Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates

Demirbolat, ilker; Yelekci, Kemal; Bingöl Özakpınar, Özlem; Ogan, Ayse; Liu, Jianyang; Jakobson, Per-Johan; kulabaş, necla; GURBOGA, MERVE; ÇİFTÇİ, GAMZE; Danış, Özkan; Küçükgüzel, İlkay

doi:10.25135/acg.oc.142.2212.2651

Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates

İlker DEMİRBOLAT, (Bezmialem Vakıf Üniversitesi, Bezmialem Fitoterapi Eğitim, Uygulama ve Araştırma Merkezi, İstanbul, Türkiye)

Necla KULABAŞ, (Marmara Üniversitesi, Eczacılık Fakültesi, Farmasötik Kimya Anabilim Dalı, İstanbul, Türkiye)

MERVE GURBOGA, (Marmara Üniversitesi, Eczacılık Fakültesi, Biyokimya Anabilim Dalı, İstanbul, Türkiye)

Özlem BİNGÖL ÖZAKPINAR, (Marmara Üniversitesi, Eczacılık Fakültesi, Biyokimya Anabilim Dalı, İstanbul, Türkiye)

Gamze ÇİFTÇİ, (Kadir Has Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümü, İstanbul, Türkiye)

Kemal YELEKÇİ, (Kadir Has Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümü, İstanbul, Türkiye)

Jianyang Liu, (Karolinska Institutet & Karolinska University Hospital, Rheumatology Division, Department of Medicine, Stockholm, Sweden)

Per-Johan Jakobson, (Karolinska Institutet & Karolinska University Hospital, Rheumatology Division, Department of Medicine, Stockholm, Sweden)

Özkan DANIŞ, (Marmara Üniversitesi, Fen Fakültesi, Kimya Bölümü, İstanbul, Türkiye)

Ayse OGAN, (Marmara Üniversitesi, Fen Fakültesi, Kimya Bölümü, İstanbul, Türkiye)

İlkay KÜÇÜKGÜZEL, (Marmara Üniversitesi, Eczacılık Fakültesi, Farmasötik Kimya Anabilim Dalı, İstanbul, Türkiye)

Diğer Yazarlar

Organic Communications

5 1

Yıl: 2022 Cilt: 15 Sayı: 4 Sayfa Aralığı: 356 - 377 Metin Dili: İngilizce DOI: 10.25135/acg.oc.142.2212.2651 İndeks Tarihi: 16-05-2023

Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates

Öz:

Some novel triazole-bearing acetamide derivatives 9-26 were synthesized starting from carvacrol. All synthesized compounds were characterized by FTIR, 1H-NMR, 13C-NMR and MS data. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human chronic myelogenous leukemia K562, human neuroblastoma SH-SY5Y cell lines) were evaluated by MTT assay. Compounds were also tested on mouse embryonic fibroblast cells (NIH/3T3) to determine selectivity. Eighteen target compounds 9-26 were screened for their mPGES-1 and COX-1/2 inhibitory activities. Of these compounds, 26 (KUC16D425) showed the highest mPGES-1 inhibition at 10 μM. This compound has also been observed to induce apoptosis and inhibit cell migration in MCF-7 cells. In silico molecular docking calculations were performed to understand the binding interactions of compounds with target proteins. ADMET predictions were also done to evaluate drug-like properties of the novel compounds.

Anahtar Kelime:

