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Synthesis and antiproliferative activity of cyclic arylidene ketones: a direct comparison of monobenzylidene and dibenzylidene derivatives

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Abstract

To give further insight into the influence of the structural modifications of enones and dienones on their antiproliferative properties, 25 derivatives of enones: (E)-2-benzylidene-1-cyclohexanones, (E)-2-benzylidene-1-tetralones, (E)-2-benzylidene-1-indanone, and dienones: (E,E)-2,5- or 2,6-dibenzylidene-1-cyclanones, (E,E)-3,5-dibenzylidene-4-piperidones were synthesized using a newly developed “one-pot” synthetic method. Due to the fact that all of them have the same aryl substituents (phenyl or 4-chlorophenyl) in the arylidene moiety, it is possible to compare the relevant contribution of the single-point structural modifications (type of ring or N-substitution) on their potency on the basis of their IC 50 values. Their antiproliferative activity was evaluated against the following four human adherent cancer cell lines: HeLa, A431, A2780, and MCF7. The cytotoxicity screen has revealed that the dibenzylidene dienones in general dominate the monobenzylidene enones in this respect. The nitrogen-containing heterocyclic dienones at the same time displayed higher inhibitory properties toward these human carcinoma cell lines compared with their homocyclic dienone analogs. One of the eight newly prepared 4-piperidone derivatives, N-(γ-oxobutyl)-(E,E)-3,5-bis(p-chlorobenzylidene)-4-piperidone is as potent a cell growth inhibitor (IC 50 of 0.438–1.409 μM) as the N-methyl-(E,E)-3,5-bis(p-chlorobenzylidene)-4-piperidone (IC 50 of 0.447–1.048 μM), one of the most active among the previously described compounds in this series. Catalytic hydrogen-transfer isomerization of compounds with two exocyclic benzylidene double bonds to derivatives with endocyclic double bonds results in the complete loss of antiproliferative activity. The structural modifications and 50 % inhibitory concentration (IC 50) values resulted in correlations which can promote the design of more potent derivatives of the 4-piperidone dienones.

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References

  1. Dimmock JR, Kandepu NM, Nazarali AJ, Kowalchuk TP, Motaganahalli N, Quail JW, Mykytiuk PA, Audette GF, Prasad L, Perjési P, Allen TM, Santos CL, Szydlowsky J, De Clerck E, Balzarini J (1999) J Med Chem 42:1358

    Article  CAS  Google Scholar 

  2. Dimmock JR, Zello GA, Oloo EO, Quail JW, Kraatz H, Perjési P, Aradi F, Takács-Novák K, Allen TM, Santos CL, Balzarini J, De Clerck E, Stables JP (2002) J Med Chem 45:3103

    Article  CAS  Google Scholar 

  3. Perjési P, Das U, De Clerck E, Balzarini J, Kawase M, Sakagami H, Stables JP, Lóránd T, Rózmer Zs, Dimmock JR (2008) Eur J Med Chem 43:839

    Article  Google Scholar 

  4. Selvendiran K, Ahmed S, Dayton A, Kuppusamy ML, Tazi M, Bratasz A, Tong L, Rivera BK, Kálai T, Hideg K, Kuppusamy P (2010) Free Radic Biol Med 48:1228

    Article  CAS  Google Scholar 

  5. Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P, Khan SR (2006) Bioorg Med Chem 14:3491

    Article  CAS  Google Scholar 

  6. Karthikeyan NS, Sathiyanarayanan KI, Aravindan PG, Giridharan P (2011) Med Chem Res 20:81

    Article  CAS  Google Scholar 

  7. Lagisetti P, Vilekar P, Sahoo K, Anant S, Awasthi V (2010) Bioorg Med Chem 18:6109

    Article  Google Scholar 

  8. Jha A, Mukherjee C, Prasad AK, Parmar VS, De Clerck E, Balzarini J, Stables JP, Manavathu EK, Shrivastav A, Sharma RK, Nienaber KH, Zello GA, Dimmock JR (2007) Bioorg Med Chem 15:5854

    Article  CAS  Google Scholar 

  9. Pati HN, Das U, Das S, Bandy B, De Clerck E, Balzarini J, Kawase M, Sakagami H, Quail JW, Stables JP, Dimmock JR (2009) Eur J Med Chem 44:54

    Article  CAS  Google Scholar 

  10. Pati HN, Das U, Quail JW, Kawase M, Sakagami H, Dimmock JR (2008) Eur J Med Chem 43:1

    Article  CAS  Google Scholar 

  11. Das U, Alcorn J, Shrivastav A, Sharma RK, De Clerck E, Balzarini J, Dimmock JR (2007) Eur J Med Chem 42:71

    Article  CAS  Google Scholar 

  12. Das U, Sakagami H, Chu Q, Wang Q, Kawase M, Selvakumar P, Sharma RK, Dimmock JR (2010) Bioorg Med Chem Lett 20:912

    Article  CAS  Google Scholar 

  13. Dimmock JR, Padmanilayam MP, Puthucode RN, Nazarali AJ, Motaganahalli NL, Zello GA, Quail JW, Oloo EO, Kraatz H, Prisciak JA, Allen TM, Santos CL, Balzarini J, De Clerck E, Manavathu E (2001) J Med Chem 44:586

    Article  CAS  Google Scholar 

  14. Das S, Das U, Varela-Ramirez A, Lema C, Aguilera RJ, Balzarini J, De Clerck E, Dimmock SG, Gorecki DKJ, Dimmock JR (2011) ChemMedChem 6:1892

