydrase inhibitory and antioxidant effects, Med. Chem. Res., 31 (2022) 1771-1782.
  • [26] Ahmed A., Shafique I., Saeed A., Shabir G., Saleem A., Taslimi P., Tok T.T., Kirici M., Üç E.M., Hashmi M. Z., Nimesulide linked acyl thioureas potent carbonic anhydrase I, II and α-glucosidase inhibitors: Design, synthesis and molecular docking studies, Eur. J. Med. Chem. Rep., 6 (2022) 100082.
  • [27] Arif N., Shafiq Z., Mahmood K., Rafiq M., Naz S., Shahzad S. A., Farooq U., Bahkali A.H., Elgorban A.M., Yaqup M., El-Gokha A., Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H, 5H-pyrano [3,2-c] chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors, ACS Omega., 7 (2022) 28605-28617.
  • [28] Güller U., Beydemir Ş., & Küfrevioğlu Ö. İ., In vitro and in silico interactions of antiulcer, glucocorticoids and urological drugs on human carbonic anhydrase I and II isozymes, Biopharm. Drug Dispos., 43 (2022) 47-56.
  • [29] Bulut Z., Abul N., Poslu A. H., Gülçin İ., Ece A., Erçağ E., Koz Ö., Koz G., Structural characterization and biological evaluation of uracil-appended benzylic amines as acetylcholinesterase and carbonic anhydrase I and II inhibitors, J. Mol. Struct., 1280 (2023) 135047.
  • [30] Chiaramonte N., Angeli A., Sgambellone S., Bonardi A., Nocentini A., Bartolucci G., Braconi L., Dei S., Lucarini L., Teodori E., Gratteri P., Wünsch B., Supuran C.T., Romanelli M. N., 2-(2-Hydroxyethyl) piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity, Eur. J. Med. Chem., 228 (2022) 114026.
  • [31] Altıntop M. D., Sever B., Özdemir A., Kucukoglu K., Onem H., Nadaroglu H., & Kaplancıklı Z. A., Potential inhibitors of human carbonic anhydrase isozymes I and II: Design, synthesis and docking studies of new 1, 3, 4-thiadiazole derivatives, Bioorg. Med. Chem., 25 (2017) 3547-3554.

Synthesis, Anticancer Activity and Carbonic Anhydrase Inhibitory Activity of new Thiadiazole-hydrazone Derivatives

Yıl 2023, Cilt: 44 Sayı: 2, 258 - 262, 30.06.2023

Hayrani Eren Bostancı , Ulviye Acar Çevik

https://doi.org/10.17776/csj.1225497

Öz

In five steps, new compounds 5a, 5b of thiadiazole-hydrazone derivatives were synthesized. Various spectral methods, such as 1H NMR, 13C NMR, and elemental analyses, were used to clarify the structures of the compounds. Three cancer cell lines (MCF7, MDA, and HT-29) and one healthy cell line (L929) were tested for the cytotoxicity activity of synthetic compounds, as well as their inhibitory action against carbonic anhydrase I and II isoenzymes (hCA I and hCA II). Among them, the compound 5b exhibited remarkable CA inhibitory activities compared to a standard inhibitor with IC50 values at of 27 µM for hCA I and 33,46 µM for hCA II. The compounds have been found to be ineffective against cancer cell lines. Furthermore, the compounds were found to be non-toxic to the healthy cell line.

Anahtar Kelimeler

Thiadiazole Hydrazone Anticancer Carbonic anhydrase.

