9-Anilinoacridines as anticancer drugs
The information about the structures, synthesis and biological activity of 9-anilinoacridines, highly active anticancer drugs studied in the last decade was reviewed. Structure – property relationships of the leading compounds 4’-(9-acridinylamino)-metansulfon-m-anisidine (m-AMSA) and 3-(9-acridinylamino)-5-hydroximethylaniline (AHMA), their mechanism of biological action aimed at inhibition of the ternary complex of DNA – Topoisomerase II – Drug and mechanisms of their degradation and excretion were considered. Among the new derivatives of 9-anilinoacridine the hybrids of AHMA and DNA minor groove binding agents, such as Distamycin A or Netropsin, were discussed. Hybrid molecules able to interact with the DNA by anilinoacridine residue and inhibit topoisomerase II, as well as conjugate to the minor groove of DNA, should show significant increasing of selectivity and proper high activity, and will also less contribute to drug resistance in cancer cells. Investigation of biological activity of 5-(9-acridinylamino)-o, m, p-toluidines and 5-(9-acridinylamino)-o, m, p-anisidines, which were synthesized in order to design of an anticancer agent molecule having high activity and low toxicity, was considered. The modification of the 9-anilinoacridine molecule by the variety of substituents and linkers, and the synthesis and cytotoxicity of hybrid compounds composed from 9-anilinoacridine molecule and nitrogen mustards attached to aniline and acridine residues were discussed in details.
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World Health Organisation, Cancer. WHO Fact sheet N°297, 2014. (accessed August 23, 2014).
Su, T. L. Development of DNA topoisomerase II-mediated anticancer agents, 3-(9-acridinylamino)-5-hydroxymethyl-anilines (AHMAs) and related compounds. Curr. Med. Chem., 2002, vol. 9, no. 18, P. 1677‒1688.
Dopierala, A., Wrosz, P., Mazerski, J. Acridines as antitumor drugs. Postepy Hig. Medyc. Dosw. (Online), 2011, vol. 65, P. 263‒269.
Denny, W. A. Acridine derivatives as chemotherapeutic agents. Curr. Med. Chem., 2002, vol. 9, no. 18, P. 1655‒1665.
Martinez, R., Chacon-Garcia, L. The search of DNA-intercalators as antitumoral drugs: what it worked and what did not work. Curr. Med. Chem., 2005, vol. 12, no. 2, P. 127‒151.
Guichard, S. M., Danks, M. K. Topoisomerase enzymes as drug targets. Curr. Opin. Oncology, 1999, vol. 11, no. 6, P. 482‒489.
Kaufmann, W. K., Boyer, J. C., Estabrooks, L. L., Wilson, S. J. Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes. Mol. Cell. Biology, 1991, vol. 11, no. 7, P. 3711‒3718.
Denny, W. A. Emerging DNA topisomerase inhibitors as anticancer drugs. Expert Opin. on Emerg. Drugs., 2004, vol. 9, no. 1, P. 105‒133.
Gao, H., Denny, W. A., Garg, R., Hansch, C. Quantitative structure-activity relationships (QSAR) for 9-anilinoacridines: a comparative analysis. Chem.-Biol. Inter., 1998, vol. 116, no. 3, P. 157‒180.
Loza-Mejia, M. A., Castillo, R., Lira-Rocha, A. Molecular modeling of tricyclic compounds with anilino substituents and their intercalation complexes with DNA sequences. J. Mol. Graphics & Modelling, 2009, vol. 27, no. 8, P. 900‒907.
Hardy, J. R. CI-921 : a clinical, pharmacokinetic and metabolic study of a potential new cytotoxic agent. Thesis (MD). – University of Auckland., 1989, 315 p.
Fyfe, D., Raynaud, F., Langley, R. E., Newell, D. R., Halbert, G., Gardner, C., Clayton, K., Woll, P. J., Judson, I., Carmichael, J. A study of amsalog (CI-921) administered orally on a 5-day schedule, with bioavailability and pharmacokinetically guided dose escalation. Cancer Chemother. Pharm., 2002, vol. 49, no. 1, P. 1‒6.
