Synthesis of novel salicylic acid-pyrrolone conjugates and
investigation of their cytotoxic and genotoxic effects in
Allium cepa root tip cells

ERDEN, SEMA; halepliler, sultan; SERIN, MEHMET SAMI; Gonca, Serpil; Gümüş, Mehmet; Eroğlu, Halil Erhan; Can, Selin; KOCA, IRFAN

doi:10.25135/acg.oc.111.21.06.2118

Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells

Serpil GONCA, (Mersin Üniversitesi, Eczacılık Fakültesi, Farmasotik Mikrobiyoloji Anabilim Dalı, Mersin, Türkiye)

Mehmet GÜMÜŞ, (Akdağmadeni Health College, Yozgat Bozok University, Yozgat, Türkiye)

Mehmet Sami SERİN, (Mersin Üniversitesi, Eczacılık Fakültesi, Farmasotik Mikrobiyoloji Anabilim Dalı, Mersin, Türkiye)

Selin CAN, (Department of Biology, Faculty of Art & Sciences, Yozgat Bozok University, Yozgat, Türkiye)

Sultan HALEPLİLER, (Mersin Erdemli Devlet Hastanesi, Mikrobiyoloji Laboratuvarı, Mersin, Türkiye)

HALİL ERHAN EROĞLU, (Department of Biology, Faculty of Art & Sciences, Yozgat Bozok University, Yozgat, Türkiye)

Sema ERDEN ERTÜRK, (Mersin Üniversitesi, Sağlık Hizmetleri Meslek Yüksekokulu, Mersin, Türkiye)

İrfan KOCA (Department of Chemistry, Faculty of Art & Sciences, Yozgat Bozok University, Yozgat, Türkiye)

Organic Communications

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Yıl: 2021 Cilt: 14 Sayı: 3 Sayfa Aralığı: 280 - 293 Metin Dili: İngilizce DOI: 10.25135/acg.oc.111.21.06.2118 İndeks Tarihi: 08-06-2022

Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells

Öz:

: In the 20th century, many new drugs have been designed and synthesized to be used for therapeutic purposes. In these syntheses, especially the salicylic acid group is included in the structure of many drugs. The salicylic acid molecule is the starting material of aspirin and is a structurally important compound. There are many commercial products on the market that are synthesized from salicylic acid or contain salicylic acid group. In this study, the synthesis of salicylic acid-pyrrolone hybrid compounds was carried out from the reactions of furan-3-one compounds with 4-aminosalicylic acid and 5-aminosalicylic acid reagents. The synthesis reactions were achieved in three steps and in these synthesis, biologically active pyrrolone and salicylic acid groups were integrated. The characterizations of these compounds that were purified by column chromatography and crystallization method were made by FTIR, NMR and HRMS techniques. The cytotoxic and genotoxic potentials of the novel compounds (7a-e) were evaluated at five different concentrations (6.25, 12.5, 25, 50 and 100 μM) using the Allium test system. As a result of cytogenetic analysis, it was determined that high concentrations of some hybrid compounds significantly reduced the number of divisions of A. cepa cells (cytotoxicity in 7a and 7c) and caused chromosomal abnormalities in dividing cells (genotoxicity in 7a, 7c, 7e, and especially 7d)

Anahtar Kelime:

Rubella and Cytomegalovirus seropositivity’ in pregnant women, Mersin 2018

Öz:

Aim: Viral infections caused by rubella and CMV may cause serious damage to the fetus when transmitted during pregnancy. In this study, it was aimed to examine the seropositivity of anti-Rubella and anti-CMV antibodies and its age distribution in pregnant women who were followed up routinely due to pregnancy. Method: In the study, the presence of anti-Rubella and anti-CMV antibodies in blood samples taken from pregnant women who were sent to the Microbiology Laboratory of Mersin Erdemli State Hospital between January and December 2018, was investigated by obtaining from the hospital records. Results: Of the total 1639 serum samples that were tested for anti-Rubella IgG, 91.7% were found to be positive, 6.2% negative and 2.1% as limit value. In 1736 total serum samples that were tested for Anti-Rubella IgM, 0.5% was determined as positive, 99.3% as negative and 0.2% as the limit value. A total of 1703 (100%) serum samples that were tested for anti-CMV IgG were all detected as positive. Of the 1728 serum samples, which were tested for anti-CMV IgM, 0.3% was found to be positive, 99.4% negative and 0.3% suspicious. Conclusion: As a result of the study, all pregnant women were found be positive for anti-CMV IgG seropositivity. These data support that all pregnant women in the study had CMV infection until pregnancy. Anti-Rubella IgG seropositivity was determined as 91.7%. This positivity changes with age. Besides it can be concluded that the first 10-year age band before 2006 may be risky. For this reason, rubella follow-up is utmost important in the follow-up of women who are planning pregnancy in this age group.

