Synthesis of New Benzothiazole Acylhydrazones as Anticancer Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Cytotoxicity Test
2.2.2. DNA Synthesis Inhibition Assay
2.2.3. Flow Cytometric Analysis
3. Materials and Methods
3.1. Chemistry
3.1.1. General Synthesis Procedure for 4-Substitutebenzaldehyde Derivatives (1a–1e)
3.1.2. General Procedure for Ethyl 2-(5-Substitutedbenzothiazol-2-yl-thio)acetate (2a–2b)
3.1.3. General Procedure for 2-((5-Substitutedbenzothiazol-2-yl)thio)acetohydrazide (3a–3b)
3.1.4. General Synthesis Procedure of Compounds (4a–4j)
3.2. Biological Evaluation
3.2.1. Cytotoxicity Test
3.2.2. DNA Synthesis Inhibition Assay
3.2.3. Flow Cytometric Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
- Gabr, M.T.; El-Gohary, N.S.; El-Bendary, E.R.; El-Kerdawy, M.M. Synthesis and in vitro antitumor activity of new series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives. Eur. J. Med. Chem. 2014, 85, 576–592. [Google Scholar] [CrossRef] [PubMed]
- Farkona, S.; Diamandis, E.P.; Blasutig, I.M. Cancer immunotherapy: The beginning of the end of cancer? BMC Med. 2016, 14, 73. [Google Scholar] [CrossRef] [PubMed]
- Tuylu, B.A.; Zeytinoglu, H.S.; Isikdag, I. Synthesis and mutagenicity of 2-aryl-substitute (o-hydroxy-, m-bromo-, o-methoxy-, o-nitro-phenyl or 4-pyridyl) benzothiazole derivatives on Salmonella typhimurium and human lymphocytes exposed in vitro. Biologia 2007, 62, 626–632. [Google Scholar]
- Lion, C.J.; Matthews, C.S.; Wells, G.; Bradshaw, T.D.; Stevens, M.F.; Westwell, A.D. Antitumour properties of fluorinated benzothiazole substituted hydroxycyclohexa-2,5-dienones (‘quinols’). Bioorg. Med. Chem. Lett. 2006, 16, 5005–5008. [Google Scholar] [CrossRef] [PubMed]
- Choi, S.J.; Park, H.J.; Lee, S.K.; Kim, S.W.; Han, G.; Choo, H.Y. Solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity. Bioorg. Med. Chem. 2006, 14, 1229–1235. [Google Scholar] [CrossRef] [PubMed]
- Hutchinson, I.; Chua, M.S.; Browne, H.L.; Trapani, V.; Bradshaw, T.D.; Westwell, A.D. Antitumor benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl) benzothiazoles. J. Med. Chem. 2001, 44, 1446–1455. [Google Scholar] [CrossRef] [PubMed]
- Hutchinson, I.; Jennings, S.A.; Vishnuvajjala, B.R.; Westwell, A.D.; Stevens, M.F. Antitumor benzothiazoles. 16. Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid prodrugs. J. Med. Chem. 2002, 45, 744–747. [Google Scholar] [CrossRef] [PubMed]
- Hutchinson, I.; Bradshaw, T.D.; Matthews, C.S.; Stevens, M.F.; Westwell, A.D. Antitumour benzothiazoles. Part 20: 3′-cyano and 3′-alkynylsubstituted 2-(4′-aminophenyl)benzothiazoles as new potent and selective analogues. Bioorg. Med. Chem. Lett. 2003, 13, 471–474. [Google Scholar] [CrossRef]
- Bhuva, H.A.; Kini, S.G. Synthesis, anticancer activity and docking of some substituted benzothiazoles as tyrosine kinase inhibitors. J. Mol. Graph. Model. 2010, 29, 32–37. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Fan, J.; Vu, K.; Hong, K.; Le Brazidec, J.Y.; Shi, J. 7′-substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors. J. Med. Chem. 2006, 49, 5352–5362. [Google Scholar] [CrossRef] [PubMed]
