7-(2-Thienyl)-7-deazaadenosine (AB61), a new potent nucleoside cytostatic with a complex mode of action (original) (raw)
Related papers
Biochemical Pharmacology, 1982
Abstraet-Studies on the mechanism of action of a new oncolytic nucleoside, 2-P-D-rihofuranosylthiazoie-4-carboxamide, have been undertaken using P388 murine leukemia cells growing in culture. The title compound was cytotoxic at micromolar levels, but a number of simple substitutions of both the ring and sugar moieties nullified cytotoxicity. Cyto~uorimetric analysis revealed that the drug arrests cells in the "S phase" of the cel1 cycle. At antiproliferative concentrations, the agent inhibited the synthesis of both RNA and DNA. The macromolecular incorporation of preformed pyrimidines, including thymidine, was inhibited by the drug but, among the purines, this effect extended only to members of the adenine family and, in fact. the utilization of guanine and its congeners was reproducibly stimulated. When an examination was made of the ability of a comprehensive series of preformed purines and pyrimidines to overcome the inhibition of thymidine incorporation provoked by exposure to the thiazole nucleosidc, the guanines were notably effective. but xanthosine also was shown to be an active antidote. Confirmation that the drug was producing a state of guanine deprivation was provided by high performance liquid chromatography (HPLC) analysis of acid-soluble extracts: a time-dependent fall in the concentrations of GMP and GTP ensued upon exposure to the drug; on the other hand, IMP concentrations increased by -lS-fold. Pursuant to these findings, an examination was made of the enzymoiogic steps unique to the biosynthesis of guanine nucleotides in ceils exposed to cytotoxic concentrations of the drug. No prominent inhibition of GMP synthetase could be demonstrated in uirro or in culture, but the specific activity of IMP dehydrogenase underwent substantial reductions in both of these cases. HPLC analyses of extracts of cultures exposed to supralethal concentrations of the title compound provided evidence of modest anabolism to the 5'-monophosphate among other products; in oitro a chemically synthesized sample of 2-ED-ribofuranosyithiazole-4-carboxamide-5'monophosphate was twenty times more potent than the parent nucleoside in inhibiting IMP dehydrogenase. On kinetic analysis, this inhibition was non-competitive with IMP as the variable substrate.
Biochemical Pharmacology, 2000
Previous studies from our laboratories have shown that (a) Triapine ™ is a potent inhibitor of ribonucleotide reductase activity and (b) hydroxyurea-resistant L1210 leukemia cells are fully sensitive to Triapine. In an analogous manner, Triapine was similarly active against the wild-type and a hydroxyurearesistant subline of the human KB nasopharyngeal carcinoma. Triapine was active in vivo against the L1210 leukemia over a broad range of dosages and was curative for some mice. This agent also caused pronounced inhibition of the growth of the murine M109 lung carcinoma and human A2780 ovarian carcinoma xenografts in mice. Optimum anticancer activity required twice daily dosing due to the duration of inhibition of DNA synthesis which lasted about 10 hr in L1210 cells treated with Triapine in vivo. DNA synthesis in normal mouse tissues (i.e. duodenum and bone marrow) uniformly recovered faster than that in L1210 leukemia cells, demonstrating a pharmacological basis for the therapeutic index of this agent. Triapine was more potent than hydroxyurea in inhibiting DNA synthesis in L1210 cells in vivo, and the effects of Triapine were more pronounced. In addition, the duration of the inhibition of DNA synthesis in leukemia cells from mice treated with Triapine was considerably longer than in those from animals treated with hydroxyurea. Combination of Triapine with various classes of agents that damage DNA (e.g. etoposide, cisplatin, doxorubicin, and 1-acetyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine) resulted in synergistic inhibition of the L1210 leukemia, producing long-term survivors of tumor-bearing mice treated with several dosage levels of the combinations, whereas no enhancement of survival was found when Triapine was combined with gemcitabine or cytosine arabinoside. The findings demonstrate the superiority of Triapine over hydroxyurea as an anticancer agent and further suggest that prevention by Triapine of repair of DNA lesions created by agents that damage DNA may result in efficacious drug combinations for the treatment of cancer. BIOCHEM PHARMACOL 59;8: 983-991, 2000.
Molecular Cancer, 2011
Background A novel anticancer drug 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs) in tumor cells. Methods Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD), which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of γ-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and...
Biochemical Pharmacology, 1973
Treatment of Ehrlich ascites carcinoma bearing mice with DGA, the amide of diazoacetyl-glycine, leads to an inhibition of labelled thymidine incorporation into DNA of the tumour cells. This inhibition is not due to impairment of the aucleoside transport into the cell or to a modification in the activity of thymidine kinase. A possible explanation of the DGA effects resides in its partial inhibition of DNA polymerase and in its ability to alter the template activity of native DNA.