Anahtar Kelime:

Gebelerde Rubella ve Cytomegalovirus seropozitifliği, Mersin 2018

Öz:

Amaç: Rubella ve CMV kaynaklı viral infeksiyonlar gebelik döneminde geçirildiğinde fetüste ciddi hasarlara sebep olabilmektedir. Bu çalışmada gebelik dolayısı ile rutin takip edilen gebelerdeki anti-Rubella ve anti-CMV antikorlarının seropozitifliğini ve bunun yaşa dağılımını incelemek amaçlanmıştır. Yöntem: Çalışmada, 2018 yılı Ocak-Aralık ayları arasında Erdemli Devlet Hastanesi Mikrobiyoloji laboratuvarına gebelik takibi ile gönderilen, gebelerden alınan kan örneklerinde anti-Rubella ve anti-CMV antikorlarının varlığı hastanenin kayıtlarından elde edilerek araştırılmıştır. Bulgular: Bu çalışmada anti-Rubella IgG testi yapılan toplam 1639 serum örneğinin %91.7’si pozitif, %6.2’i negatif ve %2.1’ü sınır değer olarak tespit edildi. Anti-Rubella IgM testi yapılan 1736 toplam serum örneğinin %0.5’i pozitif, %99.3’ü negatif ve %0.2’si sınır değer olarak tespit edildi. Anti-CMV IgG testi yapılan toplam 1703 serum örneğinin %100’ü pozitif olarak tespit edildi. Anti-CMV IgM testi yapılan toplam 1728 serum örneğinin %0.3’ü pozitif, %99.4’ü negatif ve %0.3’ü sınır değer olarak tespit edildi. Sonuç: Çalışmanın sonuçlarına göre gebelerin tümü anti-CMV IgG açısından seropozitiftir. Bu veriler çalışmadaki gebe kadıların tümünün gebelik dönemine kadar CMV infeksiyonu geçirdiğini desteklemektedir. Anti-Rubella IgG seropozitifliği ise %91.7 olarak tespit edilmiştir. Bu pozitiflik yaşla beraber değişkenlik göstermektedir. Ayrıca 2006 yılından önceki ilk 10 yıllık yaş bandının riskli olabileceği sonucuna varılabilir. Bu nedenle bu yaş grubunda gebelik planlayan kadınların izleminde rubella takibi daha önem taşımaktadır.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Bakacak M, Bostancı MS, Köstü B, Ercan Ö, Serin S, Avcı F, et al. Gebelerde Toxoplasma gondii, rubella ve sitomegalovirüs seroprevalansı. Dicle Tıp Derg. 2014; 41(2): 326–31.
[1] Rainsford, K.D. Aspirin and Related Drugs, Taylor & Francis Ltd., London, UK., 2004, 770 pp.
2. Alghalibi S, Abdullah Q, Arnoot S, Al-Thobhani A. Seroprevalence of Cytomegalovirus among Pregnant Women in Hodeidah city, Yemen. J Hum Virol Retrovirology. 2016; 3(5): 00106.
[2] Hedner, T.; Everts, B. The early clinical history of salicylates in rheumatology and pain. Clin. Rheumatol. 1998, 17(1), 17-25.
3. Özdemir ÖMA, Alk L, Nurdan Y, Elif Y. Konjenital Sitomegalovirüs İ nfeksiyonu Olgu Sunumu. Van Tıp Derg. 2012; 19(4): 189–92.
[3] Hauso, O.; Martinsen, T.C.; Waldum, H. 5-Aminosalicylic acid, a specific drug for ulcerative colitis. Scand. J. Gastroenterol. 2015, 50(8), 933-941.
4. Centers for Disease Control and Prevention. Cytomegalovirus (CMV) and Congenital CMV Infection. 2020 [https://www.cdc.gov/cmv/index.html]. (Erişim tarihi: 21.02.21)
[4] Omoteyama, K.; Sato, T.; Arito, M.; Sato, M.; Suematsu, N.; Kurokawa, M.S.; Kato, T. Effects of salazosulfapyridine on the profile of cell surface proteins, revealed by biotinylation of cell surface proteins and 2-dimensional electrophoresis. Biochim. Biophys. Acta Proteins Proteom. 2019, 1867(1), 47-56.
5. Madendağ Y, Eraslan Şahin M, Çöl Madendağ İ, Şahin E, Açmaz G, Müderris İİ. Hastanemize başvuran gebelerde toksoplazma, sitomegalovirüs ve rubella seroprevalansının araştırılması. Perinat J. 2018; 26(1): 7–10.
[5] Seferoğlu, B.; Altaş, E.U.; Şenel, K. Antimalarials and sulfasalazine, Turkiye Klinikler. J PM&R-Special Top. 2014, 7(4), 20-24.
6. Doğan K, Güraslan H, Özel G, Aydan Z, Yaşar L. Gebelerde Toxoplasma gondii, Rubella, Sitomegalovirus, Sifiliz ve Hepatit B Seropozitiflik Oranları. Türkiye Parazitoloji Derg. 2014; 38(4): 228–33.
[6] Yeonhwa, S.; Ran, S.H.; Jaewoo, J.; Tae-Hoon, S.; Mun, B.S.; Seung-Jae, M.; Mun, B.S.; Seung-Jae, M.; Jin-Sun, K.; Mo, K.K.; Seung-Jae, M.; Kyung, C. Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res. 2017, 36(1), 38.
7. Pekintürk N. Doğurganlık Yaş Grubundaki Kadınlarda Rubella ve Sitomegalovirüs Seroprevalansı. J Clin Anal Med. 2015; 6(1): 69–71.