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

[1] Kamel, M. M.; Megally Abdo, N. Y. Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents. Eur. J. Med. Chem. 2014, 86, 75–80.
[2] Khazir, J.; Hyder, I.; Gayatri, J.; Prasad, L.; Nalla, N.; Chasoo, G.; Mahajan, A.; Saxena, A. K.; Alam, M. S.; Qazi, G. N.; Sampath, H. M. Design and synthesis of novel 1,2,3-triazole derivatives of coronopilin as anti-cancer compounds. Eur. J. Med. Chem. 2014, 82, 255–262.
[3] Santucci, C.; Carioli, G.; Bertuccio, P.; Malvezzi, M.; Pastorino, U.; Boffetta, P.; Negri, E.; Bosetti, C.; La Vecchia, C. Progress in cancer mortality, incidence, and survival: a global overview. Eur. J. Cancer Prev. 2020, 29 (5), 367–381.
[4] Panathur, N.; Dalimba, U.; Venkat, P.; Alvala, M.; Yogeeswari, P.; Sriram, D.; Kumar, V. Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition. Eur. J. Med. Chem. 2013, 69, 125–138.
[5] Kulabaş, N.; Tatar, E.; Bingöl Özakpınar, Ö.; Özsavcı, D.; Pannecouque, C.; De Clercq, 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.
[6] Ruan, D.; So, D. R. Prostaglandin E2 produced by inducable COX-2 and MPGEs-1 promoting cancer cell proliferation in vitro and in vivo. Life Sci. 2014, 116 (1), 43–50.
[7] Bülbül, B.; Küçükgüzel, İ. Microsomal prostaglandin E2 synthase-1 as a new macromolecular drug target in the prevention of inflammation and cancer. Anticancer. Agents Med. Chem. 2019, 19 (10), 1205–1222.
[8] Sasaki, Y.; Nakatani, Y.; Hara, S. Role of microsomal prostaglandin E synthase-1 (MPGES-1)-derived prostaglandin E2 in colon carcinogenesis. Prostaglandins Other Lipid Mediat. 2015, 121, 42–45.
[9] Chang, H. H.; Song, Z.; Wisner, L.; Tripp, T.; Gokhale, V.; Meuillet, E. J. Identification of a novel class of anti-inflammatory compounds with anti-tumor activity in colorectal and lung cancers. Invest. New Drugs. 2012, 30, 1865–1877.
[10] Howe, L. R.; Subbaramaiah, K.; Kent, C. V.; Zhou, X. K.; Chang, S. H.; Hla, T.; Jakobsson, P. J.; Hudis, C. A.; Dannenberg, A. J. Genetic deletion of microsomal prostaglandine synthase-1 suppresses mouse mammary tumor growth and angiogenesis. Prostaglandins Other Lipid Mediat. 2013, 106, 99– 105.
[11] Hanaka, H.; Pawelzik, S. C.; Johnsen, J. I.; Rakonjac, M.; Terawaki, K.; Rasmuson, A.; Sveinbjörnsson, B.; Schumacher, M. C.; Hamberg, M.; Samuelsson, B.; Jakobsson, P. J.; Kogner, P.; Rådmark, O. Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells. Proc. Natl. Acad. Sci. 2009, 106, 18757–18762.
[12] Van Rees, B. P.; Sivula, A.; Thorén, S.; Yokozaki, H.; Jakobsson, P. J.; Offerhaus, G. J. A.; Ristimäki, A. Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines. Int. J. Cancer 2003, 107, 551–556.
[13] Kock, A.; Larsson, K.; Bergqvist, F.; Eissler, N.; Elfman, L. H. M.; Raouf, J.; Korotkova, M.; Johnsen, J. I.; Jakobsson, P. J.; Kogner, P. Inhibition of microsomal prostaglandin E synthase-1 in cancerassociated fibroblasts suppresses neuroblastoma tumor growth. eBioMedicine 2018, 32, 84–92.
[14] Jakobsson, P.-. J.; Thoren, S.; Morgenstern, R.; Samuelsson, B. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc. Natl. Acad. Sci. 1999, 96, 7220–7225.
[15] Finetti, F.; Terzuoli, E.; Bocci, E.; Coletta, I.; Polenzani, L.; Mangano, G.; Al-isi, M. A.; Cazzolla, N.; Giachetti, A.; Ziche, M.; Donnini, S. Pharmacological inhibition of microsomal prostaglandin E synthase-1 suppresses epidermal growth factor receptor-mediated tumor growth and angiogenesis. PLoS One 2012, 7 (7), e40576.
[16] Li, Y.; Yin, S.; Nie, D.; Xie, S.; Ma, L.; Wang, X.; Wu, Y.; Xiao, J. MK886 inhibits the proliferation of HL-60 leukemia cells by suppressing the expression of MPGES-1 and reducing prostaglandin E2 synthesis. Int. J. Hematol. 2011, 94 (5), 42–478.
[17] Bergqvist, F.; Ossipova, E.; Idborg, H.; Raouf, J.; Checa, A.; Englund, K.; Englund, P.; Khoonsari, P. E.; Kultima, K.; Wheelock, C. E.; Larsson, K.; Korotkova, M.; Jakobsson, P. J. Inhibition of MPGES- 1 or COX-2 results in different proteomic and lipidomic profiles in A549 lung cancer cells. Front. Pharmacol. 2019, 10 (June), 1–15.
[18] Larsson, K.; Kock, A.; Idborg, H.; Arsenian Henriksson, M.; Martinsson, T.; Johnsen, J. I.; Korotkova, M.; Kogner, P.; Jakobsson, P.-J. COX/MPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. Proc. Natl. Acad. Sci. 2015, 112, 8070–8075.
[19] Nakanishi, M.; Rosenberg, D. W. Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol. 2013, 35, 123–137.