Harvey, V. J., Hardy, J. R., Smith, S., Grove, W., Baguley, B. C. Phase II study of the amsacrine analogue CI-921 (NSC 343499) in non-small cell lung cancer. Eur. J. Cancer, 1991, vol. 27, no. 12, P. 1617‒1620.
Robertson, I. G., Kestell, P., Dormer, R. A., Paxton, J. W. Involvement of glutathione in the metabolism of the anilinoacridine antitumour agents CI-921 and amsacrine. Drug metabolism and drug interactions, 1988, vol. 6, no. 3‒4, P. 371‒381.
Robertson, I. G., Palmer, B. D., Paxton, J. W., Shaw, G. J. Differences in the metabolism of the antitumour agents amsacrine and its derivative CI-921 in rat and mouse. Xenobiotica, 1992, vol. 22, no. 6, P. 657‒669.
Kestell, P., Paxton, J. W., Evans, P. C., Young, D., Jurlina, J. L., Robertson, I. G., Baguley, B. C. Disposition of amsacrine and its analogue 9-([2-methoxy-4-[(methylsulfonyl)amino]phenyl]-amino)-N,5-dimethyl-4-acridinecarboxamide (CI-921) in plasma, liver, and Lewis lung tumors in mice. Cancer research, 1990, vol. 50, no. 3, P. 503‒508.
Jangir, D. K., Kundu, S., Mehrotra, R. Role of minor groove width and hydration pattern on amsacrine interaction with DNA. PloS one, 2013, vol. 8, no. 7, e69933.
Kaldor, J. M., Day, N. E., Hemminki, K. Quantifying the carcinogenicity of antineoplastic drugs. Eur. J. Cancer & Clinical Oncology, 1988, vol. 24, no. 4, P. 703‒711.
Su, T. L., Chou, T. C., Kim, J. Y., Huang, J. T., Ciszewska, G., Ren, W. Y., Otter, G. M., Sirotnak, F. M., Watanabe, K. A. 9-Substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relation-ships. J. Med. Chem., 1995, vol. 38, no. 17, P. 3226‒3235.
Scarborough, A., Su, T.-L., Leteutre, F. F., Pommier, Y., Chou, T.-C. DNA interaction and topoisomerase II inhibition by the antitumor agent 3′-(9-Acridinylamino)-5′-hydroxy-methylaniline and derivatives. Bioorg. Chem., 1996, vol. 24, no. 3, P. 229‒241.
Su, T. L., Chen, C. H., Huang, L. F., Chen, C. H., Basu, M. K., Zhang, X. G., Chou, T. C. Synthesis and structure-activity relationships of potential anticancer agents: alkylcarbamates of 3-(9-acridinylamino)-5-hydroxy-methylaniline. J. Med. Chem., 1999, vol. 42, no. 23, P. 4741‒4748.
Siniakov, A. N., Riabinin, V. A., Seregin, S. V., Lokhov, S. G., Kutiavin, I. V., Gamper, H. B., Mayer, R. B. Selective stabilization of AT-rich DNA duplexes by oligodeoxyribonucleotide conjugates with distamycin analogues. Bioorganicheskaia khimiia, 1997, vol. 23, no. 7, P. 544‒552.
Wartell, R. M., Larson, J. E., Wells, R. D. Netropsin. A specific probe for A-T regions of duplex deoxyribonucleic acid. J. Biol. Chem., 1974, vol. 249, no. 21, P. 6719‒6731.
Kopka, M. L., Yoon, C., Goodsell, D., Pjura, P., Dickerson, R. E. The molecular origin of DNA-drug specificity in netropsin and distamycin. Proc. Natl. Acad. Sci. USA 1985, vol. 82, no. 5, P. 1376‒1380.
Neidle, S., Pearl, L. H., Skelly, J. V. DNA structure and perturbation by drug binding. Biochem. J., 1987, vol. 243, no. 1, P. 1‒13.
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, vol. 45, no. 20, P. 4485‒4493.
Chang, J. Y., Lin, C. F., Pan, W. Y., Bacherikov, V., Chou, T. C., Chen, C. H., Dong, H., Cheng, S. Y., Tasi, T. J., Lin, Y. W., Chen, K. T., Chen, L. T., Su, T. L. New analogues of AHMA as potential antitumor agents: synthesis and biological activity. Bioorg. Med. Chem., 2003, vol. 11, no. 23, P. 4959‒4969.
