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Yıl 2020, Cilt: 24 Sayı: 5, 670 - 680, 27.06.2025

Belgin Sever , Gülşen Akalın Çiftçi , Ahmet Özdemir , Mehlika Dilek Altıntop

https://doi.org/10.35333/jrp.2020.222
Cited By: 1

Öz

Kaynakça

  • [1] Ruiz-Ceja, KA, Chirino, YI. Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection. Biomed Pharmacother. 2017; 90: 24-37. [CrossRef]
  • [2] Gyoba J, Shan S, Roa W, Bédard ELR. Diagnosing lung cancers through examination of micro-RNA biomarkers in blood, plasma, serum and sputum: a review and summary of current literature. Int J Mol Sci. 2016; 17(4): 494. [CrossRef]
  • [3] Li L, Zhu T, Gao Y-F, Zheng W, Wang C-J, Xiao L, Huang MS, Yin JY, Zhou HH, Liu ZQ. Targeting DNA damage response in the radio(chemo)therapy of non-small cell lung cancer. Int J Mol Sci. 2016; 17(6): E839. [CrossRef]
  • [4] Nascimento AV, Bousbaa H, Ferreira D, Sarmento B. Non-Small Cell Lung Carcinoma: An Overview on Targeted Therapy. Curr Drug Targets. 2015; 16(13): 1448-1463. [CrossRef]
  • [5] Mattsson JSM, Bergman B, Grinberg M, Edlund K, Marincevic M, Jirström K, Pontén F, Hengstler JG, Rahnenführer J, Karlsson MG, Karlsson C, Helenius G, Botling J, Micke P, Gulyas M. Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression. Cancer Lett. 2015; 356: 837-845. [CrossRef]
  • [6] Crosby CG, DuBois RN. The cyclooxygenase-2 pathway as a target for treatment or prevention of cancer. Expert Opin Emerg Drugs. 2003; 8(1): 1‐ 7. [CrossRef]
  • [7] Misra, S.; Sharma, K. COX-2 Signaling and cancer: New players in old arena. Curr Drug Targets. 2014; 15: 347-359. [CrossRef]
  • [8] Hashemi Goradel, N.; Najafi, M.; Salehi, E.; Farhood, B.; Mortezaee K. Cyclooxygenase-2 in cancer: A review. J Cell Physiol. 2019; 234(5): 5683‐ 5699. [CrossRef]
  • [9] Liu, R.; Xu, K.-P.; Tan, G.-S. Cyclooxygenase-2 inhibitors in lung cancer treatment: Bench to bed. Eur J Pharmacol. 2015; 769: 127-133. [CrossRef]
  • [10] Mahboubi Rabbani, S.M.I.; Zarghi, A. Selective COX-2 inhibitors as anticancer agents: A patent review (2014-2018). Expert Opin Ther Pat. 2019; 29(6): 407-427. [CrossRef]
  • [11] Moorthy NSHN, Cerqueira NMFSA, Ramos MJ, Fernandes PA. Aryl- and heteroaryl-thiosemicarbazone derivatives and their metal complexes: A pharmacological template. Recent Pat Anti-Cancer Drug Discov. 2013; 8(2): 168-182. [CrossRef]
  • [12] Yu Y, Kalinowski DS, Kovacevic Z, Siafakas AR, Jansson PJ, Stefani C, Lovejoy DB, Sharpe PC, Bernhardt PV, Richardson DR. Thiosemicarbazones from the old to new: Iron chelators that are more than just ribonucleotide reductase inhibitors. J Med Chem. 2009; 52(17): 5271-5294. [CrossRef]
  • [13] Barry VC, Conalty ML, McCormick JE, McElhinney RS, McInerney MR, O'Sullivan JF. Anticancer agents. IV. The antitumor activity of some 1,4- and 1,5-(bisthiosemicarbazones) and of related heterocycles. J Med Chem. 1970; 13(3): 421-427. [CrossRef]
  • [14] Kalinowski DS, Quach P, Richardson DR. Thiosemicarbazones: The new wave in cancer treatment. Future Med Chem. 2009; 1(6): 1143-1151. [CrossRef]