[20] Olesch, C.; Sha, W.; Angioni, C.; Sha, L. K.; Acaf, E.; Patrignani, P.; Jakobsson, P. J.; Radeke, H. H.; Grosch, S.; Geisslinger, G.; von Knethen, A.; Weigert, A.; Brune, B. MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. Oncotarget 2015, 6, 10284–10296.
[21] Nakanishi, M.; Menoret, A.; Tanaka, T.; Miyamoto, S.; Montrose, D. C.; Vella, A. T.; Rosenberg, D. W. Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity. Cancer Prev. Res. 2011, 4, 1198–1208.
[22] Küçükgüzel, I.; Küçükgüzel, S. G.; Rollas, S.; Kiraz, M. Some 3-thioxo/alkylthio-1,2,4-triazoles with a substituted thiourea moiety as possible antimycobacterials. Bioorg. Med. Chem. Lett. 2001, 11 (13), 1703–1707.
[23] Küçükgüzel, S. G.; Küçükgüzel, I.; Tatar, E.; Rollas, S.; Sahin, 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 agents. Eur. J. Med. Chem. 2007, 42 (7), 893–901.
[24] He, S.; Li, C.; Liu, Y.; Lai, L. Discovery of highly potent microsomal prostaglandin E2 synthase 1 inhibitors using the active conformation structural model and virtual screen. J. Med. Chem. 2013, 56 (8), 3296–3309.
[25] Erensoy, G.; Ding, K.; Zhan, C. G.; Çiftçi, G.; Yelekçi, K.; Duracık, M.; Bingöl Özakpınar, Ö.; Aydemir, E.; Yılmaz, Z. N.; Şahin, F.; Kulabaş, N.; Tatar, E.; Küçükgüzel, İ. Synthesis, in vitro and in silico studies on novel 3-Aayloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as potent inhibitors of MPGES-1. J. Mol. Struct. 2023, 1272, 134154.
[26] Bülbül, B.; Ding, K.; Zhan, C. G.; Çiftçi, G.; Yelekçi, K.; Gürboğa, M.; Özakpınar, Ö. B.; Aydemir, E.; Baybağ, D.; Şahin, F.; Kulabaş, N.; Helvacıoğlu, S.; Charehsaz, M.; Tatar, E.; Özbey, S.; Küçükgüzel, İ. Novel 1,2,4-Triazoles derived from ibuprofen: synthesis and in vitro evaluation of their MPGES-1 inhibitory and antiproliferative activity. Mol. Divers. 2022, (Early Access).
[27] Al-Hussain, S. A.; Farghaly, T. A.; Zaki, M. E. A.; Abdulwahab, H. G.; Al-Qurashi, N. T.; Muhammad, Z. A. Discovery of novel indolyl-1,2,4-triazole hybrids as potent vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with potential anti-renal cancer activity. Bioorg. Chem. 2020, 105 (July), 104330.
[28] Zengin, M.; Unsal Tan, O.; Arafa, R. K.; Balkan, A. Design and synthesis of new 2-oxoquinoxalinyl- 1,2,4-triazoles as antitumor VEGFR-2 inhibitors. Bioorg. Chem. 2022, 121, 105696.
[29] Sharifi-Rad, M.; Varoni, E. M.; Iriti, M.; Martorell, M.; Setzer, W. N.; Del Mar Contreras, M. Salehi, B., Soltani-Nejad, A., Rajabi, S., Tajbakhsh, M., & Sharifi-Rad, J. Carvacrol and human health: a comprehensive review. Phyther. Res. 2018, 32 (9), 1675–1687.
[30] Kordali, S.; Cakir, A.; Ozer, H.; Ckamakcı, R.; Kesdek, M.; Mete, E. Antifungal, phytotoxic and insecticidal proporteis of essentiaol oil isolated turkish orifanum acutidens and its three components carvacrol, thymol and p-cymene. Bioresour. Technol. 2008, 99, 8788–8795.
[31] Guarda, A.; Rubilar, J. F.; Miltz, J.; Galotto, M. J. The antimicrobial activity of microencapsulated thymol and carvacrol. Int. J. Food Microbiol. 2011, 146, 144-150.
[32] Ghomi, J. S.; Ebrahimabadi, A. H.; Bidgoli, Z. D.; Batooli, H. GC/MS analysis and in vitro antioxidant activity of essantial oil and methanol extracts of thymus caramicus jalas and its main constituent carvacrol. Food Chem. 2009, 115, 1524–1528.
[33] Yin, Q. H.; Yan, F. X.; Zu, X. Y.; Wu, Y. H.; Wu, X. P.; Liao, M. C.; Deng, S. W.; Yin, L. I.; Zhuang, Y. Z. Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2. Cytotechnology 2012, 64, 43–51.
[34] Fan, K.; Xiaolei, L.; Cao, Y.; Qi, H.; Li, L.; Zhang, Q.; Sun, H. Carvacrol inhibits proliferation and induces apoptosis in human colon cancer cells. Anticancer. Drugs 2015, 26 (8), 813–823.
[35] Günes-Bayır, A.; Kızıltan, H. S.; Kocyigit, A.; Güler, E. M.; Karatas, E.; Toprak, A. Effects of natural phenolic compound carvacrol on the human gastric adenocarcinoma (AGS) cells in vitro. Anticancer. Drugs 2017, 28, 522–530.
[36] Landa, P.; Kokoska, L.; Pribylova, M.; Vanek, T.; Marsik, P. In vitro anti-inflammatory activity of carvacrol: inhibitory effect on COX-2 catalyzed prostaglandin E2 biosynthesis. Arch. Pharm. Res. 2009, 32, 75–78.
[37] Lima, M. D. S.; Quintans-Junior, L.; Santana, W. A. D.; Kaneto, C. M.; Soaers, M. B. P.; Villareal, C. F. Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur. J. Pharmacol. 2013, 699, 112–117.