- Singh, M.; Singh, S.K.; Thakur, B.; Ray, P.; Singh, S.K. Design and Synthesis of Novel Schiff Base-Benzothiazole Hybrids as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors. Anti-Cancer Agents Med. Chem. 2016, 16, 722–739. [Google Scholar] [CrossRef]
- Dumas, J.; Brittelli, D.; Chen, J.; Dixon, B.; Hatoum-Mokdad, H.; König, G.; Sibley, R.; Witowsky, J.; Wong, S. Synthesis and structure activity relationships of novel small molecule cathepsin D inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 2531–2536. [Google Scholar] [CrossRef]
- Singh, M.; Singh, S.K. Benzothiazoles: How Relevant in Cancer Drug Design Strategy? Anti-Cancer Agents Med. Chem. 2014, 14, 127–146. [Google Scholar] [CrossRef]
- Caputo, R.; Calabro, M.R.; Micale, N.; Schimmer, A.D.; Ali, M.; Zappala, M.; Grasso, S. Synthesis of benzothiazole derivatives and their biological evaluation as anticancer agents. Med. Chem. Res. 2012, 21, 2644–2651. [Google Scholar] [CrossRef]
- Bao, G.; Du, B.; Ma, Y.; Zhao, M.; Gong, P.; Zhai, X. Design, Synthesis and Antiproliferative Activity of Novel Benzothiazole Derivatives Conjugated with Semicarbazone Scaffold. Med. Chem. 2016, 12, 489–498. [Google Scholar] [CrossRef] [PubMed]
- Shi, X.H.; Wang, Z.; Xia, Y.; Ye, T.H.; Deng, M.; Xu, Y.Z.; Wei, Y.Q.; Yu, L.T. Synthesis and Biological Evaluation of Novel Benzothiazole-2-thiol Derivatives as Potential Anticancer Agents. Molecules 2012, 17, 3933–3944. [Google Scholar] [CrossRef] [PubMed]
- Sharma, P.C.; Sinhmar, A.; Sharma, A.; Rajak, H.; Pal Pathak, D. Medicinal significance of benzothiazole scaffold: An insight view. J. Enzym. Inhib. Med. Chem. 2013, 28, 240–266. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.Z.; Drewe, J.; Tseng, B.; Kasibhatla, S.; Cai, S.X. Discovery and SAR of indole-2-carboxylic acid benzylidene-hydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay. Bioorg. Med. Chem. 2004, 12, 3649–3655. [Google Scholar] [CrossRef] [PubMed]
- Peterson, Q.P.; Hsu, D.C.; Goode, D.R.; Novotny, C.J.; Totten, R.K.; Hergenrother, P.J. Procaspase-3 activation as an anti-cancer strategy: Structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3. J. Med. Chem. 2009, 52, 5721–5731. [Google Scholar] [CrossRef] [PubMed]
- Lindgren, E.B.; de Brito, M.A.; Vasconcelos, T.R.; de Moraes, M.O.; Montenegro, R.C.; Yoneda, J.D.; Leal, K.Z. Synthesis and anticancer activity of (E)-2-benzothiazole hydrazones. Eur. J. Med. Chem. 2014, 30, 12–16. [Google Scholar] [CrossRef] [PubMed]
- Nogueira, A.F.; Azevedo, E.C.; Ferreira, V.F.; Araújo, A.J.; dos Santos, E.A.; Pessoa, C.; Costa-Lotufo, L.V.; Montenegro, R.C.; de Moraes, M.O.; Vasconcelos, T.R.A. Synthesis and Antitumor Evaluation of (E)-2-Benzothiazole Hydrazones. Lett. Drug Des. Discov. 2010, 7, 551–555. [Google Scholar] [CrossRef]
