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Arzneimittelforschung 2011; 61(6): 366-371
DOI: 10.1055/s-0031-1296212
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatic
Editio Cantor Verlag Aulendorf (Germany)

Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells

Kaan Kucukoglu
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey
,
Mustafa Gul
2   Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
3   Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
,
Mustafa Atalay
3   Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
,
Ebru Mete
4   Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum, Turkey
,
Cavit Kazaz
4   Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum, Turkey
,
Osmo Hanninen
3   Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
,
HaliseInci Gul
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey
› Author Affiliations
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Publication History

Publication Date:
27 November 2011 (online)

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Abstract

1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T-lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4-chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2-acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5-fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46–5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65–8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37–2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies.

Key words

Cytotoxic activity - Dimethylamine - Hydrazone - Jurkat cells - Mannich bases - Synthesis
 

  • References

  • 1 Dimmock JR, Kumar P. Anticancer and cytotoxic properties of Mannich bases. Curr Med Chem. 1997; 4: 1-22
    PubMedGoogle Scholar
  • 2 Gul HI, Vepsalainen J, Gul M, Erciyas E, Hanninen O. Cytotoxic activities of mono and bis Mannich bases derived from acetophenone against Renca and Jurkat cells. Pharm Acta Helv. 2000; 74: 393-8
    CrossrefPubMedGoogle Scholar
  • 3 Gul HI, Gul M, Erciyas E. Syntheses and stability studies of some Mannich bases of acetophenones and evaluation of their cytotoxicity against Jurkat cells. Arzneimittelforschung 2002; 52: 628-35
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Gul HI, Gul M, Hanninen O. Cytotoxic activities of some mono and bis Mannich bases derived from acetophenone in brine shrimp bioassay. Arzneimittelforschung 2002; 52: 840-3
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Gul M, Gul HI, Hänninen O. Effects of Mannich bases on cellular glutathione and related enzymes of Jurkat cells in culture conditions. Toxicol In Vitro. 2002; 16: 107-12
    CrossrefPubMedGoogle Scholar
  • 6 Gul HI, Gul M, Erciyas E. Toxicity of some bis Mannich bases and corresponding piperidinols in the brine shrimp (Artemia salina) bioassay. J Appl Toxicol. 2003; 23: 53-7
    CrossrefPubMedGoogle Scholar
  • 7 Gul HI, Gul M, Vepsalainen J, Erciyas E, Hänninen O. Cytotoxicity of some azines of acetophenone derived mono-Mannich bases against Jurkat cells. Biol Pharm Bull. 2003; 26: 631-7
    CrossrefPubMedGoogle Scholar
  • 8 Gul M, Mete E, Atalay M, Arik M, Gul HI. Cytotoxicity of 1-aryl-3-buthylamino-l-propanone hydrochlorides against Jurkat and L6 cells. Arzneimittelforschung 2009; 59: 364-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Gul HI, Yerdelen KO, Das U, Gul M, Pandit B, Li PK et al. Synthesis and cytotoxicity of novel 3-aryl-l-(3’-dibenzyl-aminomethyl-4’-hydroxyphenyl)-propenones and related compounds. Chem Pharm Bull (Tokyo) 2008; 56: 1675-81
    CrossrefPubMedGoogle Scholar
  • 10 Gul HI, Yerdelen KO, Gul M, Das U, Pandit B, Li PK et al. Synthesis of 4’-hydroxy-3’-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines. Arch Pharm (Weinheim) 2007; 340: 195-201
