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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Synthesis and Biological Evaluation of Acridine/Acridone Analogs as Potential Anticancer Agents

Author(s): Monika Gensicka-Kowalewska, Mirosława Cichorek, Anna Ronowska, Milena Deptuła, Ilona Klejbor and Krystyna Dzierzbicka*

Volume 15, Issue 7, 2019

Page: [729 - 737] Pages: 9

DOI: 10.2174/1573406414666181015145120

Price: $65

Abstract

Background: The lack of efficacious therapy for advanced melanoma and neuroblastoma makes new approaches necessary. Therefore, many scientists seek new, more effective, more selective and less toxic anticancer drugs.

Objective: We propose the synthesis of the new functionalized analogs of 1-nitroacridine/4- nitroacridone connected to tuftsin/retro-tuftsin derivatives as potential anticancer agents.

Methods: Acridine and acridone analogues were prepared by Ullmann condensation and then cyclization reaction. As a result of nucleophilic substitution reaction 1-nitro-9-phenoxyacridine or 1- chloro-4-nitro-9(10H)-acridone with the corresponding peptides, the planned acridine derivatives (10a-c, 12, 17-a-d, 19) have been obtained. The cytotoxic activity of the newly obtained analogs were evaluated against melanotic (Ma) and amelanotic (Ab) melanoma cell lines and neuroblastoma SH-SY5Y by using the XTT method. Apoptosis and cell cycle were analyzed by flow cytometry.

Results: Among the investigated analogs compound 12 exhibited the highest potency comparable to dacarbazine action for amelanotic Ab melanoma cells. FLICA test (flurochrome-labeled inhibitors of caspases) showed that this analog significantly increased the content of cells with activated caspases (C+) among both neuroblastoma lines and only Ab melanoma line. Using phosphatidylserine (PS) externalization assay, 12 induced changes in the Ab melanoma plasma membrane structure as the externalization of phosphatidylserine (An+ cells). These changes in neuroblastoma cells were less pronounced.

Conclusion: Analog 12 could be proposed as the new potential chemotherapeutic against amelanotic melanoma form especially.

Keywords: Acridine, acridone, tuftsin, retro-tuftsin, melanoma, neuroblastoma.

