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A synthesis of 3-(1H-3-indolyl)-4-(1-glycosyl-3-indolyl)furan-2,5-diones and -1H-pyrrole-2,5-diones modified with the residues of D-ribo-, D-xylo-, L-arabino-, D-galactopyranose, and D-lactose was described. Influence of the compounds prepared on DNA biosynthesis in CaOv cells was studied.

A synthesis of the derivatives of bis(indolyl)furan and bis(indolyl)pyrrole, which contain an acyclic fragment or a residue of D-ribo-, D-xylo-, L-arabino-, D-galactopyranose, or D-lactose was described. Bis(indole) aglycone was created using 1-glycosylindoles, which were synthesized by the indoline-indole method.

O6-Methyl-2'-deoxyguanosine (O6-MedG), a novel inhibitor of O6-alkylguanine-DNA alkyltransferase (O6-AGT), has been synthesized. The ability of O6-MedG to deplete the O6-AGT activity in leukemia L1210 and melanoma B16 cells in vivo has been studied. After intraperitoneal administration of O6-MedG to mice bearing leukemia L1210 or melanoma B16, the activity of O6-AGT in tumour cells decreased by 50%. Pretreatment of leukemia L1210 bearing mice with O6-MedG (200 mg/kg) 24 hours prior to ACNU (15 mg/kg) administration resulted in six out of seven 60-day survivors. Treatment of mice with ACNU (15 mg/kg) alone increased the life span by 200%. Treatment of melanoma B16 bearing mice with O6-MedG and 3 hours thereafter with ACNU resulted in a 50% inhibition of tumour growth, whereas the inhibiting effect of ACNU alone was 16%. There was no difference in leukemia growth when L1210/BCNU bearing mice were treated with O6-MedG followed by ACNU treatment. In vivo ACNU (15 mg/kg) produced a deep and prolonged inhibition of DNA, RNA and protein synthesis in leukemia L1210 cells. The DNA synthesis in leukemia L1210/BCNU cells was shown to recover more rapidly than in L1210 cells. The activities of DNA-polymerases alpha and beta and, especially, of O6-AGT were elevated in ACNU-resistant leukemia cells as compared with ACNU-sensitive cells. The activation of some repairing enzymes, such as O6-AGT, DNA-polymerases alpha and beta as well as increased levels of GSH may play a role in the development of drug resistance to ACNU.

The effect of O6-methylguanine (O6-MeG) on the therapeutic efficiency of 1-methyl-1-nitrosourea (MNU) and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) against the murine L1210 leukemia and B16 melanoma was studied in vivo. Although the level of O6-alkylguanine-DNA alkyltransferase (AGT) in L1210/BCNU leukemia cells was three times higher than in L1210 leukemia cells, no enhancement of the antitumor activity of MNU and BCNU in L1210 leukemia or B16 melanoma with O6-MeG or MNU potentiated markedly the cytotoxic effects of MNU and BCNU. Administration of O6-MeG to mice bearing L1210 leukemia led to delayed inhibition of DNA synthesis and appearance of long-term single-strand breaks in DNA of tumor cells.

Methods for the preparation of aza and deaza analogs of purine nucleosides, viz., nucleosides of imidazo[4,5-d]-v-triazines, imidazo[4,5-b]pyridines, and imidazo[4,5-c]pyridines, and their properties are described. References to the synthesis of nucleosides of imidazo[4,5-d]pyridazines, imidazo[4,5-c]pyridazines, and imidazo[4,5-b]pyrazines are also given.

Condensation of 5- or 6-nitroindoline with L-arabinose gave 1-α-L-arabinopyranosyl-5 (or 6)-nitroindolines, which, after acetylation, dehydrogenation, and removal of the protective groups, are converted to 1-α-L-arabinopyranosyl-5(or 6)-nitroindoles and then to the corresponding amino derivatives. 1-α-L-Arabinopyranosyl-6-nitro-3-bromo-(iodo)indoles were obtained. The selective 2′-O- and 3′-O-deacetylation of 1-(2′, 3′, 4′-tri-O-acetyl)-α-L-arabinopyranosyl-6-nitroindole was accomplished.

A new type of isatin analog-2,3-dioxo-2,3-dihydro-4-methyl-6-chloro-1H-pyrrolo[2,3-b]pyridine — was obtained by oxidation of 4-methyl-6-chloro-1H-pyrrolo(2,3-b]pyridine. Condensation of L-arabinose with 4-methyl-6-chloro-2,3-dihydropyrrolo[2,3-b]pyridine and subsequent acetylation and dehydrogenation gave 1-(2,3,4-tri-O-acetyl-α-L-arabinopyranosyl)-4-methyl-6-chloropyrrolo[2,3-b]pyridine, which served as the starting compound for the synthesis of 1-α-L-arabinopyranosyl-4-methyl-6-chloropyrrolo[2,3-b]pyridine. Oxidation of 1-(2,3,4-tri-O-acetylα-L-arabinopyranosyl)-4-methyl-6-chloropyrrolo[2,3-b]pyridine gave 1-(2,3.4-tri-O-acetyl-α-L-arabinopyranosyl)-2,3-dioxo-2,3-dihydro-4-methyl-6-chloropyrrolo [2,3-b]pyridine.

Das Pyrrolopyridin (I) last sich mit Chromsaure zu einem azaanalogen Isatin (II) oxidieren.

Condensation of 5- or 6-nitroindoline with L-arabinose gave 1-α-L-arabinopyranosyl-5 (or 6)-nitroindolines, which, after acetylation, dehydrogenation, and removal of the protective groups, are converted to 1-α-L-arabinopyranosyl-5(or 6)-nitroindoles and then to the corresponding amino derivatives. 1-α-L-Arabinopyranosyl-6-nitro-3-bromo-(iodo)indoles were obtained. The selective 2′-O- and 3′-O-deacetylation of 1-(2′, 3′, 4′-tri-O-acetyl)-α-L-arabinopyranosyl-6-nitroindole was accomplished.

Glycosylation of 5-trimethylsilyl- and 5-triethylsilyluracil as well as 5-trimethylsilylcytosine with 2-deoxy-3,5-di-O-p-toluyl-alpha-D-ribofuranosylchloride and subsequent deacylation led to alpha- and beta-anomers of 5-Me3SidUrd, 5-Et3SidUrd and 5-Me3SidCyd. 1-(alpha-D-Arabinofuranosyl)-5-trimethylsilyluracil was synthesized starting from the derivatives of 2,3,5-tri-O-benzoyl-D-arabinofuranose and then converted to alpha-5-Me3SidUrd via 1-(2,2'-anhydro-alpha-D-ribofuranosyl)-5-trimethylsilyluracil and 1-(2-chloro-2-deoxy-alpha-D-arabinofuranosyl)-5-trimethylsilyluracil+ ++. Out of all synthesized compounds, only alpha-5-Me3SidUrd inhibits the replication of HSV-1 both in vitro and in vivo; it also exerts a pronounced therapeutic effect in guinea pigs with herpes genitalis induced by HSV-2. The resistance of alpha-5-Me3SidUrd to pyrimidine phosphorylases facilitates its antiviral activity in vivo.

p-Di-(2-chlorathyl)-aminophenylessigsaurechlorid (II) und p-Di-(2-chlorathyl)- aminophenylbuttersaurechlorid (III) kondensiert man in Benzol/Triathylamin mit Sterinen und Steroiden.