A study of the influence of newly synthesized acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline derivatives on deoxythymidine and deoxycytidine kinase activities in human neurofibrosarcoma and ovarian cancer.

• Authors: Hanna Modrzejewska , Elżbieta Brzezińska , Marcin Dramiński , Anna Zgit-Wróblewska , Katarzyna Krzykowska , Elżbieta Rozpończyk , Janusz Greger
• Languages of publication: EN

Abstracts

EN

The influence of nine newly synthesized uracil acyclonucleosides, and 36 derivatives of 1,2,3,4-tetrahydroisoquinoline on the activity of enzymes catalysing dTMP and dGMP synthesis, on the content of dTTP and dGTP in acid soluble fraction and on the incorporation of [14C]dThd and [14C ]dGuo into DNA in tumour homogenates was studied. The influence of the compounds was studied in the cytosol from intraoperatively excised human tumours - neurofibrosarcoma and ovarian cancer. It was shown that dTMP and dGMP synthesis is inhibited competitively by 34.1±4.0% in both types of tumours by 0.2 mM 1-N-(3'-hydroxypropyl)-6-methyluracil (1) and 0.2 mM 1-N-(3'-hydroxypropyl)- 5,6- tetramethyleneuracil (2). The mentioned acyclonucleosides reduced the content of dTTP and dGTP in the acid soluble fraction of tumours (59.7±3.1% of control). 1-(4-chlorophenyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (3), 1-(2,3-dichlorophenyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (4) and 1-(3-methoxyphenyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (5) at 0.2 mM concentration caused a mixed type inhibition of the synthesis of dTMP and dGMP by, on average, 33.2±4.4%, and reduced the content of dTTP and dGTP in the acid soluble fraction (52.6±3.7% of control) but were active only in the cytosol of neurofibrosarcoma. While acyclonucleosides undergo phosphorylation in the cytosol by cellular kinases, with their triphosphates being active acyclonucleoside metabolites, active 1,3,4,5-tetrahydroisoquinoline derivatives (compounds not containing a deoxyribose moiety), cannot be phosphorylated. ACN and THI derivatives which inhibit dThd and dCyd kinase activities, inhibit also the incorporation of [14C]dThd and [14C]dGuo (ACN - 50.2±2.7%, THI - 53.4±3.9% of incorporation inhibition) into tumour DNA. The obtained results point to the mechanism of uracil acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline biological activity consisting in inhibiting the synthesis of DNA components.

Keywords

EN

deoxynucleoside kinases; 1,2,3,4-tetrahydroisoquinoline; acyclonucleosides

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2003
• Volume: 50
• Issue: 4
• Pages: 1175-1185

Dates

published

2003

received

2002-09-17

revised

2003-07-30

accepted

2003-08-19

Contributors

author

Hanna Modrzejewska

• Department of Medical Biochemistry, Institute of Physiology and Biochemistry, Medical University of Łódź, Łódź, Poland

author

Elżbieta Brzezińska

• Institute of Chemistry and Technology of Drugs, Medical University of Łódź, Łódź, Poland

author

Marcin Dramiński

• Department of General Chemistry, the Ludwik Rydygier Medical University of Bydgoszcz, Bydgoszcz, Poland

author

Anna Zgit-Wróblewska

• Department of General Chemistry, the Ludwik Rydygier Medical University of Bydgoszcz, Bydgoszcz, Poland

author

Katarzyna Krzykowska

• Department of Medical Biochemistry, Institute of Physiology and Biochemistry, Medical University of Łódź, Łódź, Poland

author

Elżbieta Rozpończyk

• Department of Medical Biochemistry, Institute of Physiology and Biochemistry, Medical University of Łódź, Łódź, Poland

author

Janusz Greger

• Department of Medical Biochemistry, Institute of Physiology and Biochemistry, Medical University of Łódź, Łódź, Poland