Biochemical Pharmacology, 1990
A series of ~-hydroxy-~~aminoguanidine (HAG) derivatives were studied and compared for their effects on ribonu~leotide reductase activity in cell-free extracts; on nucleic acid synthesis and the growth of human colon carcinoma HT-29 cells; and on mouse leukemia L1210 cells in culture. The HAG derivatives ~RCH=NNHC(=NH)NHOH-tosy~ate] studied could be grouped as: (1) hydroxybenzylidines; (2) methoxyben~lidines; and (3) nitrobenzylidines substituted at the R position. 2'-Hydroxybenzylidine-HAG, the lead compound, was relatively active in both H'T-29 cells and L1210 cells (20 rt S and 13 f 4 pM for SO% inhibition of HT-29 and L1210 cell growth respectively). The monohydroxybenzylidene compounds were generally more active than the dihydroxy-and trihydroxybenzylidene-HAG derivatives. The methoxybenzylidene-HAGS were as active as the monohydroxybenzylidene-HAGS. 2'-Hydroxy-4'-methoxybenzylidene-HAG was much more active than 2',4'dihydroxybenzylidene-HAG. The mononitrobenzylidene-HAGS were more active than the dinitrobenzylidene-HAG compound. In general, L1210 cells were more sensitive to the effects of the HAG compounds than were HT-29 cells. There was good agreement between the concentration of drng required to inhibit the growth of HT-29 cells and that required to inhibit the growth of L1210 cells. There was also good correlation between the ability of HAG derivatives to inhibit r~bonu~leotide reductase activity and to inhibit tumor cell growth. Some derivatives, such as 2',3',4'-and 3',4',5'trihydroxybenzylidene-HAG inhibited L1210 cell growth by SO% at lower concentrations (7.8 and II .9 PM respectively) than the concentrations needed for SO% inhibition of HT.29 cell growth (1% and 234 HM respectively) and r~bonucleotide reductase activity (122 and 188 PM respectively). The studies of nucleic acid synthesis in Li210 cells using j3H]cytidine as a precursor showed that 2',3',4'-trihydroxybenzylidine-HAG inhibited DNA synthesis at a lower concentration (29 FM for SO% inhibition) than was needed for the inhibition of RNA synthesis and formation of [jH]deoxycytidine nucleotides in the acid-soluble fraction (320 and 820 PM for SO% inhibition respectively). These results indicate that 2',3',4'-trihydroxybenzylidine-HAG inhibits DNA synthesis in L1210 cells through other mechanisms rather than exclusively through the inhibition of ribonucleotide reductase activity.
Journal of Medicinal Chemistry, 1996
We previously designed 1-(3-C-ethynyl--D-ribo-pentofuranosyl)uracil (EUrd) as a potential multifunctional antitumor nucleoside antimetabolite. It showed a potent and broad spectrum of antitumor activity against various human tumor cells in vitro and in vivo. To determine the structure-activity relationship, various nucleobase analogues of EUrd, such as 5-fluorouracil, thymine, cytosine, 5-fluorocytosine, adenine, and guanine derivatives, were synthesized by condensation of 1-O-acetyl-2,3,5-tri-O-benzoyl-3-C-ethynyl-R, -D-ribo-pentofuranose (6) and the corresponding pertrimethylsilylated nucleobases in the presence of SnCl 4 or TMSOTf as a Lewis acid in CH 3 CN followed by debenzoylation. The in vitro tumor cell growth inhibitory activity of these 3′-C-ethynyl nucleosides against mouse leukemia L1210 and human nasopharyngeal KB cells showed that 1-(3-C-ethynyl--D-ribo-pentofuranosyl)cytosine (ECyd) and EUrd were the most potent inhibitors in the series, with IC 50 values for L1210 cells of 0.016 and 0.13 µM and for KB cells of 0.028 and 0.029 µM, respectively. 5-Fluorocytosine, 5-fluorouracil, and adenine nucleosides showed much lower activity, with IC 50 values of 0.4-2.5 µM, while thymine and guanine nucleosides did not exhibit any activity up to 300 µM. We next evaluated the tumor cell growth inhibitory activity of ECyd and EUrd against 36 human tumor cell lines in vitro and found that they were highly effective against these cell lines with IC 50 values in the nanomolar to micromolar range. These nucleosides have a similar inhibitory spectrum. The in vivo antitumor activities of ECyd and EUrd were compared to that of 5-fluorouracil against 11 human tumor xenografts including three stomach, three colon, two pancreas, one renal, one breast, and one bile duct cancers. ECyd and EUrd showed a potent tumor inhibition ratio (73-92% inhibition relative to the control) in 9 of 11 and 8 of 11 human tumors, respectively, when administered intravenously for 10 consecutive days at doses of 0.25 and 2.0 mg/kg, respectively, while 5-fluorouracil showed potent inhibitory activity against only one tumor. Such excellent antitumor activity suggests that ECyd and EUrd are worth evaluating further for use in the treatment of human cancers.
Medicinal research reviews, 2017
7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five-membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base-pairing in DNA or RNA or better binding to enzymes. Several types of 7-deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7-hetaryl-7-deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6-hetaryl-7-deazapurine and thieno-fused deazapurine ribonucleosides, is not yet known. Many 7-deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar-mod...