Synthesis, Characterization, Anti-proliferative Evaluation, and DNA Flow Cytometry Analysis of Some 2-Thiohydantoin Derivatives

Author(s): Heba A. Elhady*, Hossa F. Al-Shareef

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 20 , Issue 18 , 2020


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Abstract:

Background and Objective: Due to the well-documented anti-proliferative activity of 2-thiohydantoin incorporated with pyrazole, oxadiazole, quinazoline, urea, β-naphthyl carbamate and Schiff bases, they are noteworthy in pharmaceutical chemistry.

Methods: An efficient approach for the synthesis of a novel series of 2-thiohydantoin derivatives incorporated with pyrazole and oxadiazole has proceeded via the reaction of the acyl hydrazide with chalcones and/or triethyl orthoformate. Schiff bases were synthesized by the reaction of the acyl hydrazide with different aromatic aldehydes. Moreover, Curtius rearrangement was applied to the acyl azide to obtain the urea derivative, quinazoline derivative, and carbamate derivative.

Results: The synthesized compounds structures were discussed and confirmed depending on their spectral data. The anticancer activity of these heterocyclic compounds was evaluated against the breast cancer cell line (MCF-7), where they showed variable activity. Compound 5d found to have a superior anticancer activity, where it has (IC50 = 2.07 ± 0.13 μg/mL) in comparison with the reference drug doxorubicin that has (IC50 = 2.79 ± 0.07 μg / mL). Then compound 5d subjected to further studies such as cell cycle analysis and apoptosis. Apoptosis was confirmed by the upregulation of Bax, downregulation of Bcl-2, and the increase of the caspase 3/7percentage.

Conclusion: Insertion of pyrazole, oxadiazole and, quinazoline moieties with 2-thiohydantoin moiety led to the enhancement of its anti-proliferative activity. Hence they can be used as anticancer agents.

Keywords: 2-Thiohydantoin, urea, carbamate, pyrazole, quinazoline, MCF-7, cell cycle analysis, apoptosis, caspase 3/7.

