Synthesis, Anticancer Activity on Prostate Cancer Cell Lines and Molecular Modeling Studies of Flurbiprofen-Thioether Derivatives as Potential Target of MetAP (Type II)

Author(s): Özgür Yılmaz, Burak Bayer, Hatice Bekçi, Abdullahi I. Uba, Ahmet Cumaoğlu, Kemal Yelekçi, Ş. Güniz Küçükgüzel*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Prostate cancer is still one of the serious causes of mortality and morbidity in men. Despite recent advances in anticancer therapy, there is a still need of novel agents with more efficacy and specificity in the treatment of prostate cancer. Because of its function on angiogenesis and overexpression in the prostate cancer, methionine aminopeptidase-2 (MetAP-2) has been a potential target for novel drug design recently.

Objective: A novel series of Flurbiprofen derivatives N-(substituted)-2-(2-(2-fluoro-[1,1'- biphenyl]-4-il)propanoyl)hydrazinocarbothioamide (3a-c), 4-substituted-3-(1-(2-fluoro-[1,1'-biphenyl]- 4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (4a-d), 3-(substitutedthio)-4-(substituted-phenyl)- 5-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4H-1,2,4-triazole (5a-y) were synthesized. The purpose of the research was to evaluate these derivatives against MetAP-2 in vitro and in silico to obtain novel specific and effective anticancer agents against prostate cancer.

Methods: The chemical structures and purities of the compounds were defined by spectral methods (1H-NMR, 13C-NMR, HR-MS and FT-IR) and elemental analysis. Anticancer activities of the compounds were evaluated in vitro by using MTS method against PC-3 and DU-143 (androgenindependent human prostate cancer cell lines) and LNCaP (androgen-sensitive human prostate adenocarcinoma) prostate cancer cell lines. Cisplatin was used as a positive sensitivity reference standard.

Results: Compounds 5b and 5u; 3c, 5b and 5y; 4d and 5o showed the most potent biological activity against PC3 cancer cell line (IC50= 27.1 μM, and 5.12 μM, respectively), DU-145 cancer cell line (IC50= 11.55 μM, 6.9 μM and 9.54 μM, respectively) and LNCaP cancer cell line (IC50= 11.45 μM and 26.91 μM, respectively). Some compounds were evaluated for their apoptotic caspases protein expression (EGFR/PI3K/AKT pathway) by Western blot analysis in androgen independent- PC3 cells. BAX, caspase 9, caspsase 3 and anti-apoptotic BcL-2 mRNA levels of some compounds were also investigated. In addition, molecular modeling studies of the compounds on MetAP-2 enzyme active site were evaluated in order to get insight into binding mode and energy.

Conclusion: A series of Flurbiprofen-thioether derivatives were synthesized. This study presented that some of the synthesized compounds have remarkable anticancer and apoptotic activities against prostate cancer cells. Also, molecular modeling studies exhibited that there is a correlation between molecular modeling and anticancer activity results.

Keywords: EGFR/PI3K/AKT pathway, LNCaP, flurbiprofen, thioether, methionine aminopeptidase, prostate cancer.

