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A series of 7-deazapurine 2'-deoxyribofuranosides were synthesized according to already known procedures and their substrate and inhibitor properties with purified E. coli purine nucleoside phosphorylase were examined. In agreement with previous findings, substrate activity was not detected for any of the compounds tested. Most of the nucleosides showed weak inhibition in the preliminary screening, i.e. at a concentration of about 100 μM. However some combinations of 6-chloro, 6-amino or 6-methoxy substituents with bulky hydrophobic groups at position 7 of the base and/or chloro, amino, methoxy or methylthio group at position 2 markedly enhanced affinity of such modified nucleosides for the E. coli enzyme. The most potent inhibition was observed for two nucleosides: 6-chloro- and 2-amino-6-chloro-7-deazapurine 2'-deoxyribofuranosides that show inhibition constants Ki = 2.4 and 2.3 μM, respectively. Several other compounds were also found to be good inhibitors, with inhibition constants in the range 5-50 μM. In all instances the inhibition was competitive vs. the nucleoside substrate 7-methylguanosine. Inhibition constants for 7-deazapurine nucleosides are in general several-fold lower than those observed for their purine counterparts. Therefore 7-deaza modification together with substitutions at positions 2, 6 and 7 of the base is a very promising approach to obtain competitive noncleavable inhibitors of E. coli PNP that may bind to the enzyme with inhibition constants in the μM range.
An approximately threefold increase in glycogenolytic activity of the neutral a-1,4-glucosidase and a twofold increase in the same activity of the acid isoform have been found in extracts of anaplastic astrocytoma and glioblastoma multiforme tumors of brain tissue. "Maltase activity" of the respective enzymes increased by 60-80% in both kinds of tumor extracts. However a significant decrease in a-amylase and almost complete disappearance of phosphorylase activities have also been found in both kinds of tumors.
Five newly synthesised monophosphates of two pyrimidine acyclonucleoside series, namely 1-N-[(2’-hydroxy)ethoxymethyl] and l-N-[(l’,3’-dihydroxy)- 2’-propoxymethyl] derivatives of 5- and 5,6-alkylated uracils were tested in vitro for chromosome aberrations and sister chromatid exchanges (SCE). Metaphase plates were obtained via microculture of human lymphocytes from heparinized peripheral blood. The compounds were tested in doses: 10, 20, 40, 80 and 150 µg per mL of culture. The tested compounds induced mainly chromatid gaps, less frequently chromosome gaps. A low number of mitoses with chromatid and chromosome breaks, acentric fragments, dicentric chromosomes and exchange figures were also observed. The tested compounds in doses: 40, 80 and 150 µg per mL, doubled or tripled the percentage of cells with chromatid gaps and chromosome gaps as compared to the control. The percentage o cells with aberrations (excluding gaps) induced by the tested compounds in all doses did not exceed 2%. The tested compounds induced a higher number of SCE per cell but less than double frequency as compared to the control. SCE frequencies and replication index (RI) values varied depending on the examined compounds. For the highest dose of the tested compounds (150 µg per mL) a significant decrease in RI values was observed for l-N-[(2’-hydroxy)ethoxymethyl]-5,6-tetramethyleneuracil monophosphate and for l-N-[(2’-hydroxy)ethoxymethyl]-5,6-dimethyluracil monophosphate. So far, the results have indicated potential clastogenicity of all the tested compounds except acycloguanosine monophosphate.
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