[7] Abdu-Allah, H.H.; El-Shorbagi, A.N.A.; Abdel-Moty, S.G.; El-Awady, R.; Abdel-Alim, A.A.M. 5- Aminosalyclic acid (5-ASA): A unique anti-inflammatory salicylate. Med. Chem. 2016, 6(5), 361/1-361/10.
8. Uzun B, Güngör S, Er H, Gökmen A, Pektaş B, Şener AG. Gebelerde rubella ve sitomegalovirus IgG avidite testlerinin değerlendirilmesi: dört yıllık deneyim. J Clin Exp Investig. 2015; 5(3): 420–3.
[8] Green, J.R; Lobo, A.J.; Holdsworth, C.D.; Leicester, R.J.; Gibson, J.A.; Kerr, G.D.; Hodgson, H.J.; Parkins, K.J.; Taylor, M.D. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group, Gastroenterology 1998, 114(1), 15-22.
9. Ağca H. Doğurganlık Çağındaki Kadınlarda Rubella ve Sitomegalovirus Antikorlarının Araştırılması. Türk Mikrobiyoloji Cemiy Derg. 2011; 41(1): 15–7.
[9] Ibrahim, M.A.; Elagawany, M.; Ibrahim, T.S. Green and catalyst-free synthesis of olsalazine analogs. Green Chem. Lett. Rev. 2016, 9(2), 91-95.
10. Bouthry E, Picone O, Hamdi G, Grangeot-Keros L, Ayoubi JM, Vauloup-Fellous C. Rubella and pregnancy: Diagnosis, management and outcomes. Prenat Diagn. 2014; 34(13): 1246–53.
[10] Pozharskii, A.K.; Ramsden, C.; Joule, J.; Zhdankin, V. Handbook of Heterocyclic Chemistry 2nd Edition, United Kingdom, Elsevier Science & Technology, 2000, 520 pp.
11. Türkiye İstatistik Kurumu. Coğrafi İstatistik Portalı. [https://cip.tuik.gov.tr/]. (Erişim Tarihi: 30.08.2021).
[11] Gholap, S.S. Pyrrole: An emerging scaffold for construction of valuable therapeutic agents. Eur. J. Med. Chem. 2016, 110, 13-31.
12. Karabulut A, Polat Y, Türk M, Balci YI. Evaluation of rubella, Toxoplasma gondii, and cytomegalovirus seroprevalences among pregnant women in Denizli province. Turkish J Med Sci. 2011; 41(1): 159–64.
[12] Snyder, R.D.; Green, J.W. A review of the genotoxicity of marketed pharmaceuticals. Mutat. Res. 2001, 488(2), 151-69.
13. Gülseren YD, Esenkaya Taşbent F, Ozdemir M. Gebelerde Sitomegalovirüs ile Rubella Seroprevalansının ve Yaşa Bağlı Dağılımının Araştırılması. Türk Mikrobiyoloji Cemiy Derg. 2019; 49(3): 154–61.
[13] Ali, Y.; Alam, M.S.; Hamid, H.; Hussain, A. 2(3H)Pyrrolone–a biologically active scaffold. Oriental J Chem. 2014, 30(1), 1-16.
14. Hamdan HZ, Abdelbagi IE, Nasser NM, Adam I. Seroprevalence of cytomegalovirus and rubella among pregnant women in western Sudan. Virol J. 2011; 8(1): 217.
[14] Mohamed, M.S.; El-Domany, R.A.; Abd El-Hameed, R.H. Synthesis of certain pyrrole derivatives as antimicrobial agents. Acta. Pharm. 2009, 59(2), 145-158.
15. Guerra AB, Siravenha LQ, Laurentino RV, Feitosa RNM, Azevedo VN, Vallinoto ACR, et al. Seroprevalence of HIV, HTLV, CMV, HBV and rubella virus infections in pregnant adolescents who received care in the city of Belém, Pará, Northern Brazil. BMC Pregnancy Childbirth. 2018; 18(1): 1–7.
[15] Alam, M.M.; Husain, A.; Hasan, S.M.; Suruchi; Answer, T. Synthesis and pharmacological evaluation of 2(3H)-Furanones and 2(3H)-Pyrrolones, combining analgesic and anti-inflammatory properties with reduced gastrointestinal toxicity and lipid peroxidation. Eur. J. Med. Chem. 2009, 44(6), 2636-2642.
16. Efe Ş, Kurdoğlu Z, Korkmaz G. Van Yöresindeki Gebelerde Sitomegalovirüs, Rubella ve Toksoplazma Antikorlarının Seroprevalansı. Van Tıp Derg. 2009; 16(1): 6–9.
[16] Husain, A.; Alam, M.M.; Siddiqui, N. Synthesis, reactions and biological activity of 3-arylidene-5-(4- methylphenyl)-2 (3H)-furanones. J. Serbian Chem. Soc. 2009, 74(2), 103-115.
17. Toklu GD. Gebelerde Toksoplazma, Rubella Virus ve Sitomegalovirus’a Karşı Oluşan Antikorların Sıklığı. J Clin Anal Med. 2013; 4(1): 38–40.
[17] Husain, A.; Alam, M.M.; Hasan, S.M.; Yar, M.S. 2(3H)-furanones and 2(3H)-pyrrolones: synthesis and antimycobacterial evaluation. Acta Pol. Pharm. 2009, 66(2), 173-180.
18. Obut M, Doğan Y, Bademkıran MH, Akgöl S, Kahveci B, Peker N, et al. Diyarbakır İlindeki Gebe Kadınlarda Toksoplazma, Rubella ve Sitomegalovirus Seroprevalansı Toxoplasma , Rubella And Cytomegalovirus Seroprevalence In Pregnant Women In Üniversitesi Gazi Yaşargil Eğitim ve Araştırma. Dicle Tıp Derg. 2019; 46(2): 189–94.
