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.