Abstract
The cytotoxic effects of novel racemic and optically active constrained N-phosphonoalkyl bicyclic β-amino acids were tested against a panel of human tumor cell lines. All of the compounds investigated exhibited different concentration-dependent antiproliferative effects against the HT-29, MDA-MB-231, HepG2 and HeLa cell lines after 24 h treatment. The most sensitive cells were the HeLa cells at various concentrations of the four compounds tested. The aminophosphonate 3 exerted the most pronounced antiproliferative effect against the HeLa cells (inhibition of the cell vitality up to 70% at 0.5 mg/ml) and was not toxic to the normal Lep3 cells at lower concentration. Furthermore, the N-phosphonophenyl derivatives 1 and 2 displayed antiproliferative effect against mainly the MDA-MB-231 tumour cells at higher concentration.
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Akkari R, Calmès M, Martinez J (2004a) Toward Diels–Alder reactions on a solid support using polymer bound N-substituted 3-hydroxy-4,4-dimethyl-2-pyrrolidinone acrylate derivatives. Eur J Org Chem 11:2441–2450
Akkari R, Calmès M, Escale F, Iapichella J, Rolland M, Martinez J (2004b) (R)- or (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic acid as a new chiral auxiliary for solid phase asymmetric Diels–Alder reactions. Tetrahedron Asymmetr 15:2515–2525
Arad D, Kende AS, Lan J (2002) Regiospecific synthesis of a bridgehead-functionalized bicyclo[2.2.2]octenone. Tetrahedron Lett 43:5237–5239
Calmès M, Didierjean C, Martinez J, Songis O (2005) (R)-(4-(Benzyloxycarbonylphenyl)-3-hydroxy-4,4-dimethyl-2-pyrrolidinone)acrylate derivative as a chiral dienophile for the synthesis of enantiopure 2-aminocyclohexane carboxylic acids. Tetrahedron Asymmetr 15:2173–2178
Carruthers W (1990) Cycloaddition reaction in organic synthesis, tetrahedron organic chemistry, series vol 8. Pergamon Press, Elmsford, NY
Fringuelli F, Tatichi A (2002) The Diels–Alder reaction: selected practical methods. Wiley, New York
Fülöp F (2001) The chemistry of 2-aminocycloalkanecarboxylic acids. Chem Rev 101:2181–2204
Gademann K, Hintermann T, Scheiber JV (1999) Beta-peptides: twisting and turning. Current Med Chem 6:905–925
Hirschmann R, Smith AB III, Taylor CM, Benkovic PA, Taylor SD, Yager KM, Sprengler PA, Benkovic SJ (1994) Peptide synthesis catalyzed by an antibody containing a binding site for variable amino acids. Science 265:234–237
Kabachnik M, Minaeva L, Beletskaya I (2009) Synthesis of novel α-aminophosphonates containing adamantyl fragment. Synthesis 14:2357–2360
Kafarski P, Lejczak B (2000) Aminophosphonic and aminophosphinic acids. In: Chemistry and biological activity. Wiley, New york, p 407
Kafarski P, Lejczak B (2001) Aminophosphonic acids of potential medical importance. Curr Med Chem Anti-Cancer Agents 1:301–312
Naydenova E, Todorov P, Topashka-Ancheva M, Momekov G, Yordanova T, Konstantinov S, Troev K (2008) Novel N-(phosphonomethyl) glycine derivatives. Design, characterization and biological activity. Eur J Med Chem 43(6):1199–1205
Naydenova E, Todorov P, Troev K (2010) Resent synthesis of aminophosphonic acids as potential biological importance. Amino Acids 38(1):23–30
Orsini F, Sello G, Sisti M (2010) Aminophosphonic acids and derivatives. Synthesis and biological applications. Curr Med Chem 17:264–289
Park K-H, Kurth MJ (2002) Cyclic amino acid derivatives. Tetrahedron 58:8629–8659
Reynolds RC, Johnson CA, Piper JR, Sirotnak FM (2001) Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo. Eur J Med Chem 36:237–242
Roberts JD, Moreland WT, Frazer W (1953) Synthesis of some 4-substituted bicyclo[2.2.2]octane carboxylic acids. J Am Chem Soc 75:637–640
Rozenfeld R, Iturrioz X, Okada M, Maigret B, Llorents-Cortes C (2003) Contribution of molecular modeling and site-directed mutagenesis to the identification of a new residue, glutamate 215, involved in the exopeptidase specificity of aminopeptidase A. Biochemistry 42:14785–14793
Smith PW, Trivedi N, Howes PD, Sollis SL, Rahim G, Bethell RC, Lynn S (1999) Synthesis of a tetrasubstituted bicyclo [2.2.2] octane as a potential inhibitor of influenza virus sialidase. Bioorg Med Chem Lett 9:611–614
Songis O, Didierjean C, Laurent C, Martinez J, Calmès M (2007) Asymmetric Diels–Alder cycloaddition of 1-aminocyclohexadiene to chiral acrylate: synthesis of enantiopure bridgehead-aminobicyclo[2.2.2]octane-2-carboxylic acid derivatives. Eur J Org Chem 3166–3172
Todorov PT, Pavlov ND, Shivachev BL, Petrova RN, Martinez J, Naydenova ED, Calmes M (2011) Synthesis of new racemic and optically active N-phosphonylalkyl bicyclic β-amino acids via Kabachnik–Fields reaction as potential biologically active compounds. Heteroatom Chem. doi:10.1002/hc.20759
Troev KD (2006) Chemistry and application of H-phosphonates. Elsevier, Amsterdam
Wang B, Miao ZW, Wang J, Chen RY, Zhang XD (2008) Synthesis and biological evaluation of novel naphthoquinone fused cyclic aminoalkylphosphonates and aminoalkylphosphonic monoester. Amino Acids 35:463–468
Widianti T, Hiraga Y, Kojima S, Abe M (2010) Novel cyclic β-aminophosphonate derivatives as efficient organocatalysts for the asymmetric Michael addition reactions of ketones to nitrostyrenes. Tetrahedron Asymmetr 21:1861–1868
Wynn CM, Vaughan WR (1968) Stereochemistry of pyrrolidine addition to bicy-clo[2.2.2]oct-2-ene-2-carbonitrile. J Org Chem 33:2371–2374
Zand R, Sellinger OZ, Water R, Harris R (1974) α-Aminocyclic and bicyclic alkane carboxylic acids: differential effects on selected amino acids of rat brain cortex. J Neurochem 23:1201–1206
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The study was supported by Grant DPOSTDOC 02/3 of the National Research Fund, Sofia, Bulgaria.
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Todorov, P.T., Wesselinova, D.W., Pavlov, N.D. et al. Cytotoxic activity of new racemic and optically active N-phosphonoalkyl bicyclic β-amino acids against human malignant cell lines. Amino Acids 43, 1445–1450 (2012). https://doi.org/10.1007/s00726-012-1217-y
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DOI: https://doi.org/10.1007/s00726-012-1217-y