  • [15] Yee EMH, Brandl MB, Black DS, Vittorio O, Kumar N. Synthesis of isoflavene-thiosemicarbazone hybrids and evaluation of their anti-tumor activity. Bioorg Med Chem Lett. 2017; 27(11): 2454-2458. [CrossRef]
  • [16] Wang Y, Gu W, Shan Y, Liu F, Xu X, Yang Y, Zhang Q, Zhang Y, Kuang H, Wang Z, Wang S. Design, synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives. Bioorg Med Chem Lett. 2017; 27: 2360- 2363. [CrossRef]
  • [17] Pape VFS, Tóth S, Füredi A, Szebényi K, Lovrics A, Szabó P, Wiese M, Szakács G. Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance. Eur J Med Chem. 2016; 117: 335-354. [CrossRef]
  • [18] Altıntop MD, Atlı Ö, Ilgın S, Demirel R, Özdemir A, Kaplancıklı ZA. Synthesis and biological evaluation of new naphthalene substituted thiosemicarbazone derivatives as potent antifungal and anticancer agents. Eur J Med Chem. 2016; 108: 406-414. [CrossRef]
  • [19] Altintop MD, Sever B, Özdemir A, Kuş G, Oztopcu-Vatan P, Kabadere S, Kaplancikli ZA. Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells. J Enzyme Inhib Med Chem. 2016; 31(3): 410-416. [CrossRef]
  • [20] Sever B, Akalın Çiftçi G, Özdemir A, Altıntop MD. Design, synthesis and in vitro evaluation of new thiosemicarbazone derivatives as potential anticancer agents. J Res Pharm. 2019; 23(1): 16-24. [CrossRef]
  • [21] Zhang X-H, Bo-Wang, Tao Y-Y, Ma Q, Wang H-J, He Z-X, Wu H-P, Li Y-H, Zhao B, Ma L-Y, Liu H-M. Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents. Eur J Med Chem. 2020; 199: 112349. [CrossRef]
  • [22] King AP, Gellineau HA, Ahn J-E, MacMillan SN, Wilson JJ. Bis(thiosemicarbazone) Complexes of cobalt(III). Synthesis, characterization, and anticancer potential. Inorg Chem. 2017; 56: 6609-6623. [CrossRef]
  • [23] Maghraby MT, Abou-Ghadir OMF, Abdel-Moty SG, Ali AY, Salem OIA. Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15- lipoxygenase enzymes. Bioorg Med Chem. 2020; 28(7): 115403. [CrossRef]
  • [24] Dawood DH, Batran RZ, Farghaly TA, Khedr MA, Abdulla MM. New coumarin derivatives as potent selective COX2 inhibitors: Synthesis, anti-inflammatory, QSAR, and molecular modeling studies. Arch Pharm Chem Life Sci. 2015; 348: 875–888. [CrossRef]
  • [25] Altıntop M.D., Özdemir A., Turan-Zitouni G., Ilgın S., Atlı Ö., Demirci F., Kaplancıklı Z.A. Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents. Molecules. 2014; 19: 14809-14820. [CrossRef]
  • [26] Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63. [CrossRef]
  • [27] Zhou H-Y, Dong F-Q, Du X-L, Zhou Z-K, Huo H-R, Wang W-H, Zhan HD, Dai YF, Jing Meng, Sui YP, Li J, Sui F, Zhai YH. Antitumor activities of biscoumarin and dihydropyran derivatives. Bioorg Med Chem Lett. 2016; 26(16): 3876-3880. [CrossRef]
  • [28] Altıntop MD, Sever B, Akalın Çiftçi G, Turan-Zitouni G, Kaplancıklı ZA, Özdemir A. Design, synthesis, in vitro and in silico evaluation of a new series of oxadiazole-based anticancer agents as potential Akt and FAK inhibitors, Eur J Med Chem. 2018; 155: 905-924. [CrossRef]

Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer

Yıl 2020, Cilt: 24 Sayı: 5, 670 - 680, 27.06.2025

Belgin Sever , Gülşen Akalın Çiftçi , Ahmet Özdemir , Mehlika Dilek Altıntop

https://doi.org/10.35333/jrp.2020.222
Cited By: 1

Öz

Thiosemicarbazones represent an important class of ligands for targeted therapy of many types of cancer including non-small cell lung cancer. In order to identify potential antitumor agents for targeted therapy of lung cancer, new bis(thiosemicarbazone) derivatives (1-11) were prepared via the reaction of 1,4-phenylenebis(thiosemicarbazide) with 5-arylfurfurals. The cytotoxic effects of compounds 1-11 on A549 human lung adenocarcinoma and L929 mouse fibroblast cells were investigated using MTT test. Compounds 1, 10 and 11 were the most potent anticancer agents in this series on A549 cell line with IC50 values of 14.33±0.47 μg/mL, 11.67±2.49 μg/mL and 16.67±5.56 μg/mL, respectively compared to cisplatin (IC50= 18.33±0.94 µg/mL). Based on their IC50 values for L929 cell line, their anticancer activities were found to be selective. Moreover, flow cytometry-based analyses were performed to examine their effects on apoptosis and mitochondrial membrane potential. The treatment of A549 cells with compounds 1, 10 and 11 at IC50 concentrations led to the induction of apoptosis along with mitochondrial membrane depolarization. In order to explore their mode of action, compounds 1, 10 and 11 were evaluated for their inhibitory effects on COX-1 and COX-2 in A549 cells. In particular, N,N'-(1,4-phenylene)bis(2-((5-(2,5-dichlorophenyl)furan-2-yl)methylene)hydrazine-1- carbothioamide) (10) was identified as a selective COX-2 inhibitor (6.96% for COX-1 and 54.81% for COX-2). According to these results, compound 10 warrants further in vitro and in vivo studies as a potential targeted anticancer agent for the management of non-small cell lung cancer.

Anahtar Kelimeler

Apoptosis bis(thiosemicarbazone) cyclooxygenase-2 itochondrial membrane potential non-small cell lung cance