Bacherikov, V. A., Chang, J. Y., Lin, Y. W., Chen, C. H., Pan, W. Y., Dong, H., Lee, R. Z., Chou, T. C., Su, T. L. Synthesis and antitumor activity of 5-(9-acridinyl-amino)anisidine derivatives. Bioorg. Med. Chem., 2005, vol. 13, no. 23, P. 6513‒6520.
Godwin, A. K., Meister, A., O'Dwyer, P. J., Huang, C. S., Hamilton, T. C., Anderson, M. E. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc. Nat. Acad.Sci.USA, 1992, vol. 89, no. 7, P. 3070‒3074.
Tanaka, T., Kurokawa, H., Matsuno, K., Matsumoto, S., Hayashida, Y. Increased glutathione level is not involved in enhanced bleomycin sensitivity in cisplatin-resistant 2780CP cells. Anticancer research 2008, vol. 28, no. 5a, P. 2663‒2668.
Shen, H., Kauvar, L., Tew, K. D. Importance of glutathione and associated enzymes in drug response. Oncology res. 1997, vol. 9, no. 6‒7, P. 295‒302.
Baguley, B. C. The possible role of electron-transfer complexes in the antitumour action of amsacrine analogues. Biophys. Chem., 1990, vol. 35, no. 2‒3, P. 203‒212.
Robertson, I. G., Palmer, B. D., Shaw, G. J. The characterization of two biliary glutathione conjugates of amsacrine using liquid secondary ion mass spectrometry. Biol. Mass Spectrom., 1993, vol. 22, no. 11, P. 661‒665.
Moorthy, N. S. H. N., Trivedi P. QSAR Modeling of some 2-methoxy acridones: cytotoxic agents in multi drug resistant cells. Int. J. Cancer Res., 2006, no. 2, P. 267‒276.
Bacherikov, V. A., Chou, T. C., Dong, H. J., Chen, C. H., Lin, Y. W., Tsai, T. J., Su, T. L., Potent antitumor N-mustard derivatives of 9-anilinoacridine, synthesis and antitumor evaluation. Bioorg. Med. Chem. Lett., 2004, vol. 14, no. 18, P. 4719‒4722.
Bacherikov, V. A., Chou, T. C., Dong, H. J., Zhang, X., Chen, C. H., Lin, Y. W., Tsai, T. J., Lee, R. Z., Liu, L. F., Su, T. L. Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: synthesis and biological activity. Bioorg. Med. Chem., 2005, vol. 13, no. 12, P. 3993‒4006.
Hande, K. R. Etoposide: four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer 1998, vol. 34, no. 10, P. 1514‒1521.
Su, T. L., Lin, Y. W., Chou, T. C., Zhang, X., Bacherikov, V. A., Chen, C. H., Liu, L. F., Tsai, T. J. Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity. J. Med. Chem., 2006, vol. 49, no. 12, P. 3710‒3718.
Belmont, P., Bosson, J., Godet, T., Tiano, M. Acridine and acridone derivatives, anticancer properties and synthetic methods: where are we now? Anti-cancer Agents in Med. Chem., 2007, vol. 7, no. 2, P. 139‒169.
Kapuriya, N., Kapuriya, K., Zhang, X., Chou, T. C., Kakadiya, R., Wu, Y. T., Tsai, T. H., Chen, Y. T., Lee, T. C., Shah, A., Naliapara, Y., Su, T. L. Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage. Bioorg. Med. Chem., 2008, vol. 16, no. 10, P. 5413‒5423.
Chu, P. M., Chiou, S. H., Su, T. L., Lee, Y. J., Chen, L. H., Chen, Y. W., Yen, S. H., Chen, M. T., Chen, M. H., Shih, Y. H., Tu, P. H., Ma, H. I. Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response. Radiation oncology (London, England), 2011, no. 6, P. 7.
