Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2309–2321 | Cite as

Synthesis, spectral characterization, DNA binding ability and anti-cancer screening of new acridine-based derivatives

  • Othman M. Salem
  • Mária Vilková
  • Jana Janočková
  • Rastislav Jendželovský
  • Peter Fedoročko
  • Ján Imrich
  • Mária Kožurková
Original Research


In this study, a series of newly synthesized acridine derivatives, compounds 4, 6a, and 6b, are described and their biological activity on HL-60 cell lines is assessed using a number of different techniques. Binding studies were also performed between the derivatives and DNA in order to characterize the mechanism of the agents’ effect in more detail. The results of ultraviolet–visible absorption spectroscopy prove that the binding of derivatives 4, 6a, and 6b had occurred with a binding constant value of K = 3.5 × 104–4.0 × 104 M−1. These findings are indicative of a strong interaction between the derivatives and DNA, and this hypothesis is supported by the results of the fluorescence emission, linear dichroism, and viscometric assays.


Acridine derivatives Topoisomerases I and II HL-60 cells DNA binding 



This study was supported by Slovak Research and Development Agency under contract VVCE-0001-07, VEGA grants No. 1/0001/13, and 1/0672/11 and MH CZ-DRO (UHHK, 00179906). The authors would like to thank Jana Kašpárkova and Viktor Brabec for their advice on LD measurement and viscometric techniques.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Barros FW, Silva TG, da Rocha Pitta MG, Bezerra DP, Costa-Lotufo LV, de Moraes MO, Pessoa C, de Moura MA, de Abreu FC, de Lima Mdo C, Galdino SL, Pitta Ida R, Goulart MO (2012) Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives. Bioorg Med Chem 20:3533–3539CrossRefPubMedGoogle Scholar
  2. Barros FW, Bezerra DP, Ferreira PM, Cavalcanti BC, Silva TG, Pitta MG, de Lima Mdo C, Galdino SL, Pitta Ida R, Costa-Lotufo LV, Moraes MO, Burbano RR, Guecheva TN, Henriques JA, Pessoa C (2013) Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives. Toxicol Appl Pharmacol 268:37–46CrossRefPubMedGoogle Scholar
  3. Basili S, Basso G, Faccio A, Granzhan A, Ihmels H, Moro S, Viola G (2008) Diazoniapolycyclic ions inhibit the activity of topoisomerase I and the growth of certain tumor cell lines. ChemMedChem 31671:e1676Google Scholar
  4. Bera R, Sahoo BK, Ghosh KS, Dasgupta S (2008) Studies on the interaction of isoxazol-curcumin with calf thymus DNA. Int J Biol Macromol 42:14–21CrossRefPubMedGoogle Scholar
  5. Busa J (2006) Octave. Technical University, KosiceGoogle Scholar
  6. Cain BF, Baguley BC, Denny WA (1978) Potential antitumor agents. 28. Deoxyribonucleic acid polyintercalating agents. J Med Chem 21:658–668CrossRefPubMedGoogle Scholar
  7. Champoux JJ (2001) DNA topoisomerases: structure, function and mechanism. Ann Rev Biochem 70:369–413CrossRefPubMedGoogle Scholar
  8. Chitrapriya N, Jang YJ, Kim SK, Lee H (2011) Non-intercalative binding mode of bridged binuclear chiral Ru(II) complexes to native duplex DNA. J Inorg Biochem 105:1569–1575CrossRefPubMedGoogle Scholar
  9. Di Giorgio C, Nikoyan A, Decome L, Botta C, Robin M, Reboul J-P, Sabatier A-S, Matta A, De Méo M (2008) DNA-damaging activity and mutagenicity of 16 newly synthesized thiazolo[5,4-a]acridine derivatives with high photo-inducible cytotoxicity. Mut Res 650:104–114CrossRefGoogle Scholar
  10. Goodell JR, Ougolkov AV, Hiasa H, Kaur H, Remmel R, Billadeau DD, Ferguson DM (2008) Acridine-based agents with topoisomerase II activity inhibit pancreatic cancer cell proliferation and induce apoptosis. J Med Chem 51:179–182CrossRefPubMedGoogle Scholar
  11. Hannon MJ, Moreno V, Prieto MJ, Moldrheim E, Sletten E, Meistermann I, Isaac CJ, Sanders KJ, Rodger A (2001) Intramolecular DNA coiling mediated by a metallo-supramolecular cylinder. Angew Chem Int Ed Engl 40:879–884CrossRefPubMedGoogle Scholar