[1]
Wechter, W.J.; Kantoci, D.; Murray, E.D., Jr; Quiggle, D.D.; Leipold, D.D.; Gibson, K.M.; McCracken, J.D. R-flurbiprofen chemoprevention and treatment of intestinal adenomas in the APC(Min)/+ mouse model: implications for prophylaxis and treatment of colon cancer. Cancer Res., 1997, 57(19), 4316-4324.
[PMID: 9331093]
[2]
Wechter, W.J.; Leipold, D.D.; Murray, E.D., Jr; Quiggle, D.; McCracken, J.D.; Barrios, R.S.; Greenberg, N.M. E-7869 (R flurbiprofen) inhibits progression of prostate cancer in the TRAMP mouse. Cancer Res., 2000, 60(8), 2203-2208.
[PMID: 10786685]
[3]
Aydın, S.; Talele, T.T.; Kaushik-Basu, N.; Akkurt, M.; Arora, P.; Çelik, İ.; Basu, A.; Büyükgüngör, O.; Nichols, D.B.; Küçükgüzel, Ş.G. Microwave assisted synthesis of some novel Flurbiprofen hydrazidehydrazones as anti-HCV NS5B and anticancer agents. Marmara Pharm. J., 2013, 17, 26-34.
[http://dx.doi.org/10.12991/201317389]
[4]
Çıkla, P.; Tatar, E.; Küçükgüzel, İ.; Şahin, F.; Yurdakul, D.; Basu, A.; Krishnan, R.; Nichols, D.B.; Kaushik-Basu, N.; Küçükgüzel, Ş.G. Synthesis and characterization of flurbiprofen hydrazide derivatives as potential anti-HCV, anticancer and antimicrobial agents. Med. Chem. Res., 2013, 22(12), 5685-5699.
[http://dx.doi.org/10.1007/s00044-013-0550-3]
[5]
Varland, S.; Osberg, C.; Arnesen, T. N-terminal modifications of cellular proteins: The enzymes involved, their substrate specificities and biological effects. Proteomics, 2015, 15(14), 2385-2401.
[http://dx.doi.org/10.1002/pmic.201400619] [PMID: 25914051]
[6]
Datta, B.; Datta, R. Induction of apoptosis due to lowering the level of eukaryotic initiation factor 2-associated protein, p67, from mammalian cells by antisense approach. Exp. Cell Res., 1999, 246(2), 376-383.
[http://dx.doi.org/10.1006/excr.1998.4313] [PMID: 9925753]
[7]
Turk, B.E.; Griffith, E.C.; Wolf, S.; Biemann, K.; Chang, Y-H.; Liu, J.O. Selective inhibition of amino-terminal methionine processing by TNP-470 and ovalicin in endothelial cells. Chem. Biol., 1999, 6(11), 823-833.
[http://dx.doi.org/10.1016/S1074-5521(99)80129-X] [PMID: 10574784]
[8]
Selvakumar, P.; Lakshmikuttyamma, A.; Kanthan, R.; Kanthan, S.C.; Dimmock, J.R.; Sharma, R.K. High expression of methionine aminopeptidase 2 in human colorectal adenocarcinomas. Clin. Cancer Res., 2004, 10(8), 2771-2775.
[http://dx.doi.org/10.1158/1078-0432.CCR-03-0218] [PMID: 15102683]
[9]
Selvakumar, P.; Lakshmikuttyamma, A.; Dimmock, J.R.; Sharma, R.K. Methionine aminopeptidase 2 and cancer. Biochim. Biophys. Acta, 2006, 1765(2), 148-154.
[PMID: 16386852]
[10]
Sin, N.; Meng, L.; Wang, M.Q.; Wen, J.J.; Bornmann, W.G.; Crews, C.M. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc. Natl. Acad. Sci. USA, 1997, 94(12), 6099-6103.
[http://dx.doi.org/10.1073/pnas.94.12.6099] [PMID: 9177176]
[11]
Griffith, E.C.; Su, Z.; Turk, B.E.; Chen, S.; Chang, Y.H.; Wu, Z.; Biemann, K.; Liu, J.O. Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chem. Biol., 1997, 4(6), 461-471.
[http://dx.doi.org/10.1016/S1074-5521(97)90198-8] [PMID: 9224570]
[12]
Griffith, E.C.; Su, Z.; Niwayama, S.; Ramsay, C.A.; Chang, Y.H.; Liu, J.O. Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. Proc. Natl. Acad. Sci. USA, 1998, 95(26), 15183-15188.
[http://dx.doi.org/10.1073/pnas.95.26.15183] [PMID: 9860943]
[13]
Xu, W.; Lu, J-P.; Ye, Q-Z. Structural analysis of bengamide derivatives as inhibitors of methionine aminopeptidases. J. Med. Chem., 2012, 55(18), 8021-8027.
[http://dx.doi.org/10.1021/jm3008695] [PMID: 22913487]
[14]
Yeh, J-R.J.; Mohan, R.; Crews, C.M. The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest. Proc. Natl. Acad. Sci. USA, 2000, 97(23), 12782-12787.
[http://dx.doi.org/10.1073/pnas.97.23.12782] [PMID: 11070090]
[15]
Kidoikhammouan, S.; Seubwai, W.; Tantapotinan, N.; Silsirivanit, A.; Wongkham, S.; Sawanyawisuth, K.; Wongkham, C. TNP-470, a methionine aminopeptidase-2 inhibitor, inhibits cell proliferation, migration and invasion of human cholangiocarcinoma cells In Vitro. Asian Pac. J. Cancer Prev., 2012, 13(Suppl.), 155-160.