References

• Abe K, Taguchi K, Wasai T, Ren J, Utsunomiya I, Shinohara T, Miyatake T, Sano T. (2001) Biochemical and pathological study of endogenous 1-benzyl-1,2,3,4-tetrahydroisoquinoline induced parkinsonism in the mouse. Brain Res.; 907: 134-8.
• Akyoshi H. (1984) Formation of deoxynucleoside 5'-monophosphate dependent on DNA synthesis in nuclei isolated from regenerating rat liver. Biochim Biophys Acta.; 782: 142-6.
• Anders K, Jensen RB. (1958) Isothiocyanates XXXII. Synthesis and reactions of 3-benzyloxypropyl isothiocyanate, enzymatically liberated from glucomalcolmin and some compounds of related structure. Acta Chem Scand.; 12: 1746-58.
• Arner ES, Eriksson S. (1995) Mammalian deoxynucleoside kinase. Pharmacol Ther.; 67: 155-186.
• Blin N, Stafford DW. (1976) General methods for isolation of high molecular DNA from eucariotes. Nucleic Acids Res.; 3: 2303-8.
• Bradford MM. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem.; 72: 248-54.
• Brzezińska E. (1996) Synthesis and pharmacological properties of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Acta Pol Pharm.; 53: 365-71.
• Buczyński B, Potter RL. (1990) Nucleoside diphosphate kinase from Xenopus oocytes: partial purification and characterisation. Biochim Biophys Acta.; 1041: 296-304.
• Daher GC, Harris BE, Diasio R. (1990) Metabolism of pyrimidine analogues and their nucleosides. Pharmacol Ther.; 48: 189-222.
• Fossey C, Laduerre D, Robba A. (1994) Synthesis of acyclic thiens [3,2-delta] pyrimidine nucleosides and azido derivatives as potential anti-HIV agents. Nucleosides & Nucleotides.; 13: 883-9.
• Goldbrunner M, Loidl G, Polossek T, Mannschreck A, Auger E. (1997) Inhibition of tubulin polymerization by 5,6-dihydro[21-alpha] isoquinoline derivatives. J Med Chem.; 40: 3524-33.
• Greger J, Dramiński M. (1989) Growth inhibition of Kirkman-Robbins hepatoma by 1(1',3'-dihydroxy-2'-propoxymethyl)-5,6-tetramethyleneuracil and possible mechanism of its biological activity. Z Naturforsch.; 44c: 985-91.
• Harnden MR, Parkin A, Parratt MJ, Perkins RM. (1993) Novel acyclonucleosides: synthesis and antiviral activity of alkenylphosphonic acid derivatives of purine and pyrimidine. J Med Chem.; 36: 1343-55.
• Ilsley DD, Lee S-H, Miller WH, Kuchta RD. (1995) A cyclic guanosine analogs inhibit DNA polymerase α, δ and ε with very different potenties and have unique mechanism of action. Biochemistry.; 34: 2504-10.
• Jullig M, Eriksson S. (2001) Apoptosis induced efflux of the mitochondrial matrix enzyme deoxyguanosine kinase. J Biol Chem.; 276: 24000-4.
• Jung Y, Surh Y. (2001) Oxidative DNA damage and cytotoxicity induced copper stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid. Free Rad Biol Med.; 30: 1407-17.
• Kawai H, Kotake Y, Ohta S. (2000) Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tertahydroisoquinoline. Chem Res Toxicol.; 13: 1294-301.
• Kotera J, Fujishige K, Michibata H, Yuasa K, Kubo A, Nakamura Y, Omori K. (2000) Characterisation and effects on methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo- 7-(2-pyridynylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate. (T-1032) a novel potent inhibitor of cGMP-binding cGMP specific phosphodiesterase. Biochem Pharm.; 60: 1333-41.
• Letnansky K. (1964) The influence of 2-deoxy-D-glucose on the nucleotide content of Ehrlich ascites carcinoma cells. Biochim Biophys Acta.; 87: 1-8.
• Lin M-C, Shun T-S, Penketh P, Sartorelli A. (1995) Synthesis and antitumor activity of 4 and 5 substituted derivatives of isoquinoline-1-carboxyaldehyde-thio-semicarba-sone. J Med Chem.; 38: 4234-45.
• Modrzejewska H, Greger J, Dramiński M, Rutkowski M. (1996) The influence of alkoxymethyl purine and pyrimidine acyclonucleosides on growth inhibition of Kirkman-Robbins hepatoma and possible mechanism of their cytostatic activity. Z Naturforsch.; 51c: 75-80.
• Modrzejewska H, Dramiński M, Zgit- Wroblewska A, Greger J. (1999) Further studies on cytostatic activity of alkoxymethyl purine and pyrimidine acyclonucleosides. Z Naturforsch.; 54c: 923-31.
• Parker WB, Shaddix SC, Rose LM, Taiwari KN, Mongomery JA, Secrist III JA, Benett LL Jr. (1995) Metabolism and metabolic action of 4-thiothymidine in L 1210 cells. Biochem Pharmacol.; 50: 687-95.
• Rutkowski M, Korczak E. (1992) Biotransformation by Enterobacter agglomerans of pyrimidine acyclonucleosides to acyclonucleotides. Experientia.; 48: 600-3.
• Usova E, Eriksson S. (1997) The effects of high salt concentration on the regulation of the substrate specificity of human recombinant deoxycytidine kinase. Eur J Biochem.; 248: 762-6.
• Wang L, Karlsson A, Arner ESJ, Eriksson S. (1993) Substrate specificity of mitochondrial 2'-deoxyguanosine kinase. J Biol Chem.; 268: 22847-52.