    CrossrefPubMedGoogle Scholar
  • 11 Gul HI, Das U, Pandit B, Li PK. Evaluation of the cytotoxicity of some mono-mannich bases and their corresponding azine derivatives against androgen-independent prostate cancer cells. Arzneimittelforschung 2006; 56: 850-4
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Gul M, Gul HI, Das U, Hanninen O. Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxo-propyl)-methylamine hydrochlorides and 4-aryl-3-arylcar-bonyl-l-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their alkylating ability towards cellular glutathione in human leukemic T cells. Arzneimittelforschung 2005; 55: 332-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Gul M, Atalay M, Gul HI, Nakao C, Lappalainen J, Hanninen O. The effects of some Mannich bases on heat shock proteins HSC70 and GRP75, and thioredoxin and glutaredoxin levels in Jurkat cells. Toxicol In Vitro. 2005; 19: 573-80
    CrossrefPubMedGoogle Scholar
  • 14 Sujith KV, Rao JN, Shetty P, Kalluraya B. Regioselective reaction: synthesis and pharmacological study of Mannich bases containing ibuprofen moiety. Eur J Med Chem. 2009; 44: 3697-702
    CrossrefPubMedGoogle Scholar
  • 15 Suleyman H, Gul HI, Asoglu M. Anti-inflammatory activity of 3-benzoyl-l-methyl-4-phenyl-4-piperidinol hydrochloride. Pharmacol Res. 2003; 47: 471-5
    CrossrefPubMedGoogle Scholar
  • 16 Suleyman H, Gul HI, Gul M, Alkan M, Gocer F. Anti-inflammatory activity of bis(3-aryl-3-oxo-propyl)methylamine hydrochloride in rat. Biol Pharm Bull. 2007; 30: 63-7
    CrossrefPubMedGoogle Scholar
  • 17 Gul HI, Suleyman H, Gul M. Evaluation of the anti-inflammatory activity of N, N’-bis(3-dimethylamino-l-phenyl-propylidene)hydrazine dihydrochloride. Pharm Biol. 2009; 47: 968-73
    CrossrefPubMedGoogle Scholar
  • 18 Dimmock JR, Jonnalagadda SS, Phillips OA, Erciyas E, Shyam K, Semple HA. Anticonvulsant properties of some Mannich bases of conjugated arylidene ketones. J Pharm Sci. 1992; 81: 436-40
    CrossrefPubMedGoogle Scholar
  • 19 Gul HI, Calis U, Vepsalainen J. Synthesis and evaluation of anticonvulsant activities of some bis Mannich bases and corresponding piperidinols. Arzneimittelforschung 2002; 52: 863-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Gul HI, Calis U, Vepsalainen J. Synthesis of some mono-Mannich bases and corresponding azine derivatives and evaluation of their anticonvulsant activity. Arzneimittelforschung 2004; 54: 359-64
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Gul HI, Calis U, Ozturk Z, Tutar E, Calikiran L. Evaluation of anticonvulsant activities of bis(3-aryl-3-oxo-propyl) ethylamine hydrochlorides and 4-aryl-3-arylcarbonyl-l-ethyl-4-piperidinol hydrochlorides. Arzneimittelforschung 2007; 57: 133-6
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Mete E, Ozelgul C, Kazaz C, Yurdakul D, Sahin F, Gul HI. Synthesis and antifungal activity of l-aryl-3-phenethyl-amino-1-propanone hydrochlorides and 3-aroyl-4-aryl-l-phenethyl-4-piperidinols. Arch Pharm (Weinheim) 2010; 343: 291-300
    PubMedGoogle Scholar
  • 23 Erciyas E, Erkaleli HI, Cosar G. Antimicrobial evaluation of some styryl ketone derivatives and related thiol adducts. J Pharm Sci. 1994; 83: 545-8
    CrossrefPubMedGoogle Scholar
  • 24 Gul HI, Denizci AA, Erciyas E. Antimicrobial evaluation of some Mannich bases of acetophenones and their representative quaternary derivatives. Arzneimittelforschung 2002; 52: 773-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Gul HI, Ojanen T, Hänninen O. Antifungal evaluation of bis Mannich bases derived from acetophenones and their corresponding piperidinols and stability studies. Biol Pharm Bull. 2002; 25: 1307-10