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[1]
Barot, K.P.; Nikolova, S.; Ivanov, I.; Ghate, M.D. Novel anticancer agents and targets: Recent advances and future perspectives. Mini Rev. Med. Chem., 2013, 13, 1239-1255.
[2]
Kaplan-Ozen, C.; Tekiner-Gulbas, B.; Foto, E.; Yildiz, I.; Diril, N.; Aki, E.; Yalcin, I. Benzothiazole derivatives as human DNA topoisomerase II alpha inhibitors. Med. Chem. Res., 2013, 22, 5798-5808.
[3]
Prasad, V.V.S.R.; Reddy, G.D.; Kathmann, I.; Amareswararao, M. Peters, G.J. Nitric oxide releasing acridone carboxamide derivatives as reverters of doxorubicin resistance in MCF7/Dx cancer cells. Bioorg. Chem., 2016, 64, 51-58.
[4]
Geddes, C.D. Optical thin film polymeric sensors for the determination of aqueous chloride, bromide and iodide ions at high pH, based on the quenching of fluorescence of two acridinium dyes. Dyes Pigm., 2000, 45, 243-251.
[5]
Dana, S.; Prusty, D.; Dhayal, D.; Gupta, M.K.; Dar, A.; Sen, S.; Mukhopadhyay, P.; Adak, T.; Dhar, S.K. Potent antimalarial activity of acriflavine in vitro and in vivo. ACS Chem. Biol., 2014, 9, 2366-2373.
[6]
Di Giorgio, C.; De Meo, M.; Chiron, J.; Delmas, F.; Nikoyan, A.; Jean, S.; Dumenil, G.; Timon-David, P.; Galy, J.P. Synthesis and antileishmanial activities of 4,5-di-substituted acridines as compared to their 4-mono-substituted homologues. Bioorg. Med. Chem., 2005, 13, 5560-5568.
[7]
Gamega, S.A.; Spicer, J.A.; Atwell, G.J.; Finlay, G.J.; Baguley, B.C.; Denny, W.A. Structure-activity relationships for substituted bis(acridine-4-carboxamides): A new class of anticancer agents. J. Med. Chem., 1999, 42, 2383-2393.
[8]
Gensicka-Kowalewska, M.; Cholewiński, G.; Dzierzbicka, K. Recent developments in the synthesis and biological activity of acridine/acridone analogues. RSC Advances, 2017, 7, 15776-15804.
[9]
Malachowska-Ugarte, M.; Cholewinski, G.; Dzierzbicka, K.; Trzonkowski, P. Synthesis and biological activity of novel mycophenolic acid conjugates containing nitro-acridine/acridone derivatives. Eur. J. Med. Chem., 2012, 54, 197-201.
[10]
Kukowska, M. Amino acid or peptide conjugates of acridine/ acridone and quinoline/quinolone-containing drugs. A critical examination of their clinical effectiveness within a twenty-year timeframe in antitumor chemotherapy and treatment of infectious diseases. Eur. J. Pharm. Sci., 2017, 109, 587-615.
[11]
Kukowska-Kaszuba, M.; Dzierzbicka, K. Synthesis and structure-activity studies of peptide-acridine/acridone conjugates. Curr. Med. Chem., 2007, 14, 3079-3104.
[12]
Siebert, A.; Gensicka-Kowalewska, M.; Cholewiński, G.; Dzierzbicka, K. Tuftsin–properties and analogs. Curr. Med. Chem., 2017, 24, 3711-3727.
[13]
Cichorek, M.; Kozłowska, K.; Bryl, E. The activity of caspases in spontaneous and camptothecin-induced death of melanotic and amelanotic melanoma cells. Cancer Biol. Ther., 2007, 6, 346-353.
[14]
Kofoed, T.; Hansen, H.F.; Ørum, H.; Koch, T. PNA synthesis using a novel Boc/acyl protecting group strategy. J. Pept. Sci., 2001, 7, 402-412.
[15]
Dzierzbicka, K.; Trzonkowski, P.; Sewerynek, P.; Kolodziejczyk, A.M.; Myśliwski, A. Synthesis and biological activity of tuftsin, its analogue and conjugates containing muramyl dipeptides or nor-muramyl dipeptides. J. Pept. Sci., 2005, 11, 123-135.
[16]
Dzierzbicka, K.; Wardowska, A.; Rogalska, M.; Trzonkowski, P. New conjugates of muramyl dipeptide and nor-muramyl dipeptide linked to tuftsin and retro-tuftsin derivatives significantly influence their biological activity. Pharmacol. Rep., 2012, 64, 217-223.
[17]
Januchta, W.; Serocki, M.; Dzierzbicka, K.; Cholewinski, G.; Skladanowski, A. Synthesis of functionalized new conjugates of batracylin with tuftsin/retro-tuftsin derivatives and their biological evaluation. Eur. J. Med. Chem., 2015, 106, 85-94.
[18]
Ledochowski, A. Ledacrin - anticancerous medicine 1-nitro-9(3-dimethyloamino-propylamino)-acridine-2HCl-H2O. Mater. Med. Pol., 1976, 8, 237-251.
[19]
Capps, D.B. Substituted 1-amino-4-nitroacridinones, pharmaceutical compositions comprising the same and processes for their production. European Patent E.P. 0145226, October 31, 1984.
[20]
Dzierzbicka, K.; Kołodziejczyk, A.M.; Wysocka-Skrzela, B.; Myśliwski, A.; Sosnowska, D. Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyl dipeptide, and desmuramylpeptides with acridine/acridone derivatives. J. Med. Chem., 2001, 44, 3606-3615.
[21]
Bomirski, A.; Slominski, A.; Bigda, J. The natural history of a family of transplantable melanomas in hamsters. Cancer Metastasis Rev., 1988, 7, 95-118.
[22]
Bielarczyk, H.; Jankowska, A.; Madziar, B.; Matecki, A.; Michno, A.; Szutowicz, A. Differential toxicity of nitric oxide, aluminum, and amyloid b-peptide in SN56 cholinergic cells from mouse septum. Neurochem. Int., 2003, 42, 323-331.
[23]
Smolewski, P.; Grabarek, J.; Halicka, H.D.; Darzynkiewicz, Z. Assay of caspase activation in situ combined with probing plasma membrane integrity to detect three distinct stages of apoptosis. J. Immunol. Methods, 2002, 265, 111-121.
[24]
Darżynkiewicz, Z.; Williamson, B.; Carswell, E.; Old, L. Cell cycle-specific effects of tumor necrosis factor. Cancer Res., 1984, 44, 83-90.
[25]
Guo, H.F.; Kooi, C.W.V. Neuropilin functions as an essential cell surface receptor. J. Biol. Chem., 2015, 290, 29120-29126.
[26]
Graziani, G.; Lacal, P.M. Neuropilin-1 as therapeutic target for malignant melanoma. Front. Oncol., 2015, 5, 125-129.

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