[38] Khan, F.; Singh, V. K.; Saeed, M.; Kausar, M. A.; Ansari, I. A. Carvacrol Induced program cell death and cell cycle arrest in androgen-independent human prostate cancer cells via inhibition of notch signaling. Anticancer. Agents Med. Chem. 2019, 19 (13), 1588–1608.
[39] Li, L.; He, L.; Wu, Y.; Zhang, Y. Carvacrol affects breast cancer cells through TRPM7 mediated cell cycle regulation. Life Sci. 2021, 266, 118894.
[40] Kulabaş, N.; Türe, A.; Bozdeveci, A.; Krishna, V. S.; Alpay Karaoğlu, Ş.; Sriram, D.; Küçükgüzel, İ. Novel fluoroquinolones containing 2-arylamino-2-oxoethyl fragment: design, synthesis, evaluation of antibacterial and antituberculosis activities and molecular modeling studies. J. Heterocycl. Chem. 2022, 59 (5), 909–926.
[41] Demirci, A.; Karayel, K. G.; Tatar, E.; Okullu, S. Ö.; Unübol, N.; Taşli, P. N.; Kocagöz, Z. T.; Sahin, F.; Küçükgüzel, I. Synthesis and evaluation of novel 1,3,4-thiadiazole–fluoroquinolone hybrids
[42] Şenkardeş, S.; Han, M. İ.; Kulabaş, N.; Abbak, M.; Çevik, Ö.; Küçükgüzel, İ.; Küçükgüzel, Ş. G. Synthesis, molecular docking and evaluation of novel sulfonyl hydrazones as anticancer agents and COX-2 inhibitors. Mol. Divers. 2020, 24 (3), 673–689.
[43] Larsson, K.; Steinmetz, J.; Bergqvist, F.; Arefin, S.; Spahiu, L.; Wannberg, J.; Pawelzik, S. C.; Morgenstern, R.; Stenberg, P.; Kublickiene, K.; Korotkova, M.; Jakobsson, P. J. Biological Characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br. J. Pharmacol. 2019, 176 (24), 4625–4638.
[44] Kuklish, S. L.; Antonysamy, S.; Bhattachar, S. N.; Chandrasekhar, S.; Fisher, M. J.; Fretland, A. J.; Gooding, K.; Harvey, A.; Hughes, N. E.; Luz, J. G.; Manninen, P. R.; McGee, J. E.; Navarro, A.; Norman, B. H.; Partridge, K. M.; Quimby, S. J.; Schiffler, M. A.; Sloan, A. V.; Warshawsky, A. M.; York, J. S.; Yu, X. P. Characterization of 3,3-dimethyl substituted n-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Bioorganic Med. Chem. Lett. 2016, 26 (19), 4824– 4828
[45] Cingolani, G.; Panella, A.; Perrone, M. G.; Vitale, P.; Di Mauro, G.; Fortuna, C. G.; Armen, R. S.; Ferorelli, S.; Smith, W. L.; Scilimati, A. Structural basis for selective inhibition of cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6). Eur. J. Med. Chem. 2017, 138, 661–668.
[46] Duggan, K. C.; Walters, M. J.; Musee, J.; Harp, J. M.; Kiefer, J. R.; Oates, J. A.; Marnett, L. J. Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen. J. Biol. Chem. 2010, 285 (45), 34950–34959.
[47] Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. Software news and updates gabedit — a graphical user interface for computational chemistry softwares. J. Comput. Chem. 2009, 30 (16), 174–182.
[48] Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem. 1998, 19 (14), 1639–1662.
[49] Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, druglikeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 1–13.
[50] Sander, T.; Freyss, J.; Von Korff, M.; Rufener, C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model. 2015, 55 (2), 460–473.
[51] Tatar, E.; Küçükgüzel, G.; Karakuş, S.; de Clercq, E.; Andrei, G.; Snoeck, R.; Pannecouque, C.; Öktem Okullu, S.; Ünübol, N.; Kocagöz, T.; Kalayci, S.; Şahİn, 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 (2), 88–102.
[52] Othman, E. M.; Fayed, E. A.; Husseiny, E. M.; Abulkhair, H. S. Apoptosis induction, PARP-1 Inhibition, and cell cycle analysis of leukemia cancer cells treated with novel synthetic 1,2,3-triazolechalcone conjugates. Bioorg. Chem. 2022, 123, 105762.
[53] Othman, E. M.; Fayed, E. A.; Husseiny, E. M.; Abulkhair, H. S. The effect of novel synthetic semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles on the apoptotic markers, VEGFR-2, and cell cycle of myeloid leukemia. Bioorg. Chem. 2022, 127, 105968.
[54] Özsavcı, D.; Erşahin, M.; Şener, A.; Bingöl Özakpinar, Ö.; Zorlu Toklu, H.; Akakín, D.; Şener, G.; Yeğen, B. Ç. The novel function of Nesfatin-1 as an anti-inflammatory and antiapoptotic peptide in subarachnoid hemorrhage-induced oxidative brain damage in rats. Neurosurgery 2011, 68, 1699–1708.
[55] Khurana, P.; Jachak, S. M. Chemistry and biology of microsomal prostaglandin E2 synthase-1 (MPGES-1) Inhibitors as novel anti-inflammatory agents: recent developments and current status. RSC Adv. 2016, 6 (34), 28343–28369.
[56] Zhao, Y. H.; Abraham, M. H.; Le, J.; Hersey, A.; Luscombe, C. N.; Beck, G.; Sherborne, B.; Cooper, I. Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res. 2002, 19 (10), 1446– 1457.