    CrossrefPubMedGoogle Scholar
  • 26 Gul HI, Ojanen T, Vepsalainen J, Gul M, Erciyas E, Hanninen O. Antifungal activity of some mono, bis and quaternary Mannich bases derived from acetophenone. Arzneimittelforschung 2001; 51: 72-5
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Ashok M, Holla BS, Poojary B. Convenient one pot synthesis and antimicrobial evaluation of some new Mannich bases carrying 4-methylthiobenzyl moiety. Eur J Med Chem. 2007; 42: 1095-101
    CrossrefPubMedGoogle Scholar
  • 28 Gul M, Gul HI, Vepsalainen J, Erciyas E, Hanninen O. Effect of acetophenone derived Mannich bases on cellular glutathione level in Jurkat cells. A possible mechanism of action. Arzneimittelforschung 2001; 51: 679-82
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Dimmock JR, Kumar P, Quail JW, Pugazhenthi U, Yang J, Chen M et al. Synthesis and cytotoxic evaluation of some styryl ketones and related compounds. Eur J Med Chem. 1995; 30: 209-17
    CrossrefPubMedGoogle Scholar
  • 30 Dimmock JR, Erciyas E, Kirkpatrick DL, King KM. Evaluation of some azines of aminomethylacetophenones and related quaternary ammonium compounds versus the EMT6 tumour. Pharmazie. 1988; 43: 614-6
    PubMedGoogle Scholar
  • 31 Wayne AS, Baird K, Egeler RM. Hematopoietic stem cell transplantation for leukemia. Pediatr Clin North Am. 2010; 57: 1-25
    CrossrefPubMedGoogle Scholar
  • 32 Hansen MB, Nielsen SE, Berg K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods. 1989; 119: 203-10
    CrossrefPubMedGoogle Scholar
  • 33 Freshny RI. Culture of animal cells: a manual of basic technique. New York: John & Wiley Sons Inc; 2005
    CrossrefGoogle Scholar
  • 34 Bentley KW, Ball JC. Acid-catalyzed rearrangements in the nepenthone series. J Org Chem. 1958; 23: 1720-5
    CrossrefPubMedGoogle Scholar
  • 35 Tadakazu T, Toyoharu M, Toyoshima S. Researches on chemotherapeutic drugs against viruses. XXVII. Synthesis and antiviral activity of l-(p-alkylphenyl)-3-dimethylami-no-1-propanol. Chem Pharm Bull. 1960; 8: 763-7
    CrossrefPubMedGoogle Scholar
  • 36 Casy AF, Parulkar AP. Studies of stereochemical influences upon anti-histaminic activity. The synthesis, configuration, and anti-histaminic properties of some isomeric aminobu-tenes. Can J Chem. 1969; 47: 423-7
    CrossrefPubMedGoogle Scholar
  • 37 Novello FC, Christy ME, Sprague JM. Synthesis of substituted cyclohexenones. J Am Chem Soc. 1953; 75: 1330-4
    CrossrefPubMedGoogle Scholar
  • 38 Applequist DE, McKenzie LF. Substituent effects in the homolytic brominolysis of substituted phenylcyclopro-panes. J Org Chem. 1976; 41: 2262-6
    CrossrefPubMedGoogle Scholar
  • 39 Lehmann F, Pilotti A, Luthman K. Efficient large scale microwave assisted Mannich reactions using substituted acetophenones. Mol Divers. 2003; 7: 145-52
    CrossrefPubMedGoogle Scholar
  • 40 Pathak VN, Singh RP. Studies in fluorinated Mannich bases. Part 2: Synthesis and biological activity of some new 3-alkylaminopropiophenones. Pharmazie. 1980; 35: 434
    PubMedGoogle Scholar
  • 41 Sielemann D, Keuper R, Risch N. Efficient preparation of substituted 5,6,7,8-tetrahydroquinolines and octahydro-acridine derivatives. J Prakt Chem. 1999; 341: 487-91
    CrossrefPubMedGoogle Scholar
  • 42 Muntwyler R, Menasse R. Hydroxyphenyl ketones. Ardsley. (NY): Ciba-Geigy Corporation; 1982
    Google Scholar
  • 43 Blicke FF, Burckhalter JH. The preparation of β-keto amines by the Mannich reaction. J Am Chem Soc. 1942; 64: 451-4
    CrossrefPubMedGoogle Scholar
  • 44 Schönenberger H, Bastug T, Bindl L, Adam A, Adam D, Petter A et al. Studies of mechanism of action on antimicrobically effective beta-aminoketones. Pharm Acta Helv. 1969; 44: 691-714
    PubMedGoogle Scholar