Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heterocyclic thiosemicarbazones, thioureas and 2-substituted pyridine N-oxides as well as representative nickel, cobalt and copper complexes were shown to be potent antineoplastic/cytotoxic agents. The cytotoxicity was demonstrated against single cell leukemia as well as cell lines derived from solid tissue (colon adenocarcinoma, HeLa, KB, skin, bronchogenic lung, bone osteosarcoma and glioma). In L1210 cells, DNA synthesis and subsequently RNA synthesis were particularly inhibited by the agents. IMP dehydrogenase activity and thus purine de novo synthesis was reduced significantly by the agents. Dihydrofolate reductase, ribonucleoside reductase, nucleoside kinase and DNA polymerase alpha activities were inhibited by the agents. d(NTP) pool levels were reduced by most of the agents. DNA strand scission was present with all of the derivatives; however, there was no evidence of intercalation, cross linking or alkylation/binding to bases of DNA. This new group of compounds may offer novel exploratory derivatives for future investigations in the treatment of cancer.
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PMID:The cytotoxicity of heterocyclic thiosemicarbazones and their metal complexes on human and murine tissue culture cells. 849 Feb 2

A series of beta-alkylaminopropiophenone derivatives were demonstrated to be potent antineoplastic agents. Several compounds showed activity against Ehrlich ascites carcinoma growth in CF1 mice by demonstrating over 70% inhibition. Most of these agents proved to be potent cytotoxic agents in inhibiting the growth of a number of murine and human cancer cell lines grown in tissue culture. Their ED50 values were comparable to those of the selected standard anticancer drugs, such as 6-MP, ara-C, hydroxyurea, 5-FU, 6-aza-UMP, etoposide, antimycin A, actinomycin D and cycloheximide. In the mode of action studies in Tmolt3 cells, beta-(3",5"-dimethyl)piperidinopropiophenone was observed to reduce DNA and RNA synthesis significantly at 25 microM within 60 min incubation. The site of action of this agent appears to involve the reduction of the activities of Tmolt3 DNA polymerase alpha 1 dihydrofolate reductase, PRPP-amido transferase and ribonucleoside reductase.
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PMID:Antineoplastic activities of 2,3,4-chloro-substituted beta-alkylaminopropiophenone derivatives in CF1 mice and in murine and human tumor cells. 886 31

1,3,5-Triazabicyclo[3.1.0]hexane-2,4-diones proved to be potent antineoplastic and cytotoxic agents in murine and human cancer cells. In L1210 lymphoid leukemia cells DNA synthesis was significantly suppressed over 60 min by the agents from 25 to 100 microM. DNA synthesis was blocked at multiple sites including DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, PRPP-amido transferase, and nucleoside kinases which would be additive overall in suppressing DNA synthesis. The DNA molecule itself did not appear to be at target of the agents since no alkylation of nucleotide bases, intercalation between base-pairs or cross-linking of strands occurred after 24 h incubation at 100 microM. Nevertheless, L1210 DNA fragmentation did occur after 24 h incubation at 100 microM which is usually associated with tumor cell apoptosis.
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PMID:The cytotoxic action of 1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones and 1,3,5-triazine-4,6-(1 H,5 H)-diones in murine and human tumor cells. 967 70

Amine-carboxyboranes with varying alkyl chain lengths were observed to be potent cytotoxic agents inhibiting the growth of a number of histological types of murine, rat, and human tumors. These agents preferentially reduced L1210 DNA synthesis with marked inhibition of the activities of regulatory enzymes of the purine pathway. Other enzyme activities which were marginally reduced were DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, t-RNA polymerase, and nucleoside kinases. Pyrimidine nucleotide pools were not reduced but DNA strand scission occurred after 24 h incubation with the agents. The amine-carboxyboranes were not DNA topoisomerase II inhibitors at 100 microM. The agents did not cause DNA protein linked breaks themselves; nevertheless, VP-16 [etoposide] induced DNA protein linked breaks were increased two fold in the presence of the agents suggesting synergistic effects. The amine-carboxyboranes decreased protein kinase C mediated phosphorylation of L1210 topoisomerase II protein, potentially decreasing its enzymatic catalytic activity. Thus, the amine-carboxyboranes did not function like VP-16 in affording cleavable products but were synergistic with VP-16 in causing DNA fragmentation. The agents were also additive with VP-16 in reducing tumor cell number, soft-agar colony growth and DNA synthesis and in producing DNA strand scission.
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PMID:Effects of alkyl amine carboxyboranes on L1210 DNA fragmentation and nucleic acid metabolism. 969 Dec 46

Two alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross-linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 microM.
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PMID:Cytotoxicity of substituted alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 lymphoid leukemia cells. 988 Oct 55

