Biological Activity of Some Pyrimidine Derivatives: Cytotoxicity and Oxidative Stress Potential in Human Lung Cancer Cell line (A549).

Mahmoud Abudayyak; Fatma Betül Şamlıoğlu; Beyza Selen; Seda Fandaklı; Nurettin Yaylı

doi:10.17776/csj.758957

Research Article

Biological Activity of Some Pyrimidine Derivatives: Cytotoxicity and Oxidative Stress Potential in Human Lung Cancer Cell line (A549).

Year 2020, Volume: 41 Issue: 4, 756 - 763, 29.12.2020

Mahmoud Abudayyak Fatma Betül Şamlıoğlu Beyza Selen Seda Fandaklı Nurettin Yaylı

https://doi.org/10.17776/csj.758957

Abstract

Compounds with pyrimidine ring in their structure have many biological activities including antimicrobial, antiviral and anticancer. Recently, studies related to their synthesis and so their applications have increased. In a previous study, a solid-phase microwave method was used to synthesized 25 new hydroxy- and methoxy-substituent 4,6-diarylpyrimidin-2 (1H) -ol and 4,6 diarylpyrimidin-2 (1H) –thiol compounds. In the present study, as a preliminary estimation of the anticancer activity, the cytotoxicity and oxidative stress induction potential of 6 derivatives that show highest antibacterial activities was evaluated in human lung epithelial cancer cell line (A549). Results of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity test indicate that pyrimidine derivatives caused concentration-dependent cell death that IC50 values were calculated between 16.7 and 41.5 µg/mL. additonally, pyrimidine derivatives induced significant changes in malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) activity; oxidative stress could be the mechanism of action of the tested pyrimidine derivatives in the cancerous cells. The results could be used to design the further in vivo and in vitro detailed studies to appreciate these pyrimidine derivatives anticancer activity, compare this activity with in-use known drugs, elucidate their mechanisms of action and estimate their safety.

Keywords

Pyrimidine, Cytotoxicity, Oxidative damage, A549 cells, Anticancer

Supporting Institution

TÜBİTAK (2209-A)