[18] Murugesan, D.; Mital, A.; Kaiser, M.; Shackleford, D.M.; Morizzi, J.; Katneni, K.; Campbell, M.; Hudson, A.; Charman, S.A.; Yeates, C.; Gilbert, I.H. Discovery and structure-activity relationships of pyrrolone antimalarials. J. Med. Chem. 2013, 56(7), 2975-2990.
19. Mutlu E, Özhak Baysan B, Çolak D. İnsan Herpesvirusları. In: Başustaoğlu AC, Yıldıran ŞT, Tanyüksel M, Yapar M (Eds.) Tıbbi Mikrobiyoloji. Ankara: Atlas Kitapçılık, 2010: 517–40.
[19] Murugesan, D.; Kaiser, M.; White, K.L.; Norval, S.; Riley, J.; Wyatt, P.G.; Charman, S.A.; Read, K.D.; Yeates, C.; Gilbert, I.H. Structure-activity relationship studies of pyrrolone antimalarial agents. ChemMedChem. 2013, 8(9), 1537-1544.
20. Sen MR, Shukla BN, Banerjee T. Prevalence of serum antibodies to TORCH infection in and around Varanasi, North India. J Clin Diagnostic Res. 2012; 6(9): 1483–5.
[20] Smith, A.B.; Charnley, A.K.; Hirschmann, R. Pyrrolinone-based peptidomimetics."Let the enzyme or receptor be the judge". Acc. Chem. Res. 2011, 44(3), 180-193.
21. Aynali A, Arıdoğan BC, Tola EN, Önal S, Çetin ES. Doğurganlık Yaş Grubundaki Kadınlarda Rubella IgM ve IgG Seroprevalansı. Süleyman Demirel Üniversitesi Sağlık Bilimleri Dergisi, 2016; 7(10): 1-10.
[21] Bassetto, M.; Leyssen, P.; Neyts, J.; Yerukhimovich, M.M.; Frick, D.N.; Brancale, A. Shape-based virtual screening, synthesis and evaluation of novel pyrrolone derivatives as antiviral agents against HCV. Bioorg. Med. Chem. Lett. 2017, 27(4), 936-940.
22. Taku NA, Ndze VN, Abernathy E, Hao LJ, Waku-Kouomou D, Icenogle JP, et al. Seroprevalence of rubella virus antibodies among pregnant women in the Center and South-West regions of Cameroon. PLoS One. 2019; 14(11): 1–10.
[22] Erden, I.; Ozer, G.; Hoarau, C.; Cao, W. Cyclocondensation of amidines with dimethyl acetylenedicarboxylate: a convenient entry into tetramic acids. J. Heterocycl. Chem. 2006, 43(2), 395-399.
23. Zahir H, Arsalane L, Elghouat G, Mouhib H, Elkamouni Y, Zouhair S. Seroprevalence of rubella in pregnant women in Southern Morocco. Pan Afr Med J. 2020; 35(Supp 1): 10.
[23] Zhang, Z.J.; Ren, Z.H.; Wang, Y.Y.; Guan, Z.H. Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2- alkyl migration of enamino amides for synthesis of pyrrolin-4-ones. Org. Lett. 2013, 15(18), 4822-4825.
24. Aşık G, Ünlü S, Er H, Yoldaş Ö, Köken G. Afyon Bölgesinde Gebelerde Toksoplazma ve Rubella Seroprevelansı. Pamukkale Tıp Derg. 2013; 6(3): 128–32.
[24] Huang, J.; Liang, Y.; Pan, W.; Yang, Y.; Dong, D. Efficient synthesis of highly substituted pyrrolin-4-ones via PIFA-mediated cyclization reactions of enaminones. Org. Lett. 2007, 9(26), 5345-5348.
25. Sasmaz T, Kurt AO, Ozturk C, Bugdayci R, Oner S. Rubella seroprevalence in women in the reproductive period, Mersin, Turkey. Vaccine. 2007; 25(5): 912–7.
[25] Gouault, N.; Le Roch, M.; Cornee, C.; David, M.; Uriac, P. Synthesis of substituted pyrrolin-4-ones from amino acids in mild conditions via a gold-catalyzed approach. J. Org. Chem. 2009, 74(15), 5614-5617.
[26] Spina, R.; Colacino, E.; Gabriele, B.; Salerno, G.; Martinez, J.; Lamaty, F. Synthesis of pyrrolin-4-ones by Pt-catalyzed cycloisomerization in PEG under microwaves. J. Org. Chem. 2013, 78(6), 2698-2702.
[27] Qiu, Y.F.; Yang, F.; Qiu, Z.H.; Zhong, M.J.; Wang, L.J.; Ye, Y.Y.; Song, B.; Liang, Y.M. Bronsted acid catalyzed and NIS-promoted cyclization of diynones: selective synthesis of 4-Pyrone, 4-Pyridone, and 3- Pyrrolone derivatives. J. Org. Chem. 2013, 78(23), 12018-12028.
[28] Fiskesjö, G. The Allium test as standart in enviromental monitoring. Hereditas. 1985, 102, 99-112.
[29] Leme, D.M.; Marin-Morales, М.А. Allium cepa test in environmental monitoring: a review on its application. Mutat. Res. 2009, 682, 71-81.