[1]
Yadav, S.; Narasimhan, B.; Lim, S.M.; Ramasamy, K.; Vasudevan, M.; Shah, S.A.A.; Selvaraj, M. Synthesis, characterization, biological evaluation and molecular docking studies of 2-(1H-benzo[d]imidazol-2-ylthio)-N-(substituted 4-oxothiazolidin-3-yl) acetamides. Chem. Cent. J., 2017, 11(1), 137.
[http://dx.doi.org/10.1186/s13065-017-0361-6] [PMID: 29274036]
[2]
Bertucci, F.; Birnbaum, D. Reasons for breast cancer heterogeneity. J. Biol., 2008, 7(2), 6.
[http://dx.doi.org/10.1186/jbiol67] [PMID: 18304379]
[3]
Yang, X.L.; Wang, A.H-J. Structural studies of atom-specific anticancer drugs acting on DNA. Pharmacol. Therapeut., 1999, 83, 181-215.
[http://dx.doi.org/10.1016/S0163-7258(99)00020-0.]
[4]
Illan-Cabeza, N. A.; Vilaplana, R. A.; Alvarez, Y.; Akdi, K.; Kamah, S.; Hueso-Urena, F.; Quiros, M.; Gonzalez-Vilchez, F.; Moreno-Carretero, M. N. Synthesis, structure and biological activity of a new and efficient Cd(II)-uracil derivative complex system for cleavage of DNA J. Biol. Inorg. Chem., 2005, 10, 924-934.
[http://dx.doi.org/10.1007/s00775-005-0045-x]
[5]
Haq, I.; Ladbury, J. Drug-DNA recognition: Energetics and implications for design. J. Mol. Recognit., 2000, 13, 188-197.
[http://dx.doi.org/10.1002/1099-1352(200007/08)13:43.0.CO;2-1.]
[6]
Barthwal, R.; Sharma, U.; Snivastava, N.; Jain, M.; Awasthi, P.; Kaur, M.; Barthwal, S.K.; Govil, G. Structure of daunomycin complexed to d-TGATCA by two-dimensional nuclear magnetic resonance spectroscopy. Eur. J. Med. Chem., 2006, 41, 27-39.
[http://dx.doi.org/10-1016/j.ejmech.2005.09.005.]
[7]
GREDI^AK, M.; JERIC ̄, I. Enediyne compounds – new promises in anticancer therapy. Acta Pharm., 2007, 57, 133-150.
[8]
Cho, S.; Kim, S.; Shin, D. Recent applications of hydantoin and thiohydantoin in medicinal chemistry. Eur. J. Med. Chem., 2019, 164, 517-545.
[9]
Abdellatif, Kh.R.A.; Fadaly, W.A.A.; Mostafa, Y.A.; Zaher, D.M.; Omar, H.A. Thiohydantoin derivatives incorporating a pyrazole core: Design, synthesis and biological evaluation as dual inhibitors of topoisomerase-I and cycloxygenase-2 with anti-cancer and anti-inflammatory activities. Bioorg. Chem., 2019, 91, 103-132.
[10]
El-Sharief, A.M.Sh.; Moussa, Z. Synthesis, characterization and derivatization of some novel types of mono- and bis-imidazolidineiminothiones and imidazolidine-iminodithiones with antitumor, antiviral, antibacterial and antifungal activities. Eur. J. Med. Chem., 2009, 44, 4315-4334.
[11]
Xu, X.; Ge, R.; Li, L.; Wang, J.; Lu, X.; Xue, S.; Chen, X.; Li, Z.; Bian, J. Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents. Eur. J. Med. Chem., 2018, 143, 1325-1344.
[12]
Moussa, Z.; El-Sharief, A.M.Sh.; El-Sharief, M.Sh. Synthesis and characterization of new types of halogenated and alkylated imidazolidineiminothiones and a comparative study of their antitumor, antibacterial, and antifungal activities. Eur. J. Med. Chem., 2011, 46, 2280-2289.
[13]
Azizmohammadi, M.; Khoobi, M.; Ramazani, A.; Emami, S.; Zarrin, A.; Firuzi, O.; Miri, R.; Abbas Shafiee, A. 2H-chromene derivatives bearing thiazolidine-2,4-dione, rhodanine or hydantoin moieties as potential anticancer agents. Eur. J. Med. Chem., 2013, 59, 15-22.
[14]
