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 cyano- and carboxyborane adducts of cyclohexylamines and toluidines were shown to be cytotoxic towards suspended single cell tumors. The carboxyborane adducts of cyclohexylamine were more potent than the cyanoborane adducts of cyclohexylamine or any of the toluidine derivatives. A number of the compounds were active at 8 mg/kg/day i.p. in the Ehrlich ascites carcinoma screen in vivo. The mode of action study with N-methylcyclohexylaminecyanoborane 10 in L-1210 lymphoid leukemia cells showed that RNA synthesis was markedly reduced followed by DNA synthesis. Purine de novo synthesis was suppressed at PRPP-amido transferase, IMP dehydrogenase, and dihydrofolate reductase enzyme sites. The agent also interfered with DNA template activity causing reduction of DNA polymerase alpha, and RNA polymerase I, II and III activities. The d[NTP] pools were marginally reduced while DNA viscosity was reduced and DNA fragmentation occurred.
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PMID:Synthesis and cytotoxicity of amine-borane adducts of cyclohexylamines and toluidines. 858 54

N-[(Trimethylamine-boryl-carbonyl]-L-tryptophan methyl ester and N[(trimethylamine-boryl)-carbonyl]-L-histidine methyl ester were obtained by synthesis using triphenyl-phosphine/carbon tetrachloride or dicyclohexyl-carbodiimide as coupling agents, respectively. Both agents reduced L1210 lymphoid leukemia DNA, RNA, and protein syntheses with the largest reductions occurring in DNA synthesis. Reductions in DNA synthesis appear to be mediated by inhibition of key enzyme activities (i.e., DNA polymerase a, IMP dehydrogenase, and PRPP amido transferase). These agents had little effect on in vitro L1210 DNA topoisomerase II activity at 100 microM but were able to cause synergistic increases in protein-linked DNA breaks when combined with etoposide (VP16). It was shown that these agents significantly reduced protein kinase C mediated phosphorylation of human topoisomerase II in vitro. Thus, inhibition of topoisomerase II phosphorylation may be a mechanism by which these agents and VP-16 are synergistic in causing protein-linked DNA breaks.
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PMID:Synthesis and antitumor activity of boronated dipeptides containing aromatic amino acids. 941 63

Mycophenolate mofetil (MMF) has been approved as an immunosuppressive agent in kidney transplant recipients and may thus be used concomitantly with antiherpetic agents, which are used for the treatment of intercurrent herpesvirus infections. We have recently demonstrated that MMF and its parent compound mycophenolic acid (MPA), which is a potent inhibitor of IMP dehydrogenase, potentiate the antiherpesvirus activity of acyclovir, ganciclovir, and penciclovir. We have now evaluated the antiviral efficacy of the combination of MPA and the novel antiherpesvirus agent H2G [(R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine]. When combined with H2G, MPA (at concentrations ranging from 0.25 to 10 microgram/ml, which are readily attainable in human plasma) markedly potentiated the antiviral efficacy of H2G against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), as reflected by a 10- to 150-fold decrease in the 50% effective concentration. Moreover, the activity of H2G against a thymidine kinase-deficient strain of HSV-1 (TK- HSV-1) was increased more than 2,500-fold when combined with MPA. MPA by itself had little or no effect on the replication of these viruses. Similar observations were made for varicella-zoster virus. Also, ribavirin (another inhibitor of IMP dehydrogenase) caused a marked enhancement of the activity of H2G against HSV-1 (10-fold), HSV-2 (10-fold), and TK- HSV-1 (>185-fold). Exogenously added guanosine reversed the potentiating effects of MPA on the antiviral activity of H2G, indicating that this potentiating effect resulted from a depletion of the endogenous dGTP pools, thus favoring the inhibitory action of the H2G triphosphate on the viral DNA polymerase.
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PMID:The antiherpesvirus activity of H2G [(R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine] is markedly enhanced by the novel immunosuppressive agent mycophenolate mofetil. 983 29

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 series of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones copper(II) complexes was evaluated for their cytotoxic mode of action in a variety of human and rodent tumor cell cultures. It was determined that these compounds may induce cytotoxicity by affecting several metabolic pathways including a reduction in de novo purine synthesis, and inhibition of IMP dehydrogenase, and DNA polymerase alpha activities. Selected compounds also demonstrated the ability to inhibit L1210 DNA topoisomerase II activity at micromolar concentrations. These agents were able to antagonize etoposide-induced formation of cleavable complexes as measured by K+/SDS precipitation and in vitro cleavage reactions.
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PMID:The cytotoxicity of copper(II) complexes of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones. 989 58

Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, ribonucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and pyrimidine nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the ribonucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.
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PMID:Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor cell differentiation. 1041 91

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

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

A number of thiosemicarbazones have been tested previously and herein are included three bis(thiosemicarbazones) for comparison to the previous derivatives. In general the uncomplexed thiosemicarbazones were more potent in the cytotoxic screens than the bis(thiosemicarbazone) except in the murine L1210 and the human colon SW480 screens. Mode of action studies have only demonstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemicarbazones) complexes of copper, nickel, zinc, and cadmium have been examined to compare them to the heterocyclic N(4)-substituted thiosemicarbazones metal complexes. These new derivatives demonstrated excellent activity against the growth of suspended lymphomas and leukemias although it should be pointed out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemicarbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breast MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cells the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase, appeared to be a major target of the complexes. However, minor inhibition of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonucleotide reductase, and nucleoside kinases occurred over the same time period. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the heterocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, their metabolic effects in the tumor cell were more focused on a single synthetic pathway.
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PMID:The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells. 1096 96


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