References

[1] Mercan S., Synthesis and Investigation of Biological Effects of Some New Pyrimidine and Pyridine Derivative Compounds [Bazı Yeni Pirimidin ve Piridin Türevi Bileşiklerin Sentezi ve Biyolojik Etkilerinin İncelenmesi], Master Thesis, Gazi University Institute of Science: Ankara, 2010.
[2] Tunç A., Synthesis of New Mercapto Pyrimidine Ringed Schiff Base and Metal Complexes, [Yeni Merkapto Pirimidin Halkalı Schiff Bazı ve Metal Komplekslerinin Sentezi], Master Thesis, Gaziantep University Institute of Science: Gaziantep, 2014.
[3] Gianolio D. A. and McLaughlin L. W., Synthesis and Triplex Forming Properties of Pyrimidine Derivative Containing Extended Functionality, Nucleos. Nucleot. Nucl., 18 (1999) 1751-1769.
[4] Patel A. A. and Mehta A. G., Synthesis of novel heterocyclic compounds and their bioglogical evalution, Der Pharma Chem., 2(1) (2010) 215-223.
[5] Xie F., Zhao H., Zhao L., LOU L. and Hu Y., Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity, Bioorg. Med. Chem. Lett., 19 (2009) 275-278.
[6] Hockova D., Holy A., Masojı´dkova M., Andrei G., Snoeck R., Clercq E. and Balzarin J. 5-Substituted - 2, 4- diamino – 6 - [2 (phosphonomethoxy) ethoxy] pyrimidines Acyclic Nucleoside Phosphonate Analogues with Antiviral Activity, J. Med. Chem., 46 (2003) 5064-5073.
[7] Kumar R., Semaine W., Johar M., Tyrrell D. L. J. and Agrawal B., Effect of various pyrimidines possessing the 1-[(2-Hydroxy-1-(hydroxymethyl) ethoxy) methyl] Moiety, able to mimic natural 2¢-Deoxyribose, on wild-type and mutant hepatitis B virus replication, J. Med. Chem., 49 (2006) 3693-3700.
[8] Wanga Y., Chen F., Balzarini J., Clercq E. D. and Pannecouque C., Synthesis and Anti-HIV Activity of 5-Alkyl-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones with a Mono- or Disubstituted 2-Amino Function as Novel *Dihydro-Alkoxy-Benzyl-Oxopyrimidine/ (DABO) Analogues, Chem. Biodıvers., 5 (2008) 168-176.
[9] Amir M., Javed S. A. and Kumar H., Synthesis and biological evaluation of some 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrimidin-2-ones/thiones as potent anti-inflammatory agents, Acta Pharm., 58 (2008) 467–477.
[10] Kappe C. O., 4-Aryldihydropyrimidines via the Biginelli Condensation: Aza-Analogs of Nifedipine-Type Calcium Channel Modulators, Molecules, 3 (1998) 1-9.
[11] Baysal K., Synthesis, Characterization, Antibacterial and Antioxidant Properties of Pyrimidine Ringed Schiff Base and Metal Complexes Containing Azo Group [Azo Grubu İhtiva Eden Pirimidin Halkalı Schiff Bazı ve Metal Komplekslerinin Sentezi, Karakterizasyonu, Antibakteriyal ve Antioksidan Özelliklerinin İncelenmesi]. Master Thesis, Yüzüncü Yıl University Institute of Science: Van, 2013.
[12] Altıparmak D., Studies on the Synthesis, Structure illumination and Cytotoxic Activities of Some Newly Synthesized Purine and Pyrimidine Nucleoside Analogue Compounds [Yeni Sentezlenmiş Bazı Pürin, Pirimidin Nükleozit Analoğu Bileşiklerin Sentez, Yapı Aydınlatması ve Sitotolsik Aktiviteleri üzerinde Çalışmalar]. Ph.D. Thesis, Ankara University Institute of Health Sciences, Department of Pharmaceutical Chemistry: Ankara, 2018.
[13] Fandaklı S., Synthesis and Biological Activities of Pyrimidine Derivative Compounds from Calcons by Microwave Method [Pirimidin Türevi Bileşiklerin Kalkonlardan Mikrodalga Yöntemi ile Sentezi ve Biyolojik Aktiviteleri]. PhD Thesis, Karadeniz Technical University, Institute of Science: Trabzon, 2016.
[14] Fandaklı S., Kahriman N., Yücel T. B., Alpay Karaoglu S. and Yaylı N. Biological evaluation and synthesis of new pyrimidine-2(1H)-ol/-thiol derivatives derived from chalcones using the solid phase microwave method, Turk. J. Chem., 42 (2018) 520-535.