[30] El-Shabhaby, O.A.; Abdel Migid, H.M.; Soliman, M.I.; Mashaly, I.A. Genotoxicity screening of industrial wastewater using the Allium cepa chromosome aberration assay. Pak. J. Biol. Sci. 2003, 6, 23-28.
[31] Kovalchuk, O.; Kovalchuk, I.; Arkhipov, A.; Telyuk, P.; Hohn, B.; Kovalchuk, L. The Allium cepa chromosome aberration test reliably measures genotoxicity of soils of inhabited areas in the Ukraine contaminated by the Chernobyl accident. Mutat. Res. 1998, 415, 47-57.
[32] Gümüş, M.; Gümüş, N.; Eroğlu, H.E.; Koca, İ. Design, synthesis and cytotoxic activities of pyrazoleperimidine hybrids. ChemistrySelect. 2020, 5(20), 5916-5921.
[33] Liman, R.; Ciğerci, I.H; Öztürk, N.S. Determination of genotoxic effects of Imazethapyr herbicide in Allium cep root cells by mitotic activity, chromosome aberration, and comet assay. Pestic. Biochem. Phys. 2015, 118, 38-42.
[34] Saripinar, E.; Guzel, Y; Onal, Z.; Ilhan, I.O.; Akcamur, Y. 4-(4-Methoxybenzoyl)-5-(4-methoxyphenyl)- 2,3-dihydro-2,3-furandione, its synthesis, thermolysis and Diels-Alder reactions with Schiff bases: experimental data and calculations. J. Chem. Soc. Pak. 2000, 22, 308-317.
[35] Saalfrank, R.W.; Lutz, T.; Hoerner, B.; Guendel, J.; Peters, K.; Von Schnering, H.G. 2,3‐Dioxo‐2,3‐ dihydrofurane, 2 Vielseitige Synthese von 2,3‐Dioxo‐2,3‐dihydrofuranen und Alkylidenbutenoliden.– kristall‐ und molekülstruktur von 5‐(4‐Chlorphenyl)‐4‐methoxycarbonyl‐2,3‐dioxo‐2,3‐dihydrofuran. Chem. Ber. 1991, 124(10), 2289-95.
[36] Ungoren, S.H.; Sacmaci, M.; Akcamur, Y.; Arici, C.; Ulku, D. Synthesis of new 2,3-dihydrofuran-3-one derivative and its reactions with some primary amines. J. Heterocycl. Chem. 2004, 41(2), 151-155.
[37] Sacmaci, M.; Bolukbasi, H.; Sahin, E. Reactions of some furan-3-ones with 2,3-diaminopyridine and its derivatives. Bull. Korean Chem. Soc. 2012, 33(1), 90-94.
[38] Koca, İ.; Sacmaci, M.; Yilmaz, F.; Üngören, S.H. Synthesis and structural characterization of Pyrrole heterocyclic systems bearing amino acid units: novel Pyrrol-3-ones, Pyrrolo[1,2-a][3,1]benzoxazines, and Pyrrolo[2,1-b][1,3]oxazoles. J. Heterocycl. Chem. 2014, 51(1), 212-218.
[39] Gümüş, M.; Dişli, A.; Yakan, M.; Yiğitcan, S.; Koca, İ. One-pot and multi-step syntheses of new 2-(4,5- dihydro-1H-pyrazol-1-yl) thiazole derivatives. Org. Commun. 2018, 112, 98-110.
[40] Webster, P.L.; Davidson, D. Changes in the duration of the mitotic cycle induced by colchicine and indol3-yl-acetic acid in Vicia faba roots. J. Exp. Bot. 1969, 20(3), 671-685.
[41] Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003, 36(3), 131-149.
[42] Vodicka, P.; Kumar, R.; Stetina, R.; Sanyal, S.; Soucek, P.; Haufroid, V.; Maria Dusinska, M.; Kuricova, M.; Zamecnikova, M.; Musak, L.; Buchancova, J.; Norppa, H.; Hirvonen, A.; Vodickova, L.; Naccarati, A.; Matousu Z.; Hemminki, K. Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA. Carcinogenesis 2004, 25(5), 757- 763.
[43] Ping, K.Y.; Darah, I.; Yusuf, U.K.; Yeng, C.; Sasidharan, S. Genotoxicity of Euphorbia hirta: an Allium cepa assay. Molecules 2012, 17, 7782-7791.
[44] Kabarity, A.; El-Bayoumi, A.; Habib, A. Effect of morphine sulphate on mitosis of Allium cepa root tips. Biol. Plant. 1974, 16, 275-282.
[45] Giri, A.K; Adhikari, N.; Khan, K.A. Comparative genotoxicity of six salicylic acid derivatives in bone marrow cells of mice. Mutat. Res. 1996, 370, 1-9.
[46] Pawar, A.A.; Vikram, A.; Tripathi, D.N.; Padmanabhan, S.; Ramarao, P.; Jena, G. Modulation of mitomycin C- induced genotoxicity by acetyl- and thio- analogues of salicylic acid. In Vivo. 2009, 23(2), 303-308.
[47] European Chemicals Agency (ECHA), Registration, Evaluation, Authorization, and Restriction of Chemical Substances (REACH) Dossier, Methyl Salicylate, https://echa.europa.eu/registration-dossier/- /registered-dossier/2227.
[48] European Chemicals Agency (ECHA), Registration, Evaluation, Authorization, and Restriction of Chemical Substances (REACH) Dossier, Sodium Salicylate, https://echa.europa.eu/registration-dossier/- /registered-dossier/13593.