APA	Demirbolat i, kulabaş n, GURBOGA M, Bingöl Özakpınar Ö, ÇİFTÇİ G, Yelekci K, Liu J, Jakobson P, Danış Ö, Ogan A, Küçükgüzel İ (2022). Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. , 356 - 377. 10.25135/acg.oc.142.2212.2651
Chicago	Demirbolat ilker,kulabaş necla,GURBOGA MERVE,Bingöl Özakpınar Özlem,ÇİFTÇİ GAMZE,Yelekci Kemal,Liu Jianyang,Jakobson Per-Johan,Danış Özkan,Ogan Ayse,Küçükgüzel İlkay Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. (2022): 356 - 377. 10.25135/acg.oc.142.2212.2651
MLA	Demirbolat ilker,kulabaş necla,GURBOGA MERVE,Bingöl Özakpınar Özlem,ÇİFTÇİ GAMZE,Yelekci Kemal,Liu Jianyang,Jakobson Per-Johan,Danış Özkan,Ogan Ayse,Küçükgüzel İlkay Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. , 2022, ss.356 - 377. 10.25135/acg.oc.142.2212.2651
AMA	Demirbolat i,kulabaş n,GURBOGA M,Bingöl Özakpınar Ö,ÇİFTÇİ G,Yelekci K,Liu J,Jakobson P,Danış Ö,Ogan A,Küçükgüzel İ Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. . 2022; 356 - 377. 10.25135/acg.oc.142.2212.2651
Vancouver	Demirbolat i,kulabaş n,GURBOGA M,Bingöl Özakpınar Ö,ÇİFTÇİ G,Yelekci K,Liu J,Jakobson P,Danış Ö,Ogan A,Küçükgüzel İ Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. . 2022; 356 - 377. 10.25135/acg.oc.142.2212.2651
IEEE	Demirbolat i,kulabaş n,GURBOGA M,Bingöl Özakpınar Ö,ÇİFTÇİ G,Yelekci K,Liu J,Jakobson P,Danış Ö,Ogan A,Küçükgüzel İ "Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates." , ss.356 - 377, 2022. 10.25135/acg.oc.142.2212.2651
ISNAD	Demirbolat, ilker vd. "Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates". (2022), 356-377. https://doi.org/10.25135/acg.oc.142.2212.2651

