Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bioassay-guided fractionation of an active methyl ethyl ketone extract of Hardwickia binata, using an assay sensitive to DNA polymerase beta inhibition, resulted in the isolation of a potent inhibitor. This proved to be a novel diterpenoid, which has been named harbinatic acid (1). The structure of 1 was established as 3alpha-O-trans-p-coumaroyl-7-labden-15-oic acid from spectroscopic analysis and by comparison with the published data for a structurally related compound. Compound 1 strongly inhibited calf thymus DNA polymerase beta, with an IC(50) value of 2.9 microM.
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PMID:Harbinatic acid, a novel and potent DNA polymerase beta inhibitor from Hardwickia binata. 1042 25

Crude plant extracts were surveyed for their ability to inhibit DNA polymerase beta. A methyl ethyl ketone extract prepared from Baeckea gunniana was identified as a potent inhibitor of the enzyme. Bioassay-guided fractionation of the extract, using an assay to monitor the inhibitory potential of individual fractions toward DNA polymerase beta, led to the isolation of four active ursane and oleanane triterpenoids (1-4). Inhibitory principle 1 is a new natural product, and 2 is a novel compound. Their structures were established as 3 beta-hydroxyrus-12,19(29)-dien-28-oic acid (1) and 3 beta-hydroxyrus-18,20(30)-dien-28-oic acid (2) by spectroscopic analysis and by comparison with the data for the structurally related compound ursolic acid (4). Also isolated as a DNA polymerase beta inhibitor was oleanolic acid (3). Compounds 1-4 had IC50 values of 5.3-8.5 microM as inhibitors of polymerase beta in the presence of bovine serum albumin (BSA) and 2.5-4.8 microM in the absence of BSA.
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PMID:DNA polymerase beta inhibitors from Baeckea gunniana. 1065 12

Bioassay-guided fractionation of an active methyl ethyl ketone extract of Tetracera boiviniana, using a sensitive assay to monitor DNA polymerase beta inhibition, resulted in the isolation of three known triterpenoids, betulinic acid (1), 3-cis-p-coumaroyl maslinic acid (2), and 3-trans-p-coumaroyl maslinic acid (3). Compounds 1-3 inhibited DNA polymerase beta with IC50 values of 14, 15, and 4.2 microM in the presence of bovine serum albumin (BSA) and 6.5, 7.5, and 2.0 microM in the absence of BSA, respectively. Further, compounds 1-3 potentiated the effects of bleomycin in cultured P-388D1 cells.
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PMID:DNA polymerase beta inhibitors from Tetracera boiviniana. 1065 14

In a survey of crude plant extracts for DNA polymerase 1 inhibitors, a methyl ethyl ketone extract prepared from Freziera sp. exhibited potent inhibition of DNA polymerase beta. Bioassay-guided fractionation of the extract, guided by an assay to detect DNA polymerase beta inhibition, resulted in the isolation of six active pentacyclic triterpenoids (1-6). These triterpenoids had IC50 values ranging from 7.5 to 16 microM in the presence of bovine serum albumin (BSA) and 2.6-5.8 microM in the absence of BSA, consistent with the possibility that these inhibitors may be of use in vivo.
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PMID:Pentacyclic triterpenoids from Freziera sp. that inhibit DNA polymerase beta. 1096 84

In a survey of crude plant extracts for DNA polymerase beta lyase inhibitors, the hexanes extracts of Cladogynus orientalis, Hymenache donacifolia, and Heteropsis integerrima, and the methyl ethyl ketone extract of Acacia pilispina were found to exhibit good inhibition of the dRP lyase activity of DNA polymerase beta. Bioassay-guided fractionation of these extracts led to the isolation of three DNA polymerase beta lyase inhibitory phytosterols, namely stigmasterol (1) and beta-sitosterol (2), isolated from the hexanes extracts, and beta-sitosterol-beta-d-glucoside (3), isolated from the methyl ethyl ketone extract. Compounds 1-3 inhibited the DNA polymerase beta lyase activity with IC(50) values of 43.6, 43.3, and 72.4 microM, respectively. Compounds 1 and 2 were found capable of potentiating the action of bleomycin in cultured human tumor cells, consistent with the possibility that lyase inhibitors may find utility in vivo.
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PMID:Plant sterols as selective DNA polymerase beta lyase inhibitors and potentiators of bleomycin cytotoxicity. 1524 1

Bioassay-guided fractionation of an active methyl ethyl ketone extract of Edgeworthia gardneri, using an assay to monitor DNA polymerase beta lyase inhibition, resulted in the isolation of three known biscoumarin derivatives, 7-hydroxy-3,7'-dicoumaryl ether (edgeworin, 1), 7-hydroxy-6-methoxy-3,7'-dicoumaryl ether (daphnoretin, 2), and 6,7-dihydroxy-3,7'-dicoumaryl ether (edgeworthin, 3). Compounds 1-3 inhibited the lyase activity of DNA polymerase beta with IC(50) values of 7.3 microg/mL (22.5 microM), 43.0 microg/mL (122.3 microM), and 32.1 microg/mL (94.8 microM), respectively.
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PMID:Biscoumarin derivatives from Edgeworthia gardneri that inhibit the lyase activity of DNA polymerase beta. 1538 73