APA	Gümüş M, Gonca S, Can S, SERIN M, Eroğlu H, halepliler s, KOCA I, ERDEN S (2021). Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. , 280 - 293. 10.25135/acg.oc.111.21.06.2118
Chicago	Gümüş Mehmet,Gonca Serpil,Can Selin,SERIN MEHMET SAMI,Eroğlu Halil Erhan,halepliler sultan,KOCA IRFAN,ERDEN SEMA Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. (2021): 280 - 293. 10.25135/acg.oc.111.21.06.2118
MLA	Gümüş Mehmet,Gonca Serpil,Can Selin,SERIN MEHMET SAMI,Eroğlu Halil Erhan,halepliler sultan,KOCA IRFAN,ERDEN SEMA Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. , 2021, ss.280 - 293. 10.25135/acg.oc.111.21.06.2118
AMA	Gümüş M,Gonca S,Can S,SERIN M,Eroğlu H,halepliler s,KOCA I,ERDEN S Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. . 2021; 280 - 293. 10.25135/acg.oc.111.21.06.2118
Vancouver	Gümüş M,Gonca S,Can S,SERIN M,Eroğlu H,halepliler s,KOCA I,ERDEN S Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. . 2021; 280 - 293. 10.25135/acg.oc.111.21.06.2118
IEEE	Gümüş M,Gonca S,Can S,SERIN M,Eroğlu H,halepliler s,KOCA I,ERDEN S "Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells." , ss.280 - 293, 2021. 10.25135/acg.oc.111.21.06.2118
ISNAD	Gümüş, Mehmet vd. "Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells". (2021), 280-293. https://doi.org/10.25135/acg.oc.111.21.06.2118

