Muhammed İhsan HAN, Hatice BEKÇİ, Ahmet CUMAOĞLU, Ş. Güniz KÜÇÜKGÜZEL

Synthesis and characterization of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-Naproxen as anticancer agents

A novel series of new naproxen derivatives (S)-ethyl{[4-(4-fluorophenyl)-5-[(1-(6-methoxynaphtalen-2- yl)ethyl)]-4H-1,2,4-triazole-3-yl]sulphanyl}acetate (5), (S)-2-({5-[1-(6-methoxynaphtalen-1-yl)ethyl]-4-fluorophenyl-4H1,2,4-triazole-3-yl}sulphanyl)acetohydrazide (6), 2-{[5-[1-(6-methoxynaphtalen-2-yl)ethyl]-4-(4-fluorophenyl)-4H-1,2,4- triazole-3-yl]sulphanyl}-N'-[(substituted)methylidene]acetohydrazides (7a-m) were synthesized, in this study. The structures of compounds 5, 6 and 7a-m were defined by spectral (1H-NMR, 13C-NMR, HR-MS and FT-IR) methods and their purity was proven by elemental analysis, thin layer chromatography and high pressure liquid chromatography. These compounds were evaluated for in vitro anticancer activity by using MTS method against PC-3 and DU-143 (androgen-independent human prostate cancer cell lines) and LNCaP (androgen-sensitive human prostate adenocarcinoma) prostate cancer cell lines. Cisplatin was used as the positive sensitivity reference standard. Compounds (7a-m) exhibited anticancer activity with IC50 values of 87.2-400 µM against prostate cancer cell lines.

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[1] Hawkey CJ. COX-2 inhibitors. The Lancet 1999; 353: 307-314.

[2] Ammar YA, Salem MA, Fayed EA, Helal MH, El-Gaby MSA, Thabet HK. Naproxen derivatives: Synthesis, reactions, and biological applications. Synth Commun. 2017; 47; 1341-1367. [CrossRef]

[3] Harris RE, Donk JB, Alshafie GA. Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer. 2008; 8: 237-242. [CrossRef]

[4] Kim MS, Kim JE, Lim DY, Huang Z, Chen H, Langfald A, Lubet RA, Grubbs CJ, Dong Z, Bode AM. Naproxen induces cell-cycle arrest and apoptosis in human urinary bladder cancer cell lines and chemically induced cancers by targeting PI3K. Cancer Prev Res. 2014; 7(2): 237-245. [CrossRef]

[5] Lubet RA, Scheiman JM, Bode A, White J, Minasian L, Juliana MM, Boring DL, Steele VE, Grubbs CJ. Prevention of chemically induced urinary bladder cancers by naproxen: protocols to reduce gastric toxicity in humans do not alter preventive efficacy. Cancer Prev Res. 2015; 8(4): 297-302. [CrossRef]

[6] Kömürcü ŞG, Rollas S, Ulgen M, Gorrod JW, Cevikbaş A. Evaluation of some arylhydrazones of p-aminobenzoic acid hydrazide as antimicrobial agents and their in-vitro hepatic microsomal metabolism. Boll Chim Farmaceutico. 1995; 134: 375-379.

[7] Küçükgüzel ŞG, Oruc EE, Rollas S, Şahin F, Ozbek A. Synthesis, characterization and biological activity of novel 4- thiazolidinones, 1,3,4-oxadiazoles and some related compounds. Eur J Med Chem. 2002; 37: 197-206. [CrossRef]

[8] Küçükgüzel ŞG, Mazı A, Şahin F, Ozturk S, Stables J. Synthesis and biological activities of diflunisal hydrazidehydrazones. Eur J Med Chem. 2003; 38: 1005-1013. [CrossRef]

[9] Rollas S, Küçükgüzel ŞG. Biological activities of hydrazone derivatives. Molecules. 2007; 12: 1910-1939. [CrossRef]

[10] Çıkla P, Özsavcı D, Bingöl Özakpınar Ö, Şener A, Çevik O, Özbaş Turan S, Akbuğa J, Şahin F, Küçükgüzel ŞG. Synthesis, cytotoxicity and pro-apoptosis of etodolac hydrazide derivatives as anticancer agents. Arch Pharm. 2013; 346: 367-379. [CrossRef]

[11] Çıkla P, Tatar E, Küçükgüzel İ, Şahin F, Yurdakul D, Basu A, Krishnan R, Nichols DB, Basu NK, Küçükgüzel ŞG. Synthesis and characterization of flurbiprofen hydrazide derivatives as potential anti-HCV, anticancer, antimicrobial agents. Med Chem Res. 2013; 22: 5685-5699. [CrossRef]

[12] Aydın S, Basu NK, Arora P, Basu A, Nichols DB, Talele TT, Akkurt M, Celik İ, Buyukgungor O, Küçükgüzel ŞG. Microwave assisted synthesis of some novel flurbiprofen hydrazide-hydrazones as anti-HCV NS5B and anticancer agents. Marmara Pharm J. 2013; 17: 26-34. [CrossRef]

[13] Küçükgüzel ŞG, Koc D, Cıkla P, Özsavcı D, Ozakpınar OB, Tiber PM, Orun O, Erzincan P, Erdem SS, Şahin F. Synthesis of tolmetin hydrazide-hydrazones and discovery of a potent apoptosis inducer in colon cancer cells. Arch Pharm. 2015; 348: 730-742. [CrossRef]