During a survey of plant secondary metabolites for DNA polymerase beta lyase inhibitors, we found that a crude methyl ethyl ketone extract prepared from Maytenus putterlickoides showed strong inhibition of the lyase activity of DNA polymerase beta in an in vitro assay. Bioassay-guided fractionation of the extract, using an in vitro assay, resulted in the discovery of a new active principle, 30-(4'-hydroxybenzoyloxy)-11alpha-hydroxylupane-20(29)-en-3-one (1), as well as a known compound, (-)-epicatechin (2). Compounds 1 and 2 exhibited DNA polymerase beta lyase inhibitory activity with IC50 values of 62.8 and 18.5 microM, respectively. Compound 2 was capable of potentiating the action of the monofunctional methylating agent methyl methanesulfonate in cultured human cancer cells, consistent with the possible utility of inhibitors of this type in vivo.
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PMID:DNA polymerase beta lyase inhibitors from Maytenus putterlickoides. 1549 54

Bioassay-directed fractionation of a methyl ethyl ketone extract of Solidago canadensis L. (Asteraceae), using an assay to detect the lyase activity of DNA polymerase beta, resulted in the isolation of the four new lupane triterpenoids 1-4 and the seven known compounds lupeol, lupeyl acetate, ursolic acid, cycloartenol, cycloartenyl palmitate, alpha-amyrin acetate, and stigmasterol. The structures of the new compounds were established as 3beta-(3R-acetoxyhexadecanoyloxy)-lup-20(29)-ene (1), 3beta-(3-ketohexadecanoyloxy)-lup-20(29)-ene (2), 3beta-(3R-acetoxyhexadecanoyloxy)-29-nor-lupan-20-one (3), and 3beta-(3-hetohexadecanoyloxy)-29-nor-lupan-20-one (4), respectively, on the basis of extensive 1D and 2D NMR spectroscopic interpretation and chemical modification studies. All 11 compounds were inhibitory to the lyase activity of DNA polymerase beta.
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PMID:New lupane triterpenoids from Solidago canadensis that inhibit the lyase activity of DNA polymerase beta. 1551 69

A survey of crude plant extracts for DNA polymerase beta inhibitors resulted in the identification of a methyl ethyl ketone extract prepared from Knema elegans that strongly inhibited the enzyme. Subsequent bioassay-guided fractionation of the extract, using an assay to monitor the activity of DNA polymerase beta, led to the isolation of two potent inhibitors, (+)-myristinins A (1) and D (2), which are known flavans having unusual structures. (+)-Myristinins A and D exhibited IC50 values of 12 and 4.3 microM, respectively, as inhibitors of DNA polymerase beta in the presence of bovine serum albumin (BSA), and 2.7 and 1.2 microM in the absence of BSA. As such, they are the most potent DNA polymerase beta inhibitors reported to date. Compounds 1 and 2 potentiated the cytotoxicity of bleomycin toward cultured P388D1 cells, reducing the number of viable cells by at least 30% when employed at 9 microM concentration for 6 h in the presence of an otherwise nontoxic concentration of bleomycin (75 nM). Principles 1 and 2 also induced strong Cu2+-dependent DNA strand scission in a DNA cleavage assay. Accordingly, 1 and 2 exhibit two activities, namely, DNA polymerase beta inhibition and DNA damage.
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PMID:(+)-Myristinins A and D from Knema elegans, which inhibit DNA polymerase beta and cleave DNA. 1630 11

Conventional therapy for human cytomegalovirus (CMV) relies on inhibition of the viral DNA polymerase. Ganciclovir (GCV) is the first-line therapy, but when GCV-resistant strains emerge, alternative therapies are extremely limited and are associated with significant toxicities. Combination of anti-CMV agents that act on different targets or stages of virus replication has not been well studied, mostly because of the limited number of anti-CMV agents. We report our investigation of combinations of agents that inhibit CMV by targeting the viral DNA polymerase, cellular kinases, or other cell/virus mechanisms yet to be discovered. The selected compounds differed by the slopes of their dose-response curve: compounds with a slope of 1 (GCV) representing one target or noncooperativity and compounds with high slopes indicating positive cooperativity. Analysis of anti-CMV drug combinations using the Bliss model (which accounts for the slope parameter) distinguished between combinations with synergistic, antagonistic, and additive activities. The combination of GCV and foscarnet was slightly synergistic; strong synergism was found when GCV was used with artemisinin-derived monomers or dimers or the MEK inhibitor U0126. The combination of GCV and cardiac glycosides (digoxin, digitoxin, and ouabain) was additive. The monomeric artemisinin artesunate was synergistic when combined with U0126 or the multikinase inhibitor sunitinib. However, the combination of artemisinin-derived dimers (molecular weights, 606 and 838) and U0126 or sunitinib was antagonistic. These results demonstrate that members of a specific drug class show similar patterns of combination with GCV and that the slope parameter plays an important role in the evaluation of drug combinations. Lastly, antagonism between different classes of CMV inhibitors may assist in target identification and improve the understanding of CMV inhibition by novel compounds.
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PMID:In vitro combination of anti-cytomegalovirus compounds acting through different targets: role of the slope parameter and insights into mechanisms of Action. 2427 30


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