APA	Demirbolat i, kulabaş n, GURBOGA M, Bingöl Özakpınar Ö, ÇİFTÇİ G, Yelekci K, Liu J, Jakobson P, Danış Ö, Ogan A, Küçükgüzel İ (2022). Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. Organic Communications, 15(4), 356 - 377. 10.25135/acg.oc.142.2212.2651
Chicago	Demirbolat ilker,kulabaş necla,GURBOGA MERVE,Bingöl Özakpınar Özlem,ÇİFTÇİ GAMZE,Yelekci Kemal,Liu Jianyang,Jakobson Per-Johan,Danış Özkan,Ogan Ayse,Küçükgüzel İlkay Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. Organic Communications 15, no.4 (2022): 356 - 377. 10.25135/acg.oc.142.2212.2651
MLA	Demirbolat ilker,kulabaş necla,GURBOGA MERVE,Bingöl Özakpınar Özlem,ÇİFTÇİ GAMZE,Yelekci Kemal,Liu Jianyang,Jakobson Per-Johan,Danış Özkan,Ogan Ayse,Küçükgüzel İlkay Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. Organic Communications, vol.15, no.4, 2022, ss.356 - 377. 10.25135/acg.oc.142.2212.2651
AMA	Demirbolat i,kulabaş n,GURBOGA M,Bingöl Özakpınar Ö,ÇİFTÇİ G,Yelekci K,Liu J,Jakobson P,Danış Ö,Ogan A,Küçükgüzel İ Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. Organic Communications. 2022; 15(4): 356 - 377. 10.25135/acg.oc.142.2212.2651
Vancouver	Demirbolat i,kulabaş n,GURBOGA M,Bingöl Özakpınar Ö,ÇİFTÇİ G,Yelekci K,Liu J,Jakobson P,Danış Ö,Ogan A,Küçükgüzel İ Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates. Organic Communications. 2022; 15(4): 356 - 377. 10.25135/acg.oc.142.2212.2651
IEEE	Demirbolat i,kulabaş n,GURBOGA M,Bingöl Özakpınar Ö,ÇİFTÇİ G,Yelekci K,Liu J,Jakobson P,Danış Ö,Ogan A,Küçükgüzel İ "Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates." Organic Communications, 15, ss.356 - 377, 2022. 10.25135/acg.oc.142.2212.2651
ISNAD	Demirbolat, ilker vd. "Synthesis and evaluation of antiproliferative and mPGES-1 inhibitory activities of novel carvacrol-triazole conjugates". Organic Communications 15/4 (2022), 356-377. https://doi.org/10.25135/acg.oc.142.2212.2651