[14] Şenkardeş S, Basu NK, Durmaz İ, Manvar D, Basu A, Atalay R, Küçükgüzel ŞG. Synthesis of novel diflunisal hydrazide-hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors. Eur J Med Chem. 2016; 108: 301-308. [CrossRef]

[15] Sarıözkan S, Gaffari T, Pelin CS, Güvenç M, Yüce A, Yay A, Cantürk F, Küçükgüzel ŞG. Effect of etodolac hydrazone, a new compound synthesized from etodolac, on sperm quality, testicular lipid peroxidation, apoptosis and sperm DNA integrity. Andrologia. 2016; 48: 177-88. [CrossRef]

[16] Tatar E, Şenkardeş S, Sellitepe HE, Küçükgüzel ŞG, Karaoğlu ŞA, Bozdeveci A, De Clercq E, Pannecouque C, Hadda TB, Kucukguzel İ. Synthesis, and prediction of molecular properties and antimicrobial activity of some acylhydrazones derived from N-(arylsulfonyl)methionine. Turk J Chem. 2016; 40: 510-34. [CrossRef]

[17] Tok F, Beyhan N, Erzurumlu Y, İlhan R, Ballar P, Kaymakcıoğlu BK. Antiproliferative activity of some tautomeric hydrazones derived from chalcones. Marmara Pharm J. 2016; 20: 157-163. [CrossRef]

[18] Keogh A, Şenkardeş S, Idle JR, Küçükgüzel ŞG, Beyoğlu D. A novel anti-hepatitis C virus and antiproliferative agent alters metabolic networks in HepG2 and Hep3B Cells. Metabolites. 2017; 7: 2-16. [CrossRef]

[19] Popiołek L, Biernasiuk A. Synthesis and investigation of antimicrobial activities of nitrofurazone analogues containing hydrazide-hydrazone moiety. Saudi Pharm J. 2017; 25: 1097-1102. [CrossRef]

[20] Küçükgüzel ŞG, Küçükgüzel İ, Tatar E, Rollas S, Şahin F, Güllüce M, De Clercq E, Kabasakal L. Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agent. Eur J Med Chem. 2007; 42: 893-901. [CrossRef]

[21] Mentese MY, Bayrak H, Uygun Y, Mermer A, Ülker S, Karaoğlu SA, Demirbaş N. Microwave assisted synthesis of some hybrid molecules derived from norfloxacin and investigation of their biological activities. Eur J Med Chem. 2013; 67: 230-242. [CrossRef]

[22] Kaplancıklı ZA, Yurttaş L, Özdemir A, Turan-Zitouni G, Çiftci GA, Yıldırım SU, Mohsen UA. Synthesis and antiproliferative activity of new 1,5-disubstituted tetrazoles bearing hydrazone moiety. Med Chem Res. 2014; 23: 1067–1075. [CrossRef]

[23] Küçükgüzel ŞG, Çıkla Süzgün P. Recent advances bioactive 1,2,4-triazole-3-thiones. Eur J Med Chem. 2015; 97: 830- 870. [CrossRef]

[24] Çıkla Süzgün P, Basu NK, Basu A, Arora P, Talele TT, Durmaz İ, Çetin Atalay R, Küçükgüzel ŞG. Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles. J Enzyme Inhib Med Chem. 2015; 30(5): 778-785. [CrossRef]

[25] Tatar E, Küçükgüzel ŞG, Karakuş S, De Clercq E, Andrei G, Snoeck R, Pannecouque C, Okullu SÖ, Ünübol N, Kocagöz T, Kalaycı, Şahin F, Küçükgüzel İ. Synthesis and biological evaluation of some new 1,3,4-thiadiazole and 1,2,4-triazole derivatives from L-methionine as antituberculosis and antiviral agents. Marmara Pharm J. 2015; 19: 88-102. [CrossRef]

[26] Kulabaş N, Tatar E, Özakpınar ÖB, Özsavcı D, Pannecouque C, De Clerck E, Küçükgüzel İ. Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4- triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells. Eur J Med Chem. 2016; 121: 58-70. [CrossRef]

[27] Harrington PJ, Lodewijk E. Twenty Years of Naproxen Technology. Organic Process Research & Development 1997; 1: 72-76.

[28] European Pharmacopoeia 7.0, Monographs N-O, p.2554-2555.

[29] Cumaoğlu A, Dayan S, Agkaya AO, Özkul Z, Özpozan NK, Synthesis and pro-apoptotic effects of new sulfonamide derivatives via activating p38/ERK phosphorylation in cancer cells. J Enzyme Inhib Med Chem. 2015; 30(3): 413-419. [CrossRef]

[30] http://www.molinspiration.com (accessed March 14, 2018)

[31] Zhao Y, Abraham MH, Lee J, Hersey A, Luscombe NC, Beck G, Sherborne B, Cooper I. Rate-limited steps of human oral absorption and QSAR studies. Pharm Res. 2002; 19: 1446-1457.

[32] Harrison IT, Lewis B, Nelson P, Rooks W, Roszkowski A, Tomolonis A, Fried JH. Nonsteroidal antiinflammatory agents. I. 6- Substituted 2-naphthylacetic acids. J Med Chem. 1970; 13 (2): 203-205.

[33] Amir M, Kumar H, Javed SA. Non-carboxylic analogues of naproxen: design, synthesis, and pharmacological evaluation of some 1,3,4-oxadiazole/ thiadiazole and 1,2,4-triazole derivatives. Arch Pharm Chem Life Sci. 2007; 340: 577-585. [CrossRef]