  12. Ilis M, Bucos M, Dumitrascu F, Circu V (2011) Mesomorphic behaviour of N-benzoyl-N′-aryl thioureas liquid crystalline compounds. J Mol Struct 987:1–6CrossRefGoogle Scholar
  13. Janočková J, Plšíková J, Kašpárková J, Brabec V, Jendželovský R, Mikeš J, Kovaľ J, Hamuľaková S, Fedoročko P, Kuča K, Kožurková M (2015a) Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds. Eur J Pharm Sci 76:192–202CrossRefPubMedGoogle Scholar
  14. Janočková J, Plšíková J, Kovaľ J, Jendželovský R, Mikeš J, Kašpárková J, Brabec V, Hamulaková S, Fedoročko P, Kožurková M (2015b) Tacrine derivatives as dual topoisomerase I and II catalytic inhibitors. Bioorg Chem 59:168–176CrossRefPubMedGoogle Scholar
  15. Jenkins TC (1997) Optical absorbance and fluorescence techniques for measuring DNA-drug interactions. In: Fox KR (ed) Drug-DNA interaction protocols. Human Press, Totowa, NJ, p 195. 218CrossRefGoogle Scholar
  16. Kamatchi TS, Chitrapriya N, Kim SK, Fronczek FR (2013) Influence of carboxylic acid functionalities in ruthenium(II) polypyridyl complexes on DNA binding, cytotoxicity and antioxidant activity: synthesis, structure and in vitro anticancer activity. Eur J Med Chem 59:253–264CrossRefGoogle Scholar
  17. Khan KM, Maharvi GM, Hayat S, Zia-Ullah, Choudhary MI, Atta-ur-Rahman (2003) An expedient esterification of aromatic carboxylic acids using sodium bromate and sodium hydrogen sulfite. Tetrahedron 59:5549–5554CrossRefGoogle Scholar
  18. Khurana JM, Chauhan S, Bansal G (2004) Facile hydrolysis of esters with KOH-methanol at ambient temperature. Monatshefte für Chemie 135:83–87CrossRefGoogle Scholar
  19. Lafayette EA, De Almeida SV, Da Rocha Pitta MG, Beltrao EIC, Da Silva TG, De Moura RO, Da Rocha Pitta I, De Carvalho Júnior LB, De Lima MDCA (2013) Synthesis, DNA binding and topoisomerase I inhibition activity of thizacridine and imidazacridine derivatives. Molecules 18:15035–15050CrossRefPubMedGoogle Scholar
  20. Lang X, Li L, Chen Y, Sun Q, Wu Q, Liu F, Tan C, Liu H, Gao C, Jiang Y (2013) Novel synthetic acridine derivatives as potent DNA-binding and apoptosis-inducing antitumor agents. Bioorg Med Chem 21:4170–4177CrossRefPubMedGoogle Scholar
  21. Li X, Ma D, Yang H, Tan G, Du H, Wang K, Zhang P, Chen H (2014) Synthesis, antitumor activity and DNA binding of acridine-polyamine conjugates. Chem J Chinese U 35:1181–1188Google Scholar
  22. Li WY, Xu JG, Guo XQ, Zhu QZ, Zhao YB (1997) Study on the interaction between rivanol and DNA and its application to DNA assay. Spectrochim Acta A 53:781–787CrossRefGoogle Scholar
  23. Ling X, Zhong WY, Huang Q, Ni KY (2008) Spectroscopic studies on the interaction of pazufloxacin with calf thymus DNA. J Photochem Photobiol B 93:172–176CrossRefPubMedGoogle Scholar
  24. McGhee JD, von Hippel PH (1974) Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one dimensional homogeneous lattice. J Mol Biol 86:469–489CrossRefPubMedGoogle Scholar
  25. Moukharskaya J, Verschraegen C (2012) Topoisomerase 1 inhibitors and cancer therapy. Hematol Oncol Clin North Am 26:507–525CrossRefPubMedGoogle Scholar
  26. Neyhart GA, Grover N, Smith SR, Kalsbeck WA, Fairley TA, Cory M, Thorp HH (1993) Binding and kinetics studies of oxidation of DNA by oxoruthenium(IV). J Am Chem Soc 115:4423–4428CrossRefGoogle Scholar
  27. Ouberai M, Asche C, Carrez D, Croisy A, Dumy P, Demeunynck M (2006) 3,4-Dihydro-1H-[1,3]oxazino[4,5-c]acridines as a new family of cytotoxic drugs. Bioorg Med Chem Lett 16:4641–4643CrossRefPubMedGoogle Scholar
  28. Patel DJ (1979) Nuclear magnetic resonance studies of drug-nucleic acid interactions at the synthetic DNA level in solution. Acc Chem Res 12:118–125CrossRefGoogle Scholar
  29. Phelps C, Lee W, Jose D, von Hippel PH, Marcus AH (2013) Single-molecule FRET and linear dichroism studies of DNA breathing and helicase binding at replication fork junction. Proc Natl Acad Sci USA 110:17320–17325CrossRefPubMedPubMedCentralGoogle Scholar