[15] Rangappa S. K., Kallappa M. H., Ramya V. S. and Mallinath H. H., Analgesic, anti-pyretic and DNA cleavage studies of novel pyrimidine derivatives of coumarin moiety, Eur. J. Med. Chem., 45 (2010) 2597-2605.
[16] Chaturvedi A. M., Mishra Y. K. and Rajawat V., Synthesis of Pyrimidine 2-ol/thiol Derivatives of Benzimidazole as a Ligand and Their Bi (III) Metal Complexes by Conventional as Well as Microwave Technique. Am. J. Phytomed., Clin. Ther., 3 (2015) 383-393.
[17] Khan S. A., Asiri A. M., Kumar S. and Sharma K., Green synthesis, antibacterial activity and computational study of pyrazoline and pyrimidine derivatives from 3‐(3,4‐dimethoxy‐phenyl‐1‐(2,5‐dimethylthiophen‐3‐yl)‐propenone, Eur. J. Chem., 5 (2014) 85-90.
[18] Patel A. A. and Mehta A. G., Synthesis of novel heterocyclic compounds and their biological evaluation, Der Pharma Chem. 2 (2010) 215-223.
[19] Kachroo M., Panda R. and Yadav Y., Synthesis and biological activities of some new pyrimidine derivatives from chalcones, Der Pharma Chem. 6 (2014) 352-359.
[20] Mohsin H. F., Synthesis of some New Pyrimidines from Chalcone Containing an Imin Group, Asian J. Research Chem., 6 (2013) 849-854.
[21] Baddar F. G., Al-Hajjar F. H. and El-Rayyes N. R., Acetylenic ketones. Part V†. Reaction of acetylenic ketones with thiourea and some of its derivatives, J. Heterocyclic Chem., 15 (1978) 105-112.
[22] Cragg G. M. and Newman D. J., Ethnomedicine and Drug Discovery In: Maurice M. Iwu M. M. and Wootton J. (Eds). Advances in Phytomedicine. Amsterdam: Elsevier Science, 2002.
[23] Jeswani G. and Paul S. D., Recent Advances in the Delivery of Chemotherapeutic Agents., In: Grumezescu M. A. (Eds). Nano- and Microscale Drug Delivery Systems, Amsterdam: Elsevier Science, 2017.
[24] Alley M. C., Scudiero D. A., Monks A., Hursey M.L., Czerwinski M.J., Fine D.L., Abbott B.J., Mayo J.G., Shoemaker R.H. and Boyd M.R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 48 (1988) 589–601.
[25] Buege J. A. and Aust S. D. Lactoperoxidase-catalyzed lipid peroxidation of microsomal and artificial membranes. Biochimica et Biophysica Acta., 444 (1976) 192. 26.
[26] Aebi H. Catalase. In Methods of Enzymatic Analysis, Bergmeyer HU (ed.). Academic Press: New York, 1974; 673-677.
[27] Bradford M. Protein reaction with dyes. Anal. Biochem., 72 (1976) 248-251.
[28] Kaya B., Kaplancıklı Z. A., Yurttaş L. and Çiftçi G. A. Synthesis and biological evaluation of some new pyrimidine bearing 2, 5-disubstituted 1, 3, 4-oxadiazole derivatives as cytotoxic agents, Turkish J. Biochem., 42(2) (2016) 131-137.
[29] Kahriman N., Serdaroğlu V., Peker K., Ayın A., Usta A., Fandaklı S. and Yaylı N. Synthesis and Biological evaluation of new 2,4,6-trisubstituted pyrimidines and their N-alkyl derivatives, Bioorg. Chem., 8 (2019) 580–594.
[30] Zitouni-Turan G., Altıntop M. D., Kaplancıklı Z. A., Özdemir A., Demirci F., Ilgın S., Atlı Ö. and Göger G. Synthesis and Evaluation of Thiazole – Pyrimidine Derivatives as New Anticandidal and Cytotoxic Agents, Pharm. Chem. J., 48 (2014) 452-5.
[31] Gömez-Jeria J. S. and Robles-Navvarro A. Quantum-Chemical Study of the Anticancer Activity of Pyrimidine Benzimidazole Hybrids against MCF-7, MGC-803, EC-9706 and SMMC-7721 cell lines, Res. J. Pharm. Biol. Chem. Sci., 6(2) (2015) 775.
[32] Ulukaya E., Ozdikicioglu F., Oral A. Y., Demirci M. The MTT assay yields a relatively lower result of growth inhibition than the ATP assay depending on the chemotherapeutic drugs tested, Toxicol. In Vitro., 22(1) (2008) :232-9.