APA	Gümüş M, Gonca S, Can S, SERIN M, Eroğlu H, halepliler s, KOCA I, ERDEN S (2021). Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. Organic Communications, 14(3), 280 - 293. 10.25135/acg.oc.111.21.06.2118
Chicago	Gümüş Mehmet,Gonca Serpil,Can Selin,SERIN MEHMET SAMI,Eroğlu Halil Erhan,halepliler sultan,KOCA IRFAN,ERDEN SEMA Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. Organic Communications 14, no.3 (2021): 280 - 293. 10.25135/acg.oc.111.21.06.2118
MLA	Gümüş Mehmet,Gonca Serpil,Can Selin,SERIN MEHMET SAMI,Eroğlu Halil Erhan,halepliler sultan,KOCA IRFAN,ERDEN SEMA Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. Organic Communications, vol.14, no.3, 2021, ss.280 - 293. 10.25135/acg.oc.111.21.06.2118
AMA	Gümüş M,Gonca S,Can S,SERIN M,Eroğlu H,halepliler s,KOCA I,ERDEN S Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. Organic Communications. 2021; 14(3): 280 - 293. 10.25135/acg.oc.111.21.06.2118
Vancouver	Gümüş M,Gonca S,Can S,SERIN M,Eroğlu H,halepliler s,KOCA I,ERDEN S Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells. Organic Communications. 2021; 14(3): 280 - 293. 10.25135/acg.oc.111.21.06.2118
IEEE	Gümüş M,Gonca S,Can S,SERIN M,Eroğlu H,halepliler s,KOCA I,ERDEN S "Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells." Organic Communications, 14, ss.280 - 293, 2021. 10.25135/acg.oc.111.21.06.2118
ISNAD	Gümüş, Mehmet vd. "Synthesis of novel salicylic acid-pyrrolone conjugates and investigation of their cytotoxic and genotoxic effects in Allium cepa root tip cells". Organic Communications 14/3 (2021), 280-293. https://doi.org/10.25135/acg.oc.111.21.06.2118