Aljofan, M.; Netter, H.J.; Aljarbou, A.N.; Hadda, T.B.; Orhan, I.E.; Sener, B.; Mungall, B.A. Anti-hepatitis B activity of isoquinoline alkaloids of plant origin. Arch. Virol., 2014, 159(5), 1119-1128.
[http://dx.doi.org/10.1007/s00705-013-1937-7] [PMID: 24311152]
[15]
Zuliani, V.; Carmi, C.; Rivara, M.; Fantini, M.; Lodola, A.; Vacondio, F.; Bordi, F.; Plazzi, P.V.; Cavazzoni, A.; Galetti, M.; Alfieri, R.R.; Petronini, P.G.; Mor, M. 5-Benzylidene-hydantoins: Synthesis and antiproliferative activity on A549 lung cancer cell line. Eur. J. Med. Chem., 2009, 44, 3471-3479.
[16]
Gangadhar, S.H.; Ramesh, D.K.; Mahajan, S.K. Synthesis, characterization and anticonvulsant activity of 3-substituted 2-thiohydantoin derivatives. IJRPC, 2013, 3, 793-796.
[17]
Trotsko, N.; Kosikowsk, U.; Paneth, A.; Wujec, M.; Malm, A. Synthesis and antibacterial activity of new (2,4-dioxothiazolidin-5-yl/ylidene)acetic acid derivatives with thiazolidine-2,4-dione, rhodanine and 2-thiohydantoin moieties. Saudi Pharmaceut J., 2018, 26, 568-577.
[18]
Yildiz, I.; Bozdag, O. Three-dimensional common-feature hypotheses for hypoglycemic flavonyl-2,4-thiazolidinedione derivatives. Med. Chem. Res., 2010, 19, 211-219.
[19]
Kumar, V.; Rana, H.; Sankolli, R.; Kaushik, M.P. Novel and efficient protocol for the syntheses of N-1 substituted thiohydantoin and a bicyclothiohydantoin under solvent-free conditions. Tetrahedron Lett., 2012, 53, 2377-2379.
[20]
Noor, A.; Qazi, N.G.; Nadeem, H.; Khan, A.U.; Paracha, R.Z.; Ali, F.; Saeed, A. Synthesis, characterization, anti-ulcer action and molecular docking evaluation of novel benzimidazole-pyrazole hybrids. Chem. Cent. J., 2017, 11(1), 85.
[http://dx.doi.org/10.1186/s13065-017-0314-0] [PMID: 29086868]
[21]
Park, H.; Lee, K.; Park, S.; Ahn, B.; Lee, J.; Cho, H.; Lee, K-I. Identification of antitumor activity of pyrazole oxime ethers. Bioorg. Med. Chem. Lett., 2005, 15, 3307-3312.
[22]
Ahmed, W.; Yan, X.; Hu, D.; Adnan, M.; Tang, R.Y.; Cui, Z.N. Synthesis and fungicidal activity of novel pyrazole derivatives containing 5-Phenyl-2-Furan. Bioorg. Med. Chem., 2019, 27(19)115048
[http://dx.doi.org/10.1016/j.bmc.2019.115048] [PMID: 31439387]
[23]
Oubella, A.; Itto, M.; Auhmani, A.; Riahi, A.; Robert, A.; Daran, J.; Morjani, H.; Parish, C.A.; Esseffar, M. Diastereoselective synthesis and cytotoxic evaluation of new isoxazoles and pyrazoles with monoterpenic skeleton. J. Mol. Struct., 2019, 1198126924
[http://dx.doi.org/10.1016/j.molstruc.2019.126924]
[24]
Romagnoli, R.; Oliva, P.; Salvador, M.K.; Camacho, M.E.; Padroni, C.; Brancale, A.; Ferla, S.; Hamel, E.; Ronca, R.; Grillo, E.; Bortolozzi, R.; Rruga, F.; Mariotto, E.; Viola, G. Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors. Eur. J. Med. Chem., 2019, 181111577
[http://dx.doi.org/10.1016/j.ejmech.2019.111577] [PMID: 31400707]
[25]
Xu, Y.; Zhang, Z.; Jiang, X.; Chen, X.; Wang, Z.; Alsulami, H.; Qin, H.L.; Tang, W. Discovery of δ-sultone-fused pyrazoles for treating Alzheimer’s disease: Design, synthesis, biological evaluation and SAR studies. Eur. J. Med. Chem., 2019, 181111598
[http://dx.doi.org/10.1016/j.ejmech.2019.111598] [PMID: 31415981]
[26]
Al-Said, M.S.; Bashandy, M.S.; Al-Qasoumi, S.I.; Ghorab, M.M. Anti-breast cancer activity of some novel 1,2-dihydropyridine, thiophene and thiazole derivatives. Eur. J. Med. Chem., 2011, 46(1), 137-141.