Kaynakça

  • [1] Ruiz-Ceja, KA, Chirino, YI. Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection. Biomed Pharmacother. 2017; 90: 24-37. [CrossRef]
  • [2] Gyoba J, Shan S, Roa W, Bédard ELR. Diagnosing lung cancers through examination of micro-RNA biomarkers in blood, plasma, serum and sputum: a review and summary of current literature. Int J Mol Sci. 2016; 17(4): 494. [CrossRef]
  • [3] Li L, Zhu T, Gao Y-F, Zheng W, Wang C-J, Xiao L, Huang MS, Yin JY, Zhou HH, Liu ZQ. Targeting DNA damage response in the radio(chemo)therapy of non-small cell lung cancer. Int J Mol Sci. 2016; 17(6): E839. [CrossRef]
  • [4] Nascimento AV, Bousbaa H, Ferreira D, Sarmento B. Non-Small Cell Lung Carcinoma: An Overview on Targeted Therapy. Curr Drug Targets. 2015; 16(13): 1448-1463. [CrossRef]
  • [5] Mattsson JSM, Bergman B, Grinberg M, Edlund K, Marincevic M, Jirström K, Pontén F, Hengstler JG, Rahnenführer J, Karlsson MG, Karlsson C, Helenius G, Botling J, Micke P, Gulyas M. Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression. Cancer Lett. 2015; 356: 837-845. [CrossRef]
  • [6] Crosby CG, DuBois RN. The cyclooxygenase-2 pathway as a target for treatment or prevention of cancer. Expert Opin Emerg Drugs. 2003; 8(1): 1‐ 7. [CrossRef]
  • [7] Misra, S.; Sharma, K. COX-2 Signaling and cancer: New players in old arena. Curr Drug Targets. 2014; 15: 347-359. [CrossRef]
  • [8] Hashemi Goradel, N.; Najafi, M.; Salehi, E.; Farhood, B.; Mortezaee K. Cyclooxygenase-2 in cancer: A review. J Cell Physiol. 2019; 234(5): 5683‐ 5699. [CrossRef]
  • [9] Liu, R.; Xu, K.-P.; Tan, G.-S. Cyclooxygenase-2 inhibitors in lung cancer treatment: Bench to bed. Eur J Pharmacol. 2015; 769: 127-133. [CrossRef]
  • [10] Mahboubi Rabbani, S.M.I.; Zarghi, A. Selective COX-2 inhibitors as anticancer agents: A patent review (2014-2018). Expert Opin Ther Pat. 2019; 29(6): 407-427. [CrossRef]
  • [11] Moorthy NSHN, Cerqueira NMFSA, Ramos MJ, Fernandes PA. Aryl- and heteroaryl-thiosemicarbazone derivatives and their metal complexes: A pharmacological template. Recent Pat Anti-Cancer Drug Discov. 2013; 8(2): 168-182. [CrossRef]
  • [12] Yu Y, Kalinowski DS, Kovacevic Z, Siafakas AR, Jansson PJ, Stefani C, Lovejoy DB, Sharpe PC, Bernhardt PV, Richardson DR. Thiosemicarbazones from the old to new: Iron chelators that are more than just ribonucleotide reductase inhibitors. J Med Chem. 2009; 52(17): 5271-5294. [CrossRef]
  • [13] Barry VC, Conalty ML, McCormick JE, McElhinney RS, McInerney MR, O'Sullivan JF. Anticancer agents. IV. The antitumor activity of some 1,4- and 1,5-(bisthiosemicarbazones) and of related heterocycles. J Med Chem. 1970; 13(3): 421-427. [CrossRef]
  • [14] Kalinowski DS, Quach P, Richardson DR. Thiosemicarbazones: The new wave in cancer treatment. Future Med Chem. 2009; 1(6): 1143-1151. [CrossRef]
  • [15] Yee EMH, Brandl MB, Black DS, Vittorio O, Kumar N. Synthesis of isoflavene-thiosemicarbazone hybrids and evaluation of their anti-tumor activity. Bioorg Med Chem Lett. 2017; 27(11): 2454-2458. [CrossRef]
  • [16] Wang Y, Gu W, Shan Y, Liu F, Xu X, Yang Y, Zhang Q, Zhang Y, Kuang H, Wang Z, Wang S. Design, synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives. Bioorg Med Chem Lett. 2017; 27: 2360- 2363. [CrossRef]
  • [17] Pape VFS, Tóth S, Füredi A, Szebényi K, Lovrics A, Szabó P, Wiese M, Szakács G. Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance. Eur J Med Chem. 2016; 117: 335-354. [CrossRef]
  • [18] Altıntop MD, Atlı Ö, Ilgın S, Demirel R, Özdemir A, Kaplancıklı ZA. Synthesis and biological evaluation of new naphthalene substituted thiosemicarbazone derivatives as potent antifungal and anticancer agents. Eur J Med Chem. 2016; 108: 406-414. [CrossRef]
  • [19] Altintop MD, Sever B, Özdemir A, Kuş G, Oztopcu-Vatan P, Kabadere S, Kaplancikli ZA. Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells. J Enzyme Inhib Med Chem. 2016; 31(3): 410-416. [CrossRef]
  • [20] Sever B, Akalın Çiftçi G, Özdemir A, Altıntop MD. Design, synthesis and in vitro evaluation of new thiosemicarbazone derivatives as potential anticancer agents. J Res Pharm. 2019; 23(1): 16-24. [CrossRef]
  • [21] Zhang X-H, Bo-Wang, Tao Y-Y, Ma Q, Wang H-J, He Z-X, Wu H-P, Li Y-H, Zhao B, Ma L-Y, Liu H-M. Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents. Eur J Med Chem. 2020; 199: 112349. [CrossRef]
  • [22] King AP, Gellineau HA, Ahn J-E, MacMillan SN, Wilson JJ. Bis(thiosemicarbazone) Complexes of cobalt(III). Synthesis, characterization, and anticancer potential. Inorg Chem. 2017; 56: 6609-6623. [CrossRef]
  • [23] Maghraby MT, Abou-Ghadir OMF, Abdel-Moty SG, Ali AY, Salem OIA. Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15- lipoxygenase enzymes. Bioorg Med Chem. 2020; 28(7): 115403. [CrossRef]
  • [24] Dawood DH, Batran RZ, Farghaly TA, Khedr MA, Abdulla MM. New coumarin derivatives as potent selective COX2 inhibitors: Synthesis, anti-inflammatory, QSAR, and molecular modeling studies. Arch Pharm Chem Life Sci. 2015; 348: 875–888. [CrossRef]
  • [25] Altıntop M.D., Özdemir A., Turan-Zitouni G., Ilgın S., Atlı Ö., Demirci F., Kaplancıklı Z.A. Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents. Molecules. 2014; 19: 14809-14820. [CrossRef]
  • [26] Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63. [CrossRef]
  • [27] Zhou H-Y, Dong F-Q, Du X-L, Zhou Z-K, Huo H-R, Wang W-H, Zhan HD, Dai YF, Jing Meng, Sui YP, Li J, Sui F, Zhai YH. Antitumor activities of biscoumarin and dihydropyran derivatives. Bioorg Med Chem Lett. 2016; 26(16): 3876-3880. [CrossRef]
  • [28] Altıntop MD, Sever B, Akalın Çiftçi G, Turan-Zitouni G, Kaplancıklı ZA, Özdemir A. Design, synthesis, in vitro and in silico evaluation of a new series of oxadiazole-based anticancer agents as potential Akt and FAK inhibitors, Eur J Med Chem. 2018; 155: 905-924. [CrossRef]
Toplam 28 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Farmasotik Kimya
Bölüm Articles
Yazarlar

