Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Author(s): Lily Andonova, Iva Valkova, Dimitrina Zheleva-Dimitrova, Maya Georgieva*, Georgi Momekov and Alexander Zlatkov

DOI: 10.2174/1871520619666190121155651

DownloadDownload PDF Flyer Cite As
Synthesis of New N1Arylpiperazine Substituted Xanthine Derivatives and Evaluation of their Antioxidant and Cytotoxic Effects

Page: [528 - 537] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Cancer is one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases in 2012, with most of the clinically used drugs being ineffective. Methylxanthines have raised more interest in research on modifying their structure because of their diverse biological activity. In addition, the piperazine nucleus is one of the most important heterocycles exhibiting remarkable pharmacological activities.

Methods: The structure of the obtained compounds was characterized and elucidated by IR, 1H and 13C NMR and LCMS spectral analysis. The purity of the substances was proven by corresponding melting points and elemental analysis. The antioxidant activity was evaluated by four common methods – DPPH, ABTS, FRAP and lipid peroxidation assay. The cytotoxic effects of the tested series were evaluated using the standard MTT-dye reduction assay on three tumour cell lines.

Results: A series of new xanthine derivatives comprising an arylpiperazine moiety at N1 were synthesized. The cytotoxicity against human T-cell leukemia cell SKW-3, human acute myeloid leukemia HL-60 and human Bcell precursor leukemia cell REH was evaluated. The relationship between the structure and citotoxicity of the compounds was investigated by quantitative structure-activity relationship (QSAR) analysis and the important structural parameters were drawn.

Conclusion: The highest antioxidant activity was demonstrated by compound 6c. The highest cytotoxic effect was observed for compound 6f. It was found that cytotoxicity against SKW-3 depends on the electron density distribution in the structures. Branching of the molecular skeleton and introduction of heteroatoms like fluorine and sulfur in the structures also significantly improved the antiproliferative activity of the compounds.

Keywords: Aralkylpiperazine, theobromine, antioxidant effect, cytotoxicity, QSAR, leukemia cell SKW-3.

Graphical Abstract

[1]
Ferlay, J.; Soerjomataram, I.; Ervik, M.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon, France: International agency for research on cancer; 2013. Available at: http://globocan. iarc.fr (Accessed May 08, 2018).
[2]
Bansal, Y.; Silakari, O. Multifunctional compounds: Smart molecules for multifactorial diseases. Eur. J. Med. Chem., 2014, 76, 31-42.
[3]
Mohsin, S.; Mahadevan, R.; Kurup, M.G. Free-radical-scavenging activity and antioxidant effect of ascophyllan from marine brown algae Padinatetrastromatica. Biomed. Prev. Nutr., 2014, 4, 75-79.
[4]
López-Alarcóna, C.; Denicola, A. Evaluating the antioxidant capacity of natural products: A review on chemical and cellular-based assays. Anal. Chim. Acta, 2013, 763, 1-10.
[5]
Boike, G.M.; Petru, E.; Sevin, B.U.; Averette, H.E.; Chou, T.C.; Penalver, M.; Donato, D.; Schiano, M.; Hilsenbeck, S.G.; Perras, J. Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line. Gynecol. Oncol., 1990, 38(3), 315-322.
[6]
Husain, A.; Rosales, N.; Schwartz, G.K.; Spriggs, D.R. Lisofylline sensitizes p53 mutant human ovarian carcinoma cells to the cytotoxic effects of cis-diamminedichloroplatinum (II). Gynecol. Oncol., 1998, 70(1), 17-22.
[7]
Smith, K.S.; Folz, B.A.; Adams, E.G.; Bhuyan, B.K. Synergistic and additive combinations of several antitumor drugs and other agents with the potent alkylating agent adozelesin. Cancer Chemother. Pharmacol., 1995, 35(6), 471-482.
[8]
Zlatkov, A.; Peikov, P.; Momekov, G.; Pencheva, I.; Tsvetkova, B. Synthesis, stability and computational study of some ester derivatives of theophylline-7-acetic acid with antiproliferative activity. Der. Pharma Chem., 2010, 2(6), 197-210.
[9]
Obniska, J.; Pawłowski, M.; Kołaczkowski, M.; Czopek, A.; Duszyńska, B.; Kłodzińska, A.; Tatarczyńska, E.; Chojnacka-Wójcik, E. Synthesis and 5-HT1A/5-HT2A receptor activity of new N-[3-(4-phenylpiperazin-1-yl)-propyl] derivatives of 3-spiro-cyclohexane pyrrolidine-2,5-dione and 3-spiro-β-tetralonepyrrolidine-2,5-dione. Pol. J. Pharmacol., 2003, 55, 553-557.
[10]
Pietrzycka, A.; Stepniewski, M.; Waszkielewicz, A.M.; Marona, H. Preliminary evaluation of antioxidant activity of some 1-(phenoxyethyl)-piperazine derivatives. Acta Poloniae Pharm. Drug Res., 2006, 63(1), 19-24.
[11]
Georgieva, M.; Kondeva-Burdina, M.; Mitkov, J.; Tzankova, V.; Momekov, G.; Zlatkov, A.L. Determination of the antiproliferative activity of new theobromine derivatives and evaluation of their in vitro hepatotoxic effects. Anticancer. Agents Med. Chem., 2016, 16, 925-932.
[12]
Andonova, L.; Zheleva-Dimitrova, D.; Georgieva, M.; Zlatkov, A.L. Synthesis and antioxidant activity of some 1-aryl/aralkyl piperazine derivativeswith xanthine moiety at N4. Biotechnol. Biotechnol. Equip., 2014, 28(6), 1165-1171.
[13]
Zheleva-Dimitrova, D.; Balabanova, V. Antioxidant and acetylcholinesterase inhibitory potential of Arnica montana cultivated in Bulgaria. Turk. J. Biol., 2012, 36, 732-737.
[14]
Arnao, M.; Cano, A.; Acosta, M. The hydrophilic and lipophilic contribution to total antioxidant activity. Food Chem., 2001, 73, 239-244.
[15]
Benzie, I.; Strain, J. The Ferric Reducing Ability of Plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal. Biochem., 1996, 239, 70-76.
[16]
Takao, T.; Kitatani, F.; Watanabe, N.; Yagi, A.; Sakata, K. A simple screening method for antioxidants and isolation of several antioxidants produced by marine bacteria from fish and shellfish. Biosci. Biotechnol. Biochem., 1994, 58, 1780-1783.
[17]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferationand cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[18]
Konstantinov, S.M.; Eibl, H.; Berger, M.R. BCR-ABL influences the antileukaemic efficacyof alkylphosphocholines. Br. J. Haematol., 1999, 107(2), 365-380.
[19]
Hocquet, A.; Langgard, M. An evaluation of the MM+force field. J. Mol. Model., 1998, 4, 94-112.
[20]
Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P. AM1: A new general purpose quantum mechanical model. J. Am. Chem. Soc., 1985, 107, 3902-3909.
[21]
Leardi, R.; Boggia, R.; Terrile, M. Genetic algorithms as a strategyfor feature selection. J. Chem., 1992, 6, 267-281.
[22]
Peikov, P.; Sidzhakova, D.; Gagausov, J. Laboratory technology of synthesis of 1-(3-iodoropropyl)-3,7-dimethylxanthine. Farmacia, 1988, 38, 1-4.