[http://dx.doi.org/10.1016/j.ejmech.2010.10.024] [PMID: 21093116]
[27]
Abdel Reheim, M.A.M.; Baker, S.M. Synthesis, characterization and in vitro antimicrobial activity of novel fused pyrazolo[3,4-c]pyridazine, pyrazolo[3,4-d]pyrimidine, thieno[3,2-c]pyrazole and pyrazolo[3′,4′:4,5]thieno[2,3-d]pyrimidine derivatives. Chem. Cent. J., 2017, 11(1), 112.
[http://dx.doi.org/10.1186/s13065-017-0339-4] [PMID: 29098473]
[28]
T’ang, A.; Lien, E.J.; Lai, M.M. Optimization of the Schiff bases of N-hydroxy-N'-aminoguanidine as anticancer and antiviral agents. J. Med. Chem., 1985, 28(8), 1103-1106.
[http://dx.doi.org/10.1021/jm00146a022] [PMID: 2991520]
[29]
Modi, J.D.; Sabnis, S.S.; Deliwala, C.V. Potential anticancer agents. 3. Schiff bases from benzaldehyde nitrogen mustards and aminophenylthiazoles. J. Med. Chem., 1970, 13(5), 935-941.
[http://dx.doi.org/10.1021/jm00299a031] [PMID: 5458385]
[30]
Abd El-Latif, N.A.; Amr, E.A.; Alusein, A.I. Synthesis, reactions, and pharmacological screening of heterocyclic derivatives using nicotinic acid as a natural synthon. Monatsh. Chem., 2007, 138, 559.
[http://dx.doi.org/10.1007/s00706-007-0628-z]
[31]
Wu, Y.; Ding, X.; Xu, S.; Yang, Y.; Zhang, X.; Wang, Ch.; Lei, H.; Zhao, Y. Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria. Bioorg. Med. Chem. Lett., 2019, 29, 496-502.
[32]
Zuo, M.; Xu, X.; Xie, Zh.; Ge, R.; Zhang, Z.; Li, Z.; Bian, J. Design and synthesis of indoline thiohydantoin derivatives based on enzalutamide as antiproliferative agents against prostate cancer. Eur. J. Med. Chem., 2017, 125, 1002-1022.
[33]
Raj, R.; Mehra, V.; Gut, J.; Rosenthal, Ph.J.; Wicht, K.J.; Egan, T.J.; Hopper, M.; Wrischnik, L.A.; Land, K.M.; Kumar, V. Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity. Eur. J. Med. Chem., 2014, 84, 425-432.
[34]
Mohamed, S.M.; Unis, M; Abd El Hady, H. Synthesis and mass spectral fragmentation patterns of some thiazole and imidazolidine derivatives. Indian J. Chem., 2006, 45(B), 1453-1462.
[35]
Aly, H.M.; Saleh, N.M. Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents. Eur. J. Med. Chem., 2011, 46, 4566-4572.
[36]
El Hady, H.A. Syntheses and anti-microbial activity of some new thiohydantoin and thiazole derivatives. Der. Pharm Chemica., 2012, 4(6), 2202-2207.
[37]
El-Hady, H.A.; Abubshait, S.A. Synthesis of imidazolinone and benzoxazole derivatives, and evaluation of their anticancer activity. Res. Chem. Intermed., 2015, 41, 1833-1834.
[38]
Elhady, H.A.; Aly, H.M.; Saleh, N.M. Syntheses and antimicrobial activity of new benzofuran, pyrrole, imidazole and thioxoimidazolidin incorporating antipyrine moiety. Int. J. Adv. Res., 2014, 2(3), 806-816.
[39]
Elhady, H.A. Convenient synthesis of 1, 3-disubstituted-2-thioxo-imidazolidin-4-ones as potential anti-tumor agents. Int. J. Adv. Res. , 2015, 3, 2340-2351.
[40]
Hussein, E.M.; Al-Shareef, H.F.; Aboellil, A.H.; Elhady, H.A. Synthesis of some novel 6′-(4-chlorophenyl)-3, 4′-bipyridine-3′-carbonitriles: assessment of their antimicrobial and cytotoxic activity. Z. Naturforsch., 2015, 70(11b), 783-795.
[41]