Belgin Sever

Gülşen Akalın Çiftçi

Ahmet Özdemir

Mehlika Dilek Altıntop

Yayımlanma Tarihi 27 Haziran 2025
Yayımlandığı Sayı Yıl 2020 Cilt: 24 Sayı: 5

Kaynak Göster

APA Sever, B., Akalın Çiftçi, G., Özdemir, A., Altıntop, M. D. (2025). Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer. Journal of Research in Pharmacy, 24(5), 670-680. https://doi.org/10.35333/jrp.2020.222
AMA Sever B, Akalın Çiftçi G, Özdemir A, Altıntop MD. Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer. J. Res. Pharm. Haziran 2025;24(5):670-680. doi:10.35333/jrp.2020.222
Chicago Sever, Belgin, Gülşen Akalın Çiftçi, Ahmet Özdemir, ve Mehlika Dilek Altıntop. “Design, Synthesis and Biological Evaluation of New bis(thiosemicarbazone) Derivatives As Potential Targeted Anticancer Agents for Non-Small Cell Lung Cancer”. Journal of Research in Pharmacy 24, sy. 5 (Haziran 2025): 670-80. https://doi.org/10.35333/jrp.2020.222.
EndNote Sever B, Akalın Çiftçi G, Özdemir A, Altıntop MD (01 Haziran 2025) Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer. Journal of Research in Pharmacy 24 5 670–680.
IEEE B. Sever, G. Akalın Çiftçi, A. Özdemir, ve M. D. Altıntop, “Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer”, J. Res. Pharm., c. 24, sy. 5, ss. 670–680, 2025, doi: 10.35333/jrp.2020.222.
ISNAD Sever, Belgin vd. “Design, Synthesis and Biological Evaluation of New bis(thiosemicarbazone) Derivatives As Potential Targeted Anticancer Agents for Non-Small Cell Lung Cancer”. Journal of Research in Pharmacy 24/5 (Haziran 2025), 670-680. https://doi.org/10.35333/jrp.2020.222.
JAMA Sever B, Akalın Çiftçi G, Özdemir A, Altıntop MD. Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer. J. Res. Pharm. 2025;24:670–680.
MLA Sever, Belgin vd. “Design, Synthesis and Biological Evaluation of New bis(thiosemicarbazone) Derivatives As Potential Targeted Anticancer Agents for Non-Small Cell Lung Cancer”. Journal of Research in Pharmacy, c. 24, sy. 5, 2025, ss. 670-8, doi:10.35333/jrp.2020.222.
Vancouver Sever B, Akalın Çiftçi G, Özdemir A, Altıntop MD. Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer. J. Res. Pharm. 2025;24(5):670-8.

Cited By

Design, synthesis, and biological evaluation of new celecoxib analogs as apoptosis inducers and cyclooxygenase‐2 inhibitors
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https://doi.org/10.1002/ardp.202200190