Kaynakça

  • [1] Tapera M., Kekeçmuhammed H., Tüzün B., Sarıpınar E., Koçyiğit Ü. M., Yıldırım E., Doğen M., Zorlu Y., Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular docking studies of new imidazolyl hydrazone derivatives, J. Mol. Struct., 1269 (2022) 133816.
  • [2] Bilginer S., Bardaweel S. K., Demir Y., Gulcin I., & Kazaz C., Synthesis, cytotoxicities, and carbonic anhydrase inhibition activities of pyrazoline–benzenesulfonamide derivatives harboring phenol/polyphenol moieties, Med. Chem. Res., (2022) 1-11.
  • [3] Bonardi A., Bua S., Combs J., Lomelino C., Andring J., Osman S. M., Toti A., Mannelli L.D.C., Gratteri P., Ghelardini C., McKennac R., Nocentini A., The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII, J. Enzyme Inhib. Med. Chem., 37(2022) 930-939.
  • [4] Arrighi G., Puerta A., Petrini A., Hicke F. J., Nocentini A., Fernandes M. X., Padron J.M., Supuran C.T., Fernandes-Bolanos J.M., López Ó., Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations, Int. J. Mol. Sci., 23 (2022) 7685.
  • [5] Tawfik H. O., Petreni A., Supuran C. T., & El-Hamamsy M. H., Discovery of new carbonic anhydrase IX inhibitors as anticancer agents by toning the hydrophobic and hydrophilic rims of the active site to encounter the dual-tail approach, Eur. J. Med. Chem., 232 (2022) 114190.
  • [6] Al-Warhi T., Elbadawi M. M., Bonardi A., Nocentini A., Al-Karmalawy A. A., Aljaeed N., Alotaibi O.J., Abdel-Aziz H.A., Supuran C.T., Eldehna W. M., Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII, J. Enzyme inhib. Med. Chem., 37(2022) 2635-2643.
  • [7] Elimam D. M., Eldehna W. M., Salem R., Bonardi A., Nocentini A., Al-Rashood S. T., Elaasser M.M., Gratteri P., Supuran C.T., Allam H. A., Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors, Eur. J. Med. Chem., 228 (2022) 114008.
  • [8] Vanjare B. D., Choi N. G., Eom Y. S., Raza H., Hassan M., Lee K. H., & Kim S. J., Synthesis, carbonic anhydrase inhibition, anticancer activity, and molecular docking studies of 1, 3, 4-oxadiazole derivatives, Mol. Diver. (2022) 1-16.
  • [9] Hagras M., Saleh M. A., Ezz Eldin R. R., Abuelkhir A. A., Khidr E. G., El-Husseiny A. A., El-Mahdy H.A., Elkaeed E.B., Eissa I. H., 1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies. J. Enzyme inhib. Med. Chem., 37 (2022) 386-402.
  • [10] Abdelgawad M. A., Bukhari S. N., Musa A., Elmowafy M., Elkomy M. H., Nayl A. A., ... & Elshemy, H. A., New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling, Pharmaceuticals., 15 (2022) 1134.
  • [11] Elkamhawy A., Woo J., Nada H., Angeli A., Bedair T. M., Supuran C. T., & Lee K., Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies, Int. J. Mol. Sci., 23 (2022) 2540.
  • [12] Abdel‐Mohsen H. T., Omar M. A., Petreni A., & Supuran C. T., Novel 2‐substituted thioquinazoline‐benzenesulfonamide derivatives as carbonic anhydrase inhibitors with potential anticancer activity, Arch. Pharm., (2022) e2200180.
  • [13] Nada H., Elkamhawy A., Abdellattif M. H., Angeli A., Lee C. H., Supuran C. T., & Lee K., 4-Anilinoquinazoline-based benzenesulfonamides as nanomolar inhibitors of carbonic anhydrase isoforms I, II, IX, and XII: design, synthesis, in-vitro, and in-silico biological studies, J. Enzyme Inhib. Med. Chem., 37 (2022) 994-1004.
  • [14] Janowska S., Khylyuk D., Gornowicz A., Bielawska A., Janowski M., Czarnomysy R., ... & Wujec M., Synthesis and Anticancer Activity of 1, 3, 4-Thiadiazoles with 3-Methoxyphenyl Substituent, Molecules., 27 (2022) 6977.
  • [15] Janowska S., Khylyuk D., Gornowicz A., Bielawska A., Janowski M., Czarnomysy R., ... & Wujec M., Synthesis and Anticancer Activity of 1, 3, 4-Thiadiazoles with 3-Methoxyphenyl Substituent. Molecules., 27 (2022) 6977.
  • [16] Janowska S., Khylyuk D., Bielawska A., Szymanowska A., Gornowicz A., Bielawski K., ... & Wujec M., New 1,3,4-Thiadiazole Derivatives with Anticancer Activity, Molecules., 27 (2022) 1814.
  • [17] Ibrahim S. A., Salem M. M., Abd Elsalam H. A., & Noser A. A., Design, synthesis, in-silico and biological evaluation of novel 2-Amino-1,3,4-thiadiazole based hydrides as B-cell lymphoma-2 inhibitors with potential anticancer effects, J. Mol. Struct., 1268 (2022) 133673.
