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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-Acyl- and 1,2-diacyl-1,2,4-triazolidine-3,5-diones were found to be potent cytotoxic agents in murine and human cancer cell lines, e.g. L1210, P388, Tmolt3, colon adenocarcinoma, Hela cells and glioma. In vivo activity was demonstrated at 8 mg/kg/day against Ehrlich ascites carcinoma growth. In L1210 cells, 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione, 41, reduced DNA synthesis significantly with moderate reduction in RNA synthesis. Enzyme sites in L1210 cells which were markedly affected were m- and r-RNA polymerase, PRPP amidotransferase, IMP dehydrogenase, dihydrofolate reductase, thymidine, TMP and TDP kinases. Kinetic studies suggest the inhibition of rate limiting enzymes in the purine pathway by 41 was responsible for its cytotoxicity. Acute toxicity studies in mice indicated 41 was safe for therapeutic use at 20, 50, and 100 mg/ky/day.
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PMID:Antineoplastic activities and cytotoxicity of 1-acyl and 1,2-diacyl-1,2,4-triazolidine-3,5-diones in murine and human tissue culture cells. 144 91

The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.
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PMID:Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells. 150 1

Purine and pyrimidine adducts of alpha-methylene-gamma-lactone demonstrated potent cytotoxicity against murine L1210 lymphoid leukemia growth as well as a variety of human tissue cultured tumors. The most potent compound, 9-[(2-methyl-4-methylene-5-oxotetrahydrofuran-2-yl)-methyl 1] adenine 1 demonstrated significant inhibition of DNA synthesis in L1210 leukemic cells with moderate inhibition of protein synthesis. The major enzyme activities inhibited by 1 were DNA polymerase alpha, ribonucleoside reductase and t-RNA polymerase with marginal inhibition of thymidine kinase, TMP kinase, PRPP amidotransferase and IMP dehydrogenase. The inhibition of DNA polymerase alpha activity by 1 was evident at the lowest concentration 25 microM and was evident within 15 min incubation at 100 microM. The magnitude of enzyme inhibition was consistent with the observed DNA synthesis inhibition by 1. The only deoxyribonucleotide level reduced by 1 was the dATP pool level. U.V. absorption of DNA after interacting with 1 demonstrated a hyperchromic effect and L1210 DNA strand scission was observed after 24 hr incubation with 1 suggesting some type of interference with the DNA template by the drug.
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PMID:The effects of alpha-methylene-gamma-lactone purines and pyrimidines on L1210 lymphoid leukemia nucleic acid metabolism. 201 69

N-Substituted indan-1.3-diones have proven to be potent cytotoxic agents effective against the growth of single cell leukemia tumors and cell lines derived from solid tumors. A number of the derivatives were active against growth of solid tumors e.g. colon, lung bronchogenic and osteosarcoma for which few effective agents are available to inhibit their growth. These agents inhibited DNA and RNA synthesis of L1210 cells. The de novo purine synthetic pathway was inhibited at PRPP amido transferase and IMP dehydrogenase. The pyrimidine synthetic pathway was inhibited at aspartate transcarbamylase. Other sites which demonstrate minor inhibition were DNA polymerase alpha, r- and t-RNA polymerase, ribonucleoside reductase, dihydrofolate reductase, nucleoside kinases and thymidylate synthetase. In addition d(NTP) pool levels were reduced by the drugs. L1210 DNA strand scission was evident after exposure to drugs for 24 hr. at 100 microM.
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PMID:Cytotoxicity and mode of action of substituted indan-1, 3-diones in murine and human tissue cultured cells. 784 49

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

Transcriptional attenuation of the pyrimidine biosynthetic (pyr) operon from Bacillus subtilis was reconstituted with an in vitro system that consisted of pyr DNA templates, B. subtilis RNA polymerase, four ribonucleoside triphosphates, and the purified B. subtilis PyrR regulatory protein. The templates used each specified one of the three known attenuation regions of the pyr operon. Runoff (read-though) and terminated transcripts of the predicted lengths were the only major products synthesized. Transcription of the template that specifies the 5' leader attenuation region of the operon was examined in detail. Termination of transcription at the attenuator was strongly promoted by the combination of PyrR plus UMP. The concentration of UMP required for half-maximal effect was 2.5 microM. UTP also promoted termination in the presence of PyrR, but concentrations 10-fold higher than UMP were required; UDP was only effective at 100 times the concentration of UMP. Other pyrimidine and purine metabolites tested did not affect termination. PRPP, which like UMP is a substrate for the uracil phosphoribosyltransferase activity of PyrR, antagonized UMP-dependent transcriptional termination, but uracil did not. Transcriptional attenuation by PyrR plus UMP was also demonstrated in vitro with templates from the other two pyr attenuation regions. The results strongly support the model for transcriptional regulation of the B. subtilis pyr operon previously proposed by R. J. Turner, Y. Lu, and R. L. Switzer (J. Bacteriol. 176:3708-3722, 1994).
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PMID:Transcriptional attenuation of the Bacillus subtilis pyr operon by the PyrR regulatory protein and uridine nucleotides in vitro. 895 3