- Ma, J.; Chen, D.; Lu, K.; Wang, L.; Han, X.; Zhao, Y.; Gong, P. Design, Synthesis, And Structure-Activity Relationships of Novel Benzothiazole Derivatives Bearing the Ortho-Hydroxy N-Carbamoylhydrazone Moiety as Potent Antitumor Agents. Eur. J. Med. Chem. 2014, 17, 257–269. [Google Scholar] [CrossRef] [PubMed]
- Prangya, S.; Pany, P.; Bommisetti, P.; Diveshkumar, K.V.; Pradeepkumar, P.I. Benzothiazole hydrazones of furylbenzamides preferentially stabilize c-MYC and c-KIT1 promoter G-quadruplex DNAs. Org. Biomol. Chem. 2016, 14, 5779–5793. [Google Scholar]
- Ma, J.; Zhang, G.; Han, X.; Bao, G.; Wang, L.; Zhai, X.; Gong, P. Synthesis and Biological Evaluation of Benzothiazole Derivatives Bearing the ortho-Hydroxy-N-acylhydrazone Moiety as Potent Antitumor Agents. Arch. Pharm. Chem. Life Sci. 2014, 347, 936–949. [Google Scholar] [CrossRef] [PubMed]
- Sleebs, B.E.; Kersten, W.J.A.; Kulasegaram, S.; Nikolakopoulos, G.; Hatzis, E.; Moss, R.M.; Parisot, J.P.; Yang, H.; Czabotar, P.E.; Fairlie, W.D.; et al. Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-XL. J. Med. Chem. 2013, 56, 5514–5540. [Google Scholar] [CrossRef] [PubMed]
- Can, N.Ö.; Osmaniye, D.; Levent, S.; Sağlık, B.N.; İnci, B.; Ilgın, S.; Özkay, Y.; Kaplancıklı, Z.A. Synthesis of New Hydrazone Derivatives for MAO Enzymes Inhibitory Activity. Molecules 2017, 22, 1381. [Google Scholar] [CrossRef] [PubMed]
- Ilgın, S.; Osmaniye, D.; Levent, S.; Sağlık, B.N.; Acar Çevik, U.; Kaya Çavuşoğlu, B.; Özkay, Y.; Kaplancıklı, Z.A. Design and Synthesis of New Benzothiazole Compounds as Selective hMAO-B Inhibitors. Molecules 2017, 22, 2187. [Google Scholar] [CrossRef] [PubMed]
- Varache-Lembege, M.; Moreau, S.; Larrouture, S.; Montaudon, D.; Robert, J.; Nuhrich, A. Synthesis and antiproliferative activity of aryl- and heteroaryl-hydrazones derived from xanthone carbaldehydes. Eur. J. Med. Chem. 2008, 43, 1336–1343. [Google Scholar] [CrossRef] [PubMed]
- Malikova, J.; Swaczynova, J.; Kolar, Z.; Strnad, M. Anticancer and antiproliferative activity of natural brassinosteroids. Phytochemistry 2008, 69, 418–426. [Google Scholar] [CrossRef] [PubMed]
- Maghni, K.; Nicolescu, O.M.; Martin, J.G. Suitability of cell metabolic colorimetric assays for assessment of CD4+ T cell proliferation: Comparison to 5-bromo-2-deoxyuridine (BrdU) ELISA. J. Immunol. Methods 1999, 223, 185–194. [Google Scholar] [CrossRef]
- Fulda, S.; Debatin, K.M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 2006, 25, 4798–4811. [Google Scholar] [CrossRef] [PubMed]
- Berridge, M.V.; Herst, P.M.; Tan, A.S. Tetrazolium dyes as tools in cell biology: New insights into their cellular reduction. Biotechnol. Annu. Rev. 2005, 11, 127–152. [Google Scholar] [PubMed]
- Demir Özkay, Ü.; Can, Ö.D.; Sağlık, B.N.; Acar Çevik, U.; Levent, S.; Özkay, Y.; Ilgın, S.; Atlı, Ö. Design, synthesis, and AChE inhibitory activity of new benzothiazole-piperazines. Bioorg. Med. Chem. Lett. 2016, 26, 5387–5394. [Google Scholar] [CrossRef] [PubMed]
- Sağlık, B.N.; Ilgın, S.; Özkay, Y. Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes. Eur. J. Med. Chem. 2016, 124, 1026–1040. [Google Scholar] [CrossRef] [PubMed]