  • [18] Vilková M., Hudáčová M., Palušeková N., Jendželovský R., Almáši M., Béres T., ... & Kožurková M., Acridine Based N-Acylhydrazone Derivatives as Potential Anticancer Agents: Synthesis, Characterization and ctDNA/HSA Spectroscopic Binding Properties, Molecules., 27 (2022) 2883.
  • [19] Tapera M., Kekeçmuhammed H., Tüzün B., Sarıpınar E., Koçyiğit Ü. M., Yıldırım E., ... & Zorlu Y., Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular docking studies of new imidazolyl hydrazone derivatives, J. Mol. Struct., 1269 (2022)133816.
  • [20] Ayşen I., Çevik U. A., Çelik I., Bostancı H. E., Karayel A., Gündoğdu G., ... & Kaplancıklı Z. A., Benzimidazole-hydrazone derivatives: Synthesis, in vitro anticancer, antimicrobial, antioxidant activities, in silico DFT and ADMET studies, J. Mol. Struct., 1270 (2022) 133946.
  • [21] Valkova N., Lépine F., Labrie L., Dupont M., & Beaudet R., Purification and Characterization of PrbA, a New Esterase fromEnterobacter cloacae Hydrolyzing the Esters of 4-Hydroxybenzoic Acid (Parabens), J. Biol. Chem., 278 (2003) 12779-12785.
  • [22] Henke E., & Bornscheuer U., Esterases from Bacillus subtilis and B. stearothermophilus share high sequence homology but differ substantially in their properties. Appl. Microbiol. Biotechnol, 60 (2002) 320-326.
  • [23] Ciccone L., Cerri C., Nencetti S., & Orlandini E., Carbonic anhydrase inhibitors and epilepsy: State of the art and future perspectives, Molecules, 26 (2021) 6380.
  • [24] Ragab M. A., Eldehna W. M., Nocentini A., Bonardi A., Okda H. E., Elgendy B., Ibrahim T.S., Abd-Alhaseeb M.M., Gratteri P., Supuran, C.T., Al-Karmalawy A.A., Elagawany M., 4-(5-Amino-pyrazol-1-yl) benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments, Eur. J. Med. Chem., 250 (2023) 115180.
  • [25] Küçükoğlu K., Acar Çevik U., Nadaroglu H., Celik I., Işık A., Bostancı H. E., Ozkay Y., Kaplancıklı Z. A., Design, synthesis and molecular docking studies of novel benzimidazole-1, 3, 4-oxadiazole hybrids for their carbonic anhydrase inhibitory and antioxidant effects, Med. Chem. Res., 31 (2022) 1771-1782.
  • [26] Ahmed A., Shafique I., Saeed A., Shabir G., Saleem A., Taslimi P., Tok T.T., Kirici M., Üç E.M., Hashmi M. Z., Nimesulide linked acyl thioureas potent carbonic anhydrase I, II and α-glucosidase inhibitors: Design, synthesis and molecular docking studies, Eur. J. Med. Chem. Rep., 6 (2022) 100082.
  • [27] Arif N., Shafiq Z., Mahmood K., Rafiq M., Naz S., Shahzad S. A., Farooq U., Bahkali A.H., Elgorban A.M., Yaqup M., El-Gokha A., Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H, 5H-pyrano [3,2-c] chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors, ACS Omega., 7 (2022) 28605-28617.
  • [28] Güller U., Beydemir Ş., & Küfrevioğlu Ö. İ., In vitro and in silico interactions of antiulcer, glucocorticoids and urological drugs on human carbonic anhydrase I and II isozymes, Biopharm. Drug Dispos., 43 (2022) 47-56.
  • [29] Bulut Z., Abul N., Poslu A. H., Gülçin İ., Ece A., Erçağ E., Koz Ö., Koz G., Structural characterization and biological evaluation of uracil-appended benzylic amines as acetylcholinesterase and carbonic anhydrase I and II inhibitors, J. Mol. Struct., 1280 (2023) 135047.
  • [30] Chiaramonte N., Angeli A., Sgambellone S., Bonardi A., Nocentini A., Bartolucci G., Braconi L., Dei S., Lucarini L., Teodori E., Gratteri P., Wünsch B., Supuran C.T., Romanelli M. N., 2-(2-Hydroxyethyl) piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity, Eur. J. Med. Chem., 228 (2022) 114026.
  • [31] Altıntop M. D., Sever B., Özdemir A., Kucukoglu K., Onem H., Nadaroglu H., & Kaplancıklı Z. A., Potential inhibitors of human carbonic anhydrase isozymes I and II: Design, synthesis and docking studies of new 1, 3, 4-thiadiazole derivatives, Bioorg. Med. Chem., 25 (2017) 3547-3554.
Toplam 31 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık ve İlaç Bilimleri
Bölüm Natural Sciences
Yazarlar

Hayrani Eren Bostancı 0000-0001-8511-2316

Ulviye Acar Çevik 0000-0003-1879-1034

Yayımlanma Tarihi 30 Haziran 2023
Gönderilme Tarihi 28 Aralık 2022
Kabul Tarihi 8 Haziran 2023
Yayımlandığı Sayı Yıl 2023Cilt: 44 Sayı: 2

Kaynak Göster

APA Bostancı, H. E., & Acar Çevik, U. (2023). Synthesis, Anticancer Activity and Carbonic Anhydrase Inhibitory Activity of new Thiadiazole-hydrazone Derivatives. Cumhuriyet Science Journal, 44(2), 258-262. https://doi.org/10.17776/csj.1225497