Al-Shareef, H.F.; Elhady, H.A.; Aboellil, A.H.; Hussein, E.M. Ammonium chloride catalyzed synthesis of novel Schiff bases from spiro[indoline-3,4′-pyran]-3′-carbonitriles and evaluation of their antimicrobial and anti-breast cancer activities. Springerplus, 2016, 5(1), 887.
[http://dx.doi.org/10.1186/s40064-016-2458-0] [PMID: 27386335]
[42]
Alshareef, H.F.; Mohamed, H.A.; Salaheldin, A.M. synthesis and biological evaluation of new tacrine analogues under microwave irradiation. Chem. Pharm. Bull., 2017, 65, 732-738.
[43]
Elhady, H.A.; Al-nathali, H.S.; El-Sayed, R. Use of 2-(1-(4-bromophenyl)ethylidene)hydrazinecarbothioamide and 2-(5-chloro-2-oxoindolin-3-ylidene) hydrazinecarbothioamide in the syntheses of 2-thiohydantoin, pyrimidine derivatives: Evaluation of their antimicrobial activities. Int. J. Adv. Res., 2017, 5(10), 1716-1725.
[44]
Elhady, H.A.; Katouah, H.A. Vitro antitumor evaluation of some 3,7-disubstituted coumarin derivatives.Lat. Am. J. Pharm; , 2018, 37, pp. (1)123-130.
[45]
El-Sayed, R.; Alotaibi, H.H.; Elhady, H.A. Synthesis, surface parameters and biodegradability of water-soluble surfactants for various applications Oleo Sci., 2018, 67(5), 551-579.
[46]
Al-ghareib, S.; Elhad, H.A.; Abdallah, R.M. in vitro antitumor evaluation of some new tetra substituted 1,2,4-triazines. Lat. Am. J. Pharm., 2018, 37(5), 1035-1045.
[47]
Elhady, H.A.; El-Sayed, R.; Al-Nathali, H.S. Design, synthesis and evaluation of anticancer activity of novel 2-thioxoimidazolidin-4-one derivatives bearing pyrazole, triazole and benzoxazole moieties. Chem. Cent. J., 2018, 12(1), 51.
[http://dx.doi.org/10.1186/s13065-018-0418-1] [PMID: 29740713]
[48]
Mohamed, H.A.E.; Al-Shareef, H.F. design, synthesis, anti-Proliferative evaluation and cell cycle analysis of hybrid 2-quinolones. Anticancer. Agents Med. Chem., 2019, 19, 1132-1140.
[49]
Taha, R.H.; Saleh, N.M.; Elhady, H.A.; Khodairy, M.M. Evaluation of newly synthesized derivatives of bis(hydrazine‐1‐carbothioamide) and their metal complexes synthesized in bulk and nano size as potent anticancer agents; Appl Organometal. Chem, 2019, 33(11), 5207.
[http://dx.doi.org/10.1002/aoc.5207]
[50]
Gerlier, D.; Thomasset, N. Use of MTT colorimetric assay to measure cell activation. J. Immunol. Methods, 1986, 94, 57-63.
[51]
Meerloo, J.; Kaspers, G.J. L.; Cloos, J. Cell sensitivity assays: The MTT assay Cancer Cell Culture, 2011, 731, 237-245.
[52]
Ouyang, L.; Shi, Z.; Zhao, S.; Wang, F.T.; Zhou, T.T.; Liu, B.; Bao, J.K. Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis Cell Proliferat., 2012, 45, 487-498.
[53]
Taguchi, T.; Kato, Y.; Baba, Y.; Nishimura, G.; Tanigaki, Y.; Horiuchi, C.; Mochimatsu, I.; Tsukuda, M. Protein levels of p21, p27, cyclin E and Bax predict sensitivity to cisplatin and paclitaxel in head and neck squamous cell carcinomas. Oncol. Reports., 2004, 11, 421-426.
[54]
Lakhani, S.A.; Masud, A.; Kuida, K.; Porter, G.A.; Booth, C.J.; Mehal, W.Z.; Inayat, I.; Flavell, R.A. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science, 2006, 311, 847-851.


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VOLUME: 20
ISSUE: 18
Year: 2020
Published on: 07 December, 2020
Page: [1929 - 1941]
Pages: 13
DOI: 10.2174/1389557520666200611093510
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