[PMID: 23480758]
[16]
Küçükgüzel, Ş.G.; Çıkla-Süzgün, P. Recent advances bioactive 1,2,4-triazole-3-thiones. Eur. J. Med. Chem., 2015, 97, 830-870.
[http://dx.doi.org/10.1016/j.ejmech.2014.11.033] [PMID: 25563511]
[17]
Kallander, L.S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.; Tew, D.; Meek, T.D.; Hofmann, G.A.; Schulz-Pritchard, C.K.; Smith, W.W.; Janson, C.A.; Ryan, M.D.; Zhang, G.F.; Johanson, K.O.; Kirkpatrick, R.B.; Ho, T.F.; Fisher, P.W.; Mattern, M.R.; Johnson, R.K.; Hansbury, M.J.; Winkler, J.D.; Ward, K.W.; Veber, D.F.; Thompson, S.K. 4-Aryl-1,2,3-triazole: a novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo. J. Med. Chem., 2005, 48(18), 5644-5647.
[http://dx.doi.org/10.1021/jm050408c] [PMID: 16134930]
[18]
Hou, Y-P.; Sun, J.; Pang, Z-H.; Lv, P-C.; Li, D-D.; Yan, L.; Zhang, H.J.; Zheng, E.X.; Zhao, J.; Zhu, H.L. Synthesis and antitumor activity of 1,2,4-triazoles having 1,4-benzodioxan fragment as a novel class of potent methionine aminopeptidase type II inhibitors. Bioorg. Med. Chem., 2011, 19(20), 5948-5954.
[http://dx.doi.org/10.1016/j.bmc.2011.08.063] [PMID: 21925884]
[19]
Garrabrant, T.; Tuman, R.W.; Ludovici, D.; Tominovich, R.; Simoneaux, R.L.; Galemmo, R.A., Jr; Johnson, D.L. Small molecule inhibitors of methionine aminopeptidase type 2 (MetAP-2). Angiogenesis, 2004, 7(2), 91-96.
[http://dx.doi.org/10.1007/s10456-004-6089-7] [PMID: 15516829]
[20]
Marino, J.P., Jr; Fisher, P.W.; Hofmann, G.A.; Kirkpatrick, R.B.; Janson, C.A.; Johnson, R.K.; Ma, C.; Mattern, M.; Meek, T.D.; Ryan, M.D.; Schulz, C.; Smith, W.W.; Tew, D.G.; Tomazek, T.A., Jr; Veber, D.F.; Xiong, W.C.; Yamamoto, Y.; Yamashita, K.; Yang, G.; Thompson, S.K. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J. Med. Chem., 2007, 50(16), 3777-3785.
[http://dx.doi.org/10.1021/jm061182w] [PMID: 17636946]
[21]
Zhao, Pei-L.; Ma, Wei-F.; Duan, An-N.; Zou, M.; Yan, Yi-C.; You, Wen-W.; Wu, Shu-G. One-pot synthesis of novel isoindoline-1,3-dione derivatives bearing 1,2,4-triazole moiety and their preliminary biological evaluation. Eur. Med. Chem., 2012, 54, 813-822.
[http://dx.doi.org/10.1016/j.ejmech.2012.06.041]
[22]
Alanazi, A.M.; Al-Suwaidan, I.A.; Abdel-Aziz, A.A.M.; Mohamed, M.A.; El-Morsy, A.M.; El-Azab, A.S. Design, synthesis and biological evaluation of some novel substituted 2-mercapto–3-phenethylquinazolines as antitumor agents. Med. Chem. Res., 2013, 22, 5566-5577.
[http://dx.doi.org/10.1007/s00044-013-0546-z]
[23]
Çoruh, I.; Çevik, Ö.; Yelekçi, K.; Djikic, T.; Küçükgüzel, S.G. Synthesis, anticancer activity, and molecular modeling of etodolac thioether derivatives as potent methionine aminopeptidase (type II) inhibitors. Arch. Pharm. (Weinheim), 2018, 351(3-4)e1700195
[http://dx.doi.org/10.1002/ardp.201700195] [PMID: 29575045]
[24]
Amir, M.; Kumar, S. Synthesis of some new 2-(2-fluoro-4-biphenylyl)propionic acid derivatives as potential anti inflammatory agents. Pharmazie, 2005, 60(3), 175-180.
[PMID: 15801668]
[25]
Cumaoğlu, A.; Dayan, S.; Agkaya, A.O.; Özkul, Z.; Özpozan, N.K. 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.
[http://dx.doi.org/10.3109/14756366.2014.940938] [PMID: 25198886]
[26]
Morris, J.S.; Friston, K.J.; Büchel, C.; Frith, C.D.; Young, A.W.; Calder, A.J.; Dolan, R.J. A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain, 1998, 121(1), 47-57.
[http://dx.doi.org/10.1093/brain/121.1.47] [PMID: 9549487]
[27]
Gao, N.; Zhang, Z.; Jiang, B-H.; Shi, X. Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem. Biophys. Res. Commun., 2003, 310(4), 1124-1132.
[http://dx.doi.org/10.1016/j.bbrc.2003.09.132] [PMID: 14559232]
[28]
Murillo, H.; Huang, H.; Schmidt, L.J.; Smith, D.I.; Tindall, D.J. Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology, 2001, 142(11), 4795-4805.
[http://dx.doi.org/10.1210/endo.142.11.8467] [PMID: 11606446]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 6
Year: 2020
Published on: 06 September, 2020
Page: [735 - 749]
Pages: 15
DOI: 10.2174/1573406415666190613162322
Price: $65

Article Metrics

PDF: 31
HTML: 3
EPUB: 1
PRC: 1