Chu, P. M., Chen, L. H., Chen, M. T., Ma, H. I., Su, T. L., Hsieh, P. C., Chien, C. S., Jiang, B. H., Chen, Y. C., Lin, Y. H., Shih, Y. H., Tu, P. H., Chiou, S. H. Targeting autophagy enhances BO-1051-induced apoptosis in human malignant glioma cells. Cancer Chemother. Pharm., 2012, vol. 69, no. 3, P. 621‒633.
Chen, L. H., Loong, C. C., Su, T. L., Lee, Y. J., Chu, P. M., Tsai, M. L., Tsai, P. H., Tu, P. H., Chi, C. W., Lee, H. C., Chiou, S. H. Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway. Biochem. Pharm., 2011, vol. 81, no. 5, P. 594‒605.
Lo, W. L., Chu, P. Y., Lee, T. H., Su, T. L., Chien, Y., Chen, Y. W., Huang, P. I., Tseng, L. M., Tu, P. H., Kao, S. Y., Lo, J. F. A Combined DNA-affinic molecule and N-mustard alkylating agent has an anti-cancer effect and induces autophagy in oral cancer cells. Int. J. Mol. Sci., 2012, vol. 13, no. 3, P. 3277‒3290.
Chen, C. H., Lin, Y. W., Zhang, X., Chou, T. C., Tsai, T. J., Kapuriya, N., Kakadiya, R., Su, T. L. Synthesis and in vitro cytotoxicity of 9-anilinoacridines bearing N-mustard residue on both anilino and acridine rings. Eur. J. Med. Chem., 2009, vol. 44, no. 7, P. 3056‒3059.
Kapuriya, N., Kapuriya, K., Dong, H., Zhang, X., Chou, T. C., Chen, Y. T., Lee, T. C., Lee, W. C., Tsai, T. H., Naliapara, Y., Su, T. L. Novel DNA-directed alkylating agents: design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker. Bioorg. Med. Chem. 2009, vol. 17, no. 3, P. 1264‒1275.
Chen, K. M., Sun, Y. W., Tang, Y. W., Sun, Z. Y., Kwon, C. H. Synthesis and antitumor activity of sulfurcontaining 9-anilinoacridines. Mol. Pharmaceutics, 2005, vol. 2, no. 2, P. 118‒128.
Park, S. K., Kang, H., Kwon, C. H. Caspase-dependent cell death mediates potent cytotoxicity of sulfide derivatives of 9-anilinoacridine. Anti-cancer Drugs, 2008, vol. 19, no. 4, P. 381‒389.
Kalirajan, R., Kulshrestha, V., Sankar, S., Jubie, S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their antioxidant and anticancer activities as topoisomerase II inhibitors. Eur. J. Med. Chem., 2012, vol. 56, P. 217‒224.
Kalirajan, R., Rafick, M. H., Sankar, S., Jubie, 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), P. 1‒6.
Lang Xuliang, L. X., Gao Chunmei, Jiang Yuyang. Recent progress of acridine derivatives with antitumor activity. Progress in Chemistry 2012, vol. 24, no. 08, P. 1497‒1505.
Gellerman, G., Waintraub, S., Albeck, A., Gaisin, V. One-pot synthesis of novel antiproliferative 9-aminoacridines. Eur. J. Org. Chem., 2011, no. 22, P. 4176‒4182.
Redko, B., Albeck, A., Gellerman, G. Facile synthesis and antitumor activity of novel N(9) methylated AHMA analogs. New J. Chem., 2012, vol. 36, no. 11, P. 2188‒2191.
Kukowska-Kaszuba, M., Dzierzbicka, K. Synthesis and structure-activity studies of peptide-acridine/acridone conju-gates. Curr. Med. Chem., 2007, vol. 14, no. 29, P. 3079‒3104.
Wang, J., Luo, T., Li, S., Zhhang, Y., Wang, C., Zhao, J. Synthesis, structure-activity relationship and biological activity of acridine derivatives as potent MDR-reversing agents. Curr. Med. Chem., 2013, vol. 20, no. 32, P. 4070‒4079.
Cholewinski, G., Dzierzbicka, K., Kolodziejczyk, A. M. Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis. Pharmacol. Reports, 2011, vol. 63, no. 2, P. 305‒336.
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