  30. Rajendran A, Nair BU (2006) Unprecedented dual binding behaviour of acridine group of dye: a combined experimental and theoretical investigation for the development of anticancer chemotherapeutic agents. Biochim Biophys Acta 1760:1794–1801CrossRefPubMedGoogle Scholar
  31. Ramalinga K, Vijayalakshmi P, Kaimal TNB (2002) A mild and efficient method for esterification and transesterification catalyzed by iodine. Tetrahedron Lett 43:879–882CrossRefGoogle Scholar
  32. Rehman SU, Yaseen Z, Husain MA, Sarwar T, Ishqi HM, Tabish M (2014) Interaction of 6 mercaptopurine with calf thymus DNA—deciphering the binding mode and photoinduced DNA damage. PLoS ONE 9:e93913CrossRefPubMedPubMedCentralGoogle Scholar
  33. Salem O, Vilkova M, Plsikova J, Grolmusova A, Burikova M, Prokaiova M, Paulikova H, Imrich J, Kozurkova M (2015) DNA binding, anti-tumour activity and reactivity toward cell thiols of acridin-9-ylalkenoic derivatives. J Chem Sci 127:931–940CrossRefGoogle Scholar
  34. Salem OM, Vilková M, Janočková J, Jendželovský R, Fedoročko P, Žilecká E, Kašpárková J, Brabec V, Kožurková M (2016) New spiro tria(thia)zolidine-acridines as topoisomerase inhibitors, DNA binders and cytostatic compounds. Int J Biol Macromol 86:690–700CrossRefPubMedGoogle Scholar
  35. Su T-L, Lin Y-W, Chou T-C, Zhang X, Bacherikov VA, Chen C-H, Liu LF, Tsai TJ (2006) Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity. J Med Chem 49:3710–3718CrossRefPubMedGoogle Scholar
  36. Terenzi A, Ducani C, Male L, Barone G, Hannon MJ (2013) DNA interaction of CuII, NiII and ZnII functionalized salphen complexes: studies by linear dichroism, gel electrophoresis and PCR. Dalton Trans 42:11220–11226CrossRefPubMedGoogle Scholar
  37. Tsukamoto I, Koshio H, Kuramochi T, Saitoh C, Yanai-Inamura H, Kitada-Nozawa C, Yamamoto E, Yatsu T, Shimada Y, Sakamoto S, Tsukamoto S (2009) Synthesis and structure–activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetic acid as selective arginine vasopressin V2 receptor agonists. Bioorg Med Chem 17:3130–3141CrossRefPubMedGoogle Scholar
  38. Ungvarská Maľučká L, Vilková M, Kožíšek J, Imrich J (2016) Strong deshielding in aromatic isoxazolines. Magn Reson Chem 54:17–27CrossRefPubMedGoogle Scholar
  39. Vantova Z, Paulikova H, Sabolova D, Kozurkova M, Suchanova M, Janovec L, Kristian P, Imrich J (2009) Cytotoxic activity of acridin-3,6-diyl dithiourea hydrochlorides in human leukemia line HL-60 and resistant subline HL-60/ADR. Int J Biol Macromol 45:174–180CrossRefPubMedGoogle Scholar
  40. Vilková M, Ungvarská Maľučká L, Imrich J (2016) Prediction by 13C NMR of regioselectivity in 1,3-dipolar cycloadditions of acridin-9-yl dipolarophiles. Magn Reson Chem 54:8–16CrossRefPubMedGoogle Scholar
  41. Vos SM, Tretter EM, Schmidt BH, Berger JM (2011) All tangled up: how cells direct manages and exploits topoisomerase function. Nature Rev 12:827–841CrossRefGoogle Scholar
  42. Yao B-L, Mai Y-W, Chen S-B, Xie H-T, Yao P-F, Ou T-M, Tan J-H, Wang H-G, Li D, Huang S-L, Gu L-Q, Huang Z-S (2015) Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors. Bioorg Med Chem 92:540–553Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Othman M. Salem
    • 1
  • Mária Vilková
    • 2
  • Jana Janočková
    • 1
    • 3
  • Rastislav Jendželovský
    • 4
  • Peter Fedoročko
    • 4
  • Ján Imrich
    • 2
  • Mária Kožurková
    • 1
    • 3
  1. 1.Department of BiochemistryP. J. Šafárik UniversityKošiceSlovakia
  2. 2.Department of Organic Chemistry, Institute of ChemistryP. J. Šafárik UniversityKošiceSlovakia
  3. 3.Biomedical Research CenterUniversity Hospital Hradec KraloveHradec KraloveCzech Republic
  4. 4.Department of Cellular Biology, Faculty of Science, Institute of Biology and EcologyP. J. Šafárik UniversityKošiceSlovakia

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