    Article  CAS  Google Scholar 

  15. Dimmock JR, Smith LM, Smith PJ (1980) Can J Chem 58:984

    Article  CAS  Google Scholar 

  16. Baluja G, Municio AM, Vega S (1964) Chem Ind 2053

  17. Sun A, Lu YJ, Hu H, Shoji M, Liotta DC, Snyder JP (2009) Bioorg Med Chem Lett 19:6627

    Article  CAS  Google Scholar 

  18. Dimmock JR, Kumar P, Chen M, Quail JW, Yang J, Allen TM, Kao GY (1995) Pharmazie 50:449

    CAS  Google Scholar 

  19. Dimmock JR, Raghavan SK, Logan BM, Bigam GE (1980) Eur J Med Chem 18:248

    Google Scholar 

  20. Mutus B, Wagner JD, Talpas CJ, Dimmock JR, Phillips OA, Reid RS (1989) Anal Biochem 177:237

    Article  CAS  Google Scholar 

  21. Benvenuto JA, Connor TH, Monteith DK, Laidlow JA, Adams SC, Matney TS, Theiss JC (1993) J Pharm Sci 82:988

    Article  CAS  Google Scholar 

  22. Dimmock JR, Arora VK, Wonko SL, Hamon NW, Quail JW, Jia Z, Warrington RC, Fang WD, Lee JS (1990) Drug Res Deliv 6:183

    CAS  Google Scholar 

  23. Perjési P, Földesi A, Szabó D, Zschunke A, Mak M (1987) Chem Ber 120:1449

    Article  Google Scholar 

  24. Popkov SV, Kovalenko LV, Bobylev MM, Molchanov OY, Krimer MZ, Tashchi VP, Putsykin YG (1997) Pestic Sci 49:125

    Article  CAS  Google Scholar 

  25. Sohár P, Csámpai A, Perjési P (2003) Arkivoc (v):114

  26. Lóránd T, Szabó D, Földesi A, Párkányi L, Kálmán A, Neszmélyi A (1985) J Chem Soc Perkin 1:481

    Article  Google Scholar 

  27. George H, Roth HJ (1971) Tetrahedron Lett 12:4057

    Article  Google Scholar 

  28. Frey H, Behmann G, Kaupp G (1987) Chem Ber 120:387

    Article  CAS  Google Scholar 

  29. Huber I, Fülöp F, Dombi Gy, Bernáth G, Hermecz I, Mészáros Z (1987) J Chem Soc Perkin 1:909

    Article  Google Scholar 

  30. Fülöp F, Huber I, Dombi Gy, Bernáth G (1987) Tetrahedron 43:1157

    Article  Google Scholar 

  31. Leonard NJ, Locke DM (1955) J Am Chem Soc 77:1852

    Article  CAS  Google Scholar 

  32. Batt DG, Maynard GD, Petraitis JJ, Shaw JE, Galbraith W, Harris RR (1990) J Med Chem 33:360

    Article  CAS  Google Scholar 

  33. Hassner A, Cromwell NH, Davis SJ (1957) J Am Chem Soc 79:230

    Article  CAS  Google Scholar 

  34. El-Rayyes NR, Al-Jawhary A (1986) J Heterocycl Chem 23:135

    Article  CAS  Google Scholar 

  35. Yi WB, Cai C (2005) J Fluorine Chem 126:1553

    Article  CAS  Google Scholar 

  36. McElvain SM, Rorig K (1948) J Am Chem Soc 70:1820

    Article  CAS  Google Scholar 

  37. Kumar N, Sun G, Ni N, Chen W, Molina ADC, Wang B, Rawat DS (2013) Chem Biol Interface 3:164

    CAS  Google Scholar 

  38. Rozmer Z, Perjési P (2013) J Planar Chromatogr 26:284

    Article  CAS  Google Scholar 

  39. Pirger Z, Lubics A, Reglodi D, László Z, Márk L, Kiss T (2010) Neuropeptides 44:475

    Article  CAS  Google Scholar 

  40. Brubel R, Reglodi D, Jámbor E, Koppán M, Biró Z, Kiss P, Matkovits A, Farkas J, Lubics A, Várnagy A, Bódis J, Bay C, Veszprémi B, Tamás A, Márk L (2011) J Mass Spectr 46:189

    Article  CAS  Google Scholar 

  41. Mosmann T (1983) J Immunol Methods 65:55

    Article  CAS  Google Scholar 

  42. ChemAxon (2012) Marvin Suite vers. 5.9.4 (http://www.chemaxon.com)

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Acknowledgments

This work was supported by the University of Pécs, Faculty of Medicine Research Funds PTE ÁOK-KA-34039-12/10-11 and PTE ÁOK-KA-2013/20.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of Pécs, Rókus Street 2, Pécs, 7624, Hungary

    Imre Huber & Pál Perjési

  2. Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary

    István Zupkó, Ida J. Kovács & Renáta Minorics

  3. Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary

    Gergely Gulyás-Fekete & Gábor Maász

Authors
  1. Imre Huber
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  2. István Zupkó
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  3. Ida J. Kovács
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  4. Renáta Minorics
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  5. Gergely Gulyás-Fekete
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  6. Gábor Maász
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  7. Pál Perjési
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Corresponding author

Correspondence to Imre Huber.

Additional information

This article is considered to be part XI in the series of (E)-2-benzylidenebenzocyclanones. For part X, see Ref. [38].

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Huber, I., Zupkó, I., Kovács, I.J. et al. Synthesis and antiproliferative activity of cyclic arylidene ketones: a direct comparison of monobenzylidene and dibenzylidene derivatives. Monatsh Chem 146, 973–981 (2015). https://doi.org/10.1007/s00706-015-1426-7

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  • DOI: https://doi.org/10.1007/s00706-015-1426-7

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