A peptide fragment comprising the first 83 residues from the N-terminus of E. coli thioredoxin is purified by hydroxylamine cleavage of the intact protein. At physiological pH, the secondary and tertiary structure contents of the peptide are 70 and 35%, respectively, compared to the intact protein. Peptide 83 is able to display dual biological functions of thioredoxin, namely, a substrate for the enzyme E. coli thioredoxin-reductase and a processivity factor of T7 DNA polymerase. At present, peptide 83 represents the minimum functional and folding unit of thioredoxin. The highly conserved residue Phe 81 appears to play an important role in the folding of peptide 83, as judged from the packing analysis. Peptide 83 also mimics a particular kinetic folding intermediate of thioredoxin in terms of spectral properties and may serve as an equilibrium peptide model for the former.
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PMID:Minithioredoxin: a folded and functional peptide fragment of thioredoxin. 1044 85

4-Carbethoxy-1-methyl-2-phenacyl-3-phenylpyrrole (9), 4-carbethoxy-2-(4-methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole (10) and 2-(4-methoxybenzoyl)-3,4-bis-(4-methoxyphenyl)pyrrole (11) proved to be potent cytotoxic agents against the growth of murine and human leukemias and lymphomas. Selective toxicity was demonstrated against the growth of solid tumors, e.g., human adenocarcinoma of the colon SW480 and ileum HCT-8, glioma U-87-MG, and rat UMR-106 osteosarcoma. A mode of action study in Tmolt4 leukemia cells demonstrated that the agents inhibited de novo purine synthesis at the regulatory sites PRPP-amido transferase, IMP dehydrogenase as well as dihydrofolate reductase resulting in significant inhibition of DNA synthesis in 60 min. Other biochemical sites which were affected significantly were thymidylate synthetase, DNA polymerase alpha, RNA polymerases, nucleoside kinase and ribonucleoside reductase.
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PMID:The cytotoxicity and mode of action of 2,3,4-trisubstituted pyrroles and related derivatives in human Tmolt4 leukemia cells. 1052 73

We observed and compared alterations in 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase at the transcriptional level in unsynchronized, three-passage cultures of smooth-muscle cells from the aorta of chicks fed on a control diet (C-SMC) and those of chicks fed on a similar diet plus cholesterol (Ch-SMC). Alterations in reductase mRNA concentrations in senescent cultures were much lower. We used a modification of the competitive (c) reverse transcription polymerase chain reaction method, using a Thermus thermophilus DNA polymerase (Tth pol) to quantify the very scarce species of HMG-CoA reductase mRNA in samples of cytoplasmic SMC mRNA. We cloned and sequenced a 199 bp cDNA fragment of chicken HMG-CoA reductase, which encoded a region of 66 amino acids belonging to the catalytic domain of the enzyme. HMG-CoA reductase mRNA concentrations from young C-SMC cultures rose 3.89-fold 4 h after the change of medium and returned to base levels between 8 to 12 h afterward. Concentrations in Ch-SMC cultures increased less (2.36-fold) 8 h after the change to fresh medium. Increases in reductase mRNA in senescent cultures of Ch-SMC and C-SMC measured under similar conditions were only 1.28- and 1.39-fold, respectively.
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PMID:Alterations in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA concentration in cultured chick aortic smooth muscle cells. 1090 18

Complexes containing Ta, Fe, Co, Mo, or W metal centers that are bound to C2B4 or C2B3 small carborane ligands proved to be potent cytotoxic agents in murine and human tissue cultured cells, being more effective in suspended leukemia and lymphomas but surprisingly also effective against the growth of selected solid tumors. These complexes inhibited nucleic acid metabolism, specifically DNA and purine de novo syntheses. Key enzyme activities in nucleic acid metabolism which were inhibited by the complexes were P388 DNA polymerase a, ribonucleotide reductase, dihyrofolate reductase, PRRP-amidotransferase and IMP dehydrogenase. The complexes afforded a moderate amount of DNA-fragmentation in P388 lymhocytic leukemia cells and were moderate inhibitors of human DNA topoisomerase II activity; however, the DNA molecule itself was not a target of the complexes in that there was no evidence that the complexes caused intercalation between base pairs, caused cross-linking of the strands of DNA or alkylated the bases of DNA.
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PMID:Antitumor activity of mono- and dimetallic transition metal carborane complexes of Ta, Fe, Co, Mo, or W. 1095 95

The 2-aldo- and 2-ketopyridine-N(4)-substituted thiosemicarbazones and their copper complexes demonstrated potent cytotoxic activity against a series of murine and human suspended cultured tumor cells. Selected compounds were active against the growth of cultured cells from solid human tumors, i.e. Mck-7 breast effusion, lung A549 and lung MB-9812, bone SOS-2 and clear cell Caki renal tumor. In Tmolt4 T cell leukemia cells the compounds inhibited the syntheses of DNA, RNA and protein over 60 min at 25 to 100 microM. Multiple target sites in nucleic acid metabolism were suppressed by the agents, i.e. DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, de novo purine synthesis, thymidylate synthetase and nucleoside kinases. The total effects of the agents on DNA metabolism led to the reduction of deoxyribonucleotide pools as well as DNA fragmentation.
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PMID:Cytotoxicity of 2-aldo- and 2-ketopyridine-N(4)-substituted thiosemicarbazones and mode of action in human Tmolt4 cells. 1153 44


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