- Altıntop, M.D.; Özdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atlı, Ö.; Demirel, R.; Kaplancıklı, Z.A. A novel series of thiazolyl-pyrazoline derivatives: Synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity. Eur. J. Med. Chem. 2015, 92, 342–352. [Google Scholar] [CrossRef] [PubMed]
- Altıntop, M.D.; Özdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atlı, Ö.; Demirci, F.; Kaplancıklı, Z.A. Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents. Molecules 2014, 19, 14809–14820. [Google Scholar] [CrossRef] [PubMed]
- Yurttaş, L.; Demirayak, S.; Ilgın, S.; Atlı, Ö. In vitro antitumor activity evaluation of some 1,2,4-triazine derivatives bearing piperazine amide moiety against breast cancer cells. Bioorg. Med. Chem. 2014, 22, 6313–6323. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 4a–4j are available from the authors. |
Compounds | R1 | R2 | R3 | R4 | X |
---|---|---|---|---|---|
4a | -H | -H | -H | -Cl | -CH |
4b | -CH3 | -H | -H | -Cl | -CH |
4c | -H | -CH3 | -H | -Cl | -CH |
4d | -H | -H | -CH3 | -Cl | -CH |
4e | -H | -H | 4-methoxyphenyl | -Cl | -N |
4f | -H | -H | -H | -OCH3 | -CH |
4g | -CH3 | -H | -H | -OCH3 | -CH |
4h | -H | -CH3 | -H | -OCH3 | -CH |
4i | -H | -H | -CH3 | -OCH3 | -CH |
4j | -H | -H | 4-methoxyphenyl | -OCH3 | -N |
Compounds | IC50 (mM) | ||||
---|---|---|---|---|---|
A549 | C6 | MCF-7 | HT-29 | NIH3T3 | |
4a | 1< | 0.10 | 0.49 | 0.52 | 0.10 |
4b | 1 | 0.10 | 1< | 1 | 0.10 |
4c | 0.52 | 0.10 | 0.10 | 0.30 | 0.03 |
4d | 1< | 0.03 | 0.10 | 0.30 | 1< |
4e | 0.03 | 0.03 | 0.30 | 1< | 0.01 |
4f | 1< | 1< | 1< | 1< | 0.03 |
4g | 1< | 1< | 1< | 1< | 0.10 |
4h | 1< | 0.03 | 1< | 1< | 0.10 |
4i | 0.49 | 0.10 | 0.30 | 1 | 0.03 |
4j | 1< | 1< | 1< | 1< | 1< |
Cisplatin | 0.06 | 0.03 | 0.05 | 0.06 | 1< |
Compound | IC50/2 | IC50 | 2 × IC50 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | |
4d | 16.4 | 12.3 | 71.2 | 0.1 | 6.9 | 3.1 | 87.6 | 2.4 | 4.5 | 7.1 | 74.5 | 13.9 |
4e | 13.5 | 3.8 | 82.6 | 0 | 9.8 | 16.0 | 70.7 | 3.5 | 10.1 | 14.0 | 73.3 | 2.5 |
4h | 10.8 | 4.9 | 84.1 | 0.3 | 8.6 | 7.4 | 79.4 | 4.6 | 5.4 | 10.5 | 75.2 | 8.9 |
Cisplatin | N.D. | N.D. | N.D. | N.D. | 3.5 | 18.3 | 75.6 | 2.6 | N.D. | N.D. | N.D. | N.D. |
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Osmaniye, D.; Levent, S.; Karaduman, A.B.; Ilgın, S.; Özkay, Y.; Kaplancıklı, Z.A. Synthesis of New Benzothiazole Acylhydrazones as Anticancer Agents. Molecules 2018, 23, 1054. https://doi.org/10.3390/molecules23051054
Osmaniye D, Levent S, Karaduman AB, Ilgın S, Özkay Y, Kaplancıklı ZA. Synthesis of New Benzothiazole Acylhydrazones as Anticancer Agents. Molecules. 2018; 23(5):1054. https://doi.org/10.3390/molecules23051054
Chicago/Turabian StyleOsmaniye, Derya, Serkan Levent, Abdullah Burak Karaduman, Sinem Ilgın, Yusuf Özkay, and Zafer Asım Kaplancıklı. 2018. "Synthesis of New Benzothiazole Acylhydrazones as Anticancer Agents" Molecules 23, no. 5: 1054. https://doi.org/10.3390/molecules23051054