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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Novel Thiazine Substituted 9-Anilinoacridines: Synthesis, Antitumour Activity and Structure Activity Relationships

Author(s): R. Kalirajan*, K. Gaurav, A. Pandiselvi, B. Gowramma and S. Sankar

Volume 19 , Issue 11 , 2019

Page: [1350 - 1358] Pages: 9

DOI: 10.2174/1871520619666190408134224

Price: $65


Background: 9-anilinoacridines are acting as DNA-intercalating agents which plays an important role as antitumor drugs, due to their anti-proliferative properties. Some anticancer agents contain 9- anilinoacridines such as amsacrine (m-AMSA), and nitracrine (Ledakrine) have been already developed.

Methods: In this study, novel 9-anilinoacridines substituted with thiazines 4a-r were designed, synthesized, characterized by physical and spectral data and their cytotoxic activities against DLA cell lines were evaluated.

Results: Among those compounds, 4b, c, e, g, i, j, k, m, o, p, q, r exhibited significant short term in vitro cytotoxic activity against Daltons lymphoma ascites (DLA) cells with CTC50 value of 0.18 to 0.31μM. The compounds 4b, c, e, g, i, j, k, m, o, p, q, r are also exhibited significant long term in vitro anti-tumour activity against human tumor cell lines, HEp-2 (laryngeal epithelial carcinoma) by Sulforhodamine B assay with CTC50 value of 0.20 to 0.39μM. The compounds 4b, i, j exhibited significant in vivo antitumor activity with % Increase in Life Span (ILS) 48-82%.

Conclusion: Results obtained in this study clearly demonstrated that many of the thiazine substituted 9- anilinoacridines exert interesting anti-tumour activity. The compounds 4b, i, j have significant anti-tumour activity and useful drugs after further refinement. The above derivatives will encourage to design future antitumor agents with high therapeutic potentials.

Keywords: Acridine, thiazine, antitumor, DLA cell lines, in vitro activity, in vivo activity.