4-Hydroxyproline di- and tri-peptides and N-cbz-hydroxypropyl- glycinamides were observed to be potent cytotoxic agents against the growth of suspended single cells, L-1210, Tmolt3, and HeLa-S3. The agents were not as potent against the growth of cultured solid tumor cells. Selected derivatives were investigated for their mode of action in Tmolt3 leukemia cells. The compounds selectively inhibited DNA synthesis at 50 and 100 microM. The target site of action of the agents appeared to be the purine de novo pathway with marked inhibition of the activities of the two regulatory enzymes of the pathway, i.e. PRPP amido-transferase and IMP dehydrogenase. d[NTP] pools were reduced by the agents consistent with their overall reduction of DNA synthesis. Other marginally inhibited targets of the agents were r-RNA polymerase and TMP-kinase activities. The DNA molecule itself did not appear to be a target of these agents.
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PMID:Substituted 4-hydroxyproline di- and tri-peptides as cytotoxic agents. 1007 36

2-Etheny1-2,3-dihydrophthalazine-1,4-diones were successfully synthesized and proved to be effective cytotoxic agents against the growth of suspended murine and human leukemias and lymphomas. Selected compounds were also active in human HeLa uterine carcinoma, suspended effusion breast MCF-7 and glioma HS683 screens. These agents suppressed P388 lymphocytic leukemia DNA synthesis after 60 min at 100 microM. Their target appeared to be the de novo synthesis pathway with significant inhibition of the activities of both regulatory enzymes of the pathway, i.e. PRPP-amide transferase and IMP dehydrogenase resulting in a reduction in the d[NTP] pool levels for DNA incorporation. The compounds did not affect de novo pyrimidine synthesis and its regulatory enzymes. Very minor reduction by the agents was noted for the nucleoside kinases and the DNA and RNA polymerase activities within 60 min. DNA was not a target of the agents in that there was no alkylation of the nucleotide bases, intercalation between base pairs or cross-linking of the DNA strands; however, the agents did cause P388 DNA strand scission after 24 h at 100 microM.
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PMID:Cytotoxicity of 2-ethenyl-2,3-dihydrophthalazine-1,4-diones in murine and human tumor cultured cells. 1123 48

Vanada- and niobatricarbadecaboranyl monohalide complexes proved to be potent cytotoxic agents against murine and human leukemia and lymphoma growth as well as HeLa suspended uterine carcinoma. The vanada complex reduced the growth of KB nasopharynx, Hepe liver, HCT-8 ileum and 1-A9 ovary solid carcinomas. A mode of action study in human HL-60 promyelocytic leukemia cells showed that DNA and purine de novo syntheses were significantly inhibited with suppression of the regulatory enzymes activities of DNA polymerase alpha and PRPP-amido transferase. There was moderate inhibition of RNA synthesis and m-RNA polymerase activity. These complexes did not inhibit human topoisomerase I or II activity, although the niobium complex nicked the DNA. The complexes did activate caspases 3, 6 and 9 which are linked to apoptosis programmed cell death. These vanada- and niobatricarbadecaboranyl monohalide complexes appear to be more specific in their effects on leukemia cell metabolism than other sandwich complexes which have broad effects on multiple enzymes.
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PMID:Cytotoxicity and mode of action of vanada- and niobatricarbadecaboranyl monohalide complexes in human HL-60 promyelocytic leukemia cells. 1257 74

Poly(phenolic)-sulfonates demonstrated very good cytotoxicity against the growth of tumor cell lines (L1210, Tmolt-(3), HeLa-S(3)) and are comparable in potency with typical clinically used anticancer drugs. Four of the most active compounds, i.e. GL-2021, GL-2029, GL-2041 and GL-2063, were selected for a mode of action study in L1210 lymphoid leukemia cells at concentration of 25muM to 100muM for 60 min. The agents did not alkylate bases of ct-DNA, cause intercalation between base pairs, produce cross linking of ct-DNA strands or generate free radicals although L1210 DNA fragmentation was observed after 24 hr incubation. L1210 DNA synthesis was preferentially inhibited which was achieved by (1) suppressing DNA polymerase alpha activity which reduced the synthesis of new strands of DNA, (2) reducing of de novo purine synthesis at the regulatory enzyme PRPP amido transferase which reduced d(GMP) levels, and (3) inhibiting of nucleoside kinase activities which further reduced DNA synthesis. DNA template activity was altered by the poly(phenolic)sulfonates since they reduced DNA polymerase alpha and m-RNA and t-RNA polymerase activities. The kinetic studies at 50 muM over 2 hr demonstrated that the agents' effect on PRPP-amido transferase activity is probably a major target of the compounds.
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PMID:Cytotoxicity of poly(phenolic)sulfonates and their sodium salts in l1210 lymphoid leukemia cells. 1847 36


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