Year 2020, Volume: 41 Issue: 4, 756 - 763, 29.12.2020

Mahmoud Abudayyak Fatma Betül Şamlıoğlu Beyza Selen Seda Fandaklı Nurettin Yaylı

https://doi.org/10.17776/csj.758957

Abstract

References

[1] Mercan S., Synthesis and Investigation of Biological Effects of Some New Pyrimidine and Pyridine Derivative Compounds [Bazı Yeni Pirimidin ve Piridin Türevi Bileşiklerin Sentezi ve Biyolojik Etkilerinin İncelenmesi], Master Thesis, Gazi University Institute of Science: Ankara, 2010.
[2] Tunç A., Synthesis of New Mercapto Pyrimidine Ringed Schiff Base and Metal Complexes, [Yeni Merkapto Pirimidin Halkalı Schiff Bazı ve Metal Komplekslerinin Sentezi], Master Thesis, Gaziantep University Institute of Science: Gaziantep, 2014.
[3] Gianolio D. A. and McLaughlin L. W., Synthesis and Triplex Forming Properties of Pyrimidine Derivative Containing Extended Functionality, Nucleos. Nucleot. Nucl., 18 (1999) 1751-1769.
[4] Patel A. A. and Mehta A. G., Synthesis of novel heterocyclic compounds and their bioglogical evalution, Der Pharma Chem., 2(1) (2010) 215-223.
[5] Xie F., Zhao H., Zhao L., LOU L. and Hu Y., Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity, Bioorg. Med. Chem. Lett., 19 (2009) 275-278.
[6] Hockova D., Holy A., Masojı´dkova M., Andrei G., Snoeck R., Clercq E. and Balzarin J. 5-Substituted - 2, 4- diamino – 6 - [2 (phosphonomethoxy) ethoxy] pyrimidines Acyclic Nucleoside Phosphonate Analogues with Antiviral Activity, J. Med. Chem., 46 (2003) 5064-5073.
[7] Kumar R., Semaine W., Johar M., Tyrrell D. L. J. and Agrawal B., Effect of various pyrimidines possessing the 1-[(2-Hydroxy-1-(hydroxymethyl) ethoxy) methyl] Moiety, able to mimic natural 2¢-Deoxyribose, on wild-type and mutant hepatitis B virus replication, J. Med. Chem., 49 (2006) 3693-3700.
[8] Wanga Y., Chen F., Balzarini J., Clercq E. D. and Pannecouque C., Synthesis and Anti-HIV Activity of 5-Alkyl-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones with a Mono- or Disubstituted 2-Amino Function as Novel *Dihydro-Alkoxy-Benzyl-Oxopyrimidine/ (DABO) Analogues, Chem. Biodıvers., 5 (2008) 168-176.
[9] Amir M., Javed S. A. and Kumar H., Synthesis and biological evaluation of some 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrimidin-2-ones/thiones as potent anti-inflammatory agents, Acta Pharm., 58 (2008) 467–477.
[10] Kappe C. O., 4-Aryldihydropyrimidines via the Biginelli Condensation: Aza-Analogs of Nifedipine-Type Calcium Channel Modulators, Molecules, 3 (1998) 1-9.
[11] Baysal K., Synthesis, Characterization, Antibacterial and Antioxidant Properties of Pyrimidine Ringed Schiff Base and Metal Complexes Containing Azo Group [Azo Grubu İhtiva Eden Pirimidin Halkalı Schiff Bazı ve Metal Komplekslerinin Sentezi, Karakterizasyonu, Antibakteriyal ve Antioksidan Özelliklerinin İncelenmesi]. Master Thesis, Yüzüncü Yıl University Institute of Science: Van, 2013.
[12] Altıparmak D., Studies on the Synthesis, Structure illumination and Cytotoxic Activities of Some Newly Synthesized Purine and Pyrimidine Nucleoside Analogue Compounds [Yeni Sentezlenmiş Bazı Pürin, Pirimidin Nükleozit Analoğu Bileşiklerin Sentez, Yapı Aydınlatması ve Sitotolsik Aktiviteleri üzerinde Çalışmalar]. Ph.D. Thesis, Ankara University Institute of Health Sciences, Department of Pharmaceutical Chemistry: Ankara, 2018.
[13] Fandaklı S., Synthesis and Biological Activities of Pyrimidine Derivative Compounds from Calcons by Microwave Method [Pirimidin Türevi Bileşiklerin Kalkonlardan Mikrodalga Yöntemi ile Sentezi ve Biyolojik Aktiviteleri]. PhD Thesis, Karadeniz Technical University, Institute of Science: Trabzon, 2016.
[14] Fandaklı S., Kahriman N., Yücel T. B., Alpay Karaoglu S. and Yaylı N. Biological evaluation and synthesis of new pyrimidine-2(1H)-ol/-thiol derivatives derived from chalcones using the solid phase microwave method, Turk. J. Chem., 42 (2018) 520-535.
[15] Rangappa S. K., Kallappa M. H., Ramya V. S. and Mallinath H. H., Analgesic, anti-pyretic and DNA cleavage studies of novel pyrimidine derivatives of coumarin moiety, Eur. J. Med. Chem., 45 (2010) 2597-2605.