Graphical Abstract
Rouvier, C.S.; Barret, J.M.; Farrell, C.M.; Sharples, D.; Hill, B.T.; Barbe, J. Synthesis of 9-acridinyl sulfur derivatives: Sulfides, sulfoxides and sulfones.Comparison of their activity on tumour cells. Eur. J. Med. Chem., 2004, 39, 1029-1038.
Rastogi, K.; Chang, J.Y.; Pan, W.Y.; Chen, C.H.; Chou, T.C.; Chen, L.T.; Su, T.L. Antitumor AHMA linked to DNA minor groove binding agents: Synthesis and biological evaluation. J. Med. Chem., 2002, 45, 4485-4493.
Kalirajan, R.; Vivek, K.; Sankar, S.; Jubie, S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their anti-oxidant and anticancer activities as topo isomerase II inhibitors. Eur. J. Med. Chem., 2012, 56, 217-224.
Bacherikov, V.A.; Chou, T.C.; Dong, H.J.; Chen, C.H.; Lin, Y.W.; Tsai, T.J. Potent antitumor N-mustard derivatives of 9-anilinoacridine, synthesis and antitumor evaluation. Bioorg. Med. Chem. Lett., 2004, 14, 4719-4722.
Kalirajan, R.; Muralidharan, V.; Jubie, S.; Gowramma, B.; Gomathy, S.; Sankar, S.; Elango, K. Synthesis of some novel pyrazole substituted 9-anilino acridine derivatives and evaluation for their antioxidant and cytotoxic activities. J. Heterocycl. Chem., 2012, 49, 748-754.
Dickens, B.F.; Weglicki, W.B.; Boehme, P.A.; Mak, I.T. Antioxidant and lysosomotropic properties of acridine-propranolol: Protection against oxidative endothelial cell injury. J. Mol. Cell. Cardiol., 2002, 34, 129-137.
Nadaraj, V.; Selvi, S.T.; Mohan, S. Microwave-induced synthesis and anti-microbial activities of 7,10,11,12-tetrahydrobenzo[c] acridin-8(9H)-one derivatives. Eur. J. Med. Chem., 2009, 44, 976-982.
Gamage, S.A.; Tepsiri, N.; Wilairat, P.; Wojcik, S.J.; Figgitt, D.P.; Ralph, R.K.; Denny, W.A. Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum. J. Med. Chem., 1994, 37, 1486-1494.
Anderson, M.O.; Sherrill, J.; Madrid, P.B.; Liou, A.P.; Weisman, J.L.; DeRisib, J.L.; Guy, R.K. Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum. Bioorg. Med. Chem., 2006, 14, 334-343.
Sondhi, S.M.; Johar, M.; Nirupama, S.; Sukla, R.; Raghubir, R.S.G. Synthesis of sulpha drug acridine derivatives and their evaluation for anti-anflammatory, analgesic and anticancer acvity. Indian J. Chem., 2002, 41, 2659-2666.
Chen, Y.L.; Lu, C.M.; Chen, I.L.; Tsao, L.T.; Wang, J.P. Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives. J. Med. Chem., 2002, 45(21), 4689-4694.
Llama, E.F.; Campo, C.D.; Capo, M.; Anadon, M. Synthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine. Eur. J. Med. Chem., 1989, 24, 391-396.
Gamage, S.A.; Figgitt, D.P.; Wojcik, S.J.; Ralph, R.K.; Ransijn, A.; Mauel, J.; Yardley, V.; Snowdon, D.; Croft, S.L.; Denny, W.A. Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1′-substituted 9-anilinoacridines. J. Med. Chem., 1997, 40, 2634-2642.
Goodell, J.R.; Madhok, A.A.; Hiasa, H.; Ferguson, D.M. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg. Med. Chem., 2006, 14, 5467-5480.
Recanatini, M.; Cavalli, A.; Belluti, F.; Piazzi, L.; Rampa, A.; Bisi, A.; Gobbi, S.; Valenti, P.; Andrisano, V.; Bartolini, M.; Cavrini, V. SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetyl cholinesterase inhibitors: Synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. J. Med. Chem., 2000, 43(10), 2007-2018.
Harrison, R.J.; Cuesta, J.; Chessari, G.; Read, M.A.; Basra, S.K.; Reszka, A.P.; Morrell, J.; Gowan, S.M.; Incles, C.M.; Tanious, F.A.; Wilson, W.D.; Kelland, L.R.; Neidle, S. Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. J. Med. Chem., 2003, 46, 4463-4476.
Madkour, H.; Salem, M.; Soliman, E. mahmond, N.A. facile one-pot synthesis and antibacterial activity of aziridines and thiazines from 1,3-diarylprop-2-enones. Phosph. Sulf. Silic. Relat. Elem., 2010, 170, 15-27.
Kalirajan, R.; Sivakumar, S.U.; Jubie, S.; Gowramma, B.; Suresh, B. Synthesis and biological evaluation of some heterocyclic derivatives of chalcones. Int. J. Chemtech Res., 2009, 1, 27-34.
Shen, G.; Chen, D.; Zhang, Y.; Sun, M.; Chen, K.; Jin, C.; Li, K.; Bao, W. Synthesis of benzoxazine and 1,3-oxazine derivatives via ligand-free copper(I)-catalyzed one-pot cascade addition/cyclization reaction. Tetrahedron, 2012, 68, 166-172.
Basappa, Murugan. S.; Kavitha, C.V.; Purushothaman, A.; Nevin, K.G.; Sugahara, K.; Rangappa, K.S. A small oxazine compound as an anti-tumor agent: A novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-α. Cancer Lett., 2010, 297, 231-243.
Kalirajan, R.; Mohammed Rafick, M.H.; Jubie, S.; Sankar, S. Docking studies, synthesis, characterization and evaluation of their antioxidant and cytotoxic activities of some novel isoxazole substituted 9-anilinoacridine derivatives. Sci. World J, 2012.Article ID 165258
Rajagopal, K.; Muralidharan, V.; Jubie, S.; Sankar, S. Microwave assisted synthesis, characterization and evaluation for their antimicrobial activities of some novel pyrazole substituted 9-anilino acridine derivatives. Int. J. Health Allied Sci., 2013, 2(2), 81-87.
Giorgio, C.D.; Shimi, K.; Boyer, G.; Delmas, F.; Galy, J.P. Synthesis and antileishmanial activity of 6-mono-substituted and 3,6-di-substituted acridines obtained by acylation of proflavine. Eur. J. Med. Chem., 2007, 42, 1277-1281.
E, Llama. E.F.; Campo, C.D.; Capo, M.; Anadon, M. Synthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine. Eur. J. Med. Chem., 1989, 24, 391-395.
Kalirajan, R.; Rathore, L.; Jubie, S.; Gowramma, B.; Gomathy, S.; Sankar, S. Microwave assisted synthesis of some novel pyrazole substituted benzimidazoles and evaluation of their biological activities. Indian J. Chem., 2011, 50B, 1794-1799.
Vijayan, P.; Vinod Kumar, S.; Dhanaraj, S.A.; Shrishailappa, B.; Suresh, B. In vitro cytotoxicity and anti-tumor properties of the total alkaloid fraction of unripe fruits of Solanum pseudocapsicum. Pharm. Biol., 2002, 40(6), 456-460.
Philip, S.; Rista, S.; Dominic, S.; Anne, M.; James, M. New colorimetric cytotoxic assay for anti-cancer drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1115.

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