[16] Chaturvedi A. M., Mishra Y. K. and Rajawat V., Synthesis of Pyrimidine 2-ol/thiol Derivatives of Benzimidazole as a Ligand and Their Bi (III) Metal Complexes by Conventional as Well as Microwave Technique. Am. J. Phytomed., Clin. Ther., 3 (2015) 383-393.
[17] Khan S. A., Asiri A. M., Kumar S. and Sharma K., Green synthesis, antibacterial activity and computational study of pyrazoline and pyrimidine derivatives from 3‐(3,4‐dimethoxy‐phenyl‐1‐(2,5‐dimethylthiophen‐3‐yl)‐propenone, Eur. J. Chem., 5 (2014) 85-90.
[18] Patel A. A. and Mehta A. G., Synthesis of novel heterocyclic compounds and their biological evaluation, Der Pharma Chem. 2 (2010) 215-223.
[19] Kachroo M., Panda R. and Yadav Y., Synthesis and biological activities of some new pyrimidine derivatives from chalcones, Der Pharma Chem. 6 (2014) 352-359.
[20] Mohsin H. F., Synthesis of some New Pyrimidines from Chalcone Containing an Imin Group, Asian J. Research Chem., 6 (2013) 849-854.
[21] Baddar F. G., Al-Hajjar F. H. and El-Rayyes N. R., Acetylenic ketones. Part V†. Reaction of acetylenic ketones with thiourea and some of its derivatives, J. Heterocyclic Chem., 15 (1978) 105-112.
[22] Cragg G. M. and Newman D. J., Ethnomedicine and Drug Discovery In: Maurice M. Iwu M. M. and Wootton J. (Eds). Advances in Phytomedicine. Amsterdam: Elsevier Science, 2002.
[23] Jeswani G. and Paul S. D., Recent Advances in the Delivery of Chemotherapeutic Agents., In: Grumezescu M. A. (Eds). Nano- and Microscale Drug Delivery Systems, Amsterdam: Elsevier Science, 2017.
[24] Alley M. C., Scudiero D. A., Monks A., Hursey M.L., Czerwinski M.J., Fine D.L., Abbott B.J., Mayo J.G., Shoemaker R.H. and Boyd M.R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 48 (1988) 589–601.
[25] Buege J. A. and Aust S. D. Lactoperoxidase-catalyzed lipid peroxidation of microsomal and artificial membranes. Biochimica et Biophysica Acta., 444 (1976) 192. 26.
[26] Aebi H. Catalase. In Methods of Enzymatic Analysis, Bergmeyer HU (ed.). Academic Press: New York, 1974; 673-677.
[27] Bradford M. Protein reaction with dyes. Anal. Biochem., 72 (1976) 248-251.
[28] Kaya B., Kaplancıklı Z. A., Yurttaş L. and Çiftçi G. A. Synthesis and biological evaluation of some new pyrimidine bearing 2, 5-disubstituted 1, 3, 4-oxadiazole derivatives as cytotoxic agents, Turkish J. Biochem., 42(2) (2016) 131-137.
[29] Kahriman N., Serdaroğlu V., Peker K., Ayın A., Usta A., Fandaklı S. and Yaylı N. Synthesis and Biological evaluation of new 2,4,6-trisubstituted pyrimidines and their N-alkyl derivatives, Bioorg. Chem., 8 (2019) 580–594.
[30] Zitouni-Turan G., Altıntop M. D., Kaplancıklı Z. A., Özdemir A., Demirci F., Ilgın S., Atlı Ö. and Göger G. Synthesis and Evaluation of Thiazole – Pyrimidine Derivatives as New Anticandidal and Cytotoxic Agents, Pharm. Chem. J., 48 (2014) 452-5.
[31] Gömez-Jeria J. S. and Robles-Navvarro A. Quantum-Chemical Study of the Anticancer Activity of Pyrimidine Benzimidazole Hybrids against MCF-7, MGC-803, EC-9706 and SMMC-7721 cell lines, Res. J. Pharm. Biol. Chem. Sci., 6(2) (2015) 775.
[32] Ulukaya E., Ozdikicioglu F., Oral A. Y., Demirci M. The MTT assay yields a relatively lower result of growth inhibition than the ATP assay depending on the chemotherapeutic drugs tested, Toxicol. In Vitro., 22(1) (2008) :232-9.

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Details

Primary Language	English
Subjects	Structural Biology
Journal Section	Natural Sciences
Authors	Mahmoud Abudayyak Fatma Betül Şamlıoğlu 0000-0001-5940-2512 Beyza Selen 0000-0003-2022-2033 Seda Fandaklı 0000-0002-8199-3336 Nurettin Yaylı 0000-0003-4174-3014
Publication Date	December 29, 2020
Submission Date	June 27, 2020
Acceptance Date	December 6, 2020
Published in Issue	Year 2020Volume: 41 Issue: 4

Cite

APA	Abudayyak, M., Şamlıoğlu, F. B., Selen, B., Fandaklı, S., et al. (2020). Biological Activity of Some Pyrimidine Derivatives: Cytotoxicity and Oxidative Stress Potential in Human Lung Cancer Cell line (A549). Cumhuriyet Science Journal, 41(4), 756-763. https://doi.org/10.17776/csj.758957

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