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![Structures of a large fragment (Klenow) of Taq DNA polymerase, dNTP and DNA [10].](profile/Carlos-Pungitore-2/publication/233541698/figure/fig1/AS:669082345037824@1536533070012/Fig-1-Structures-of-a-large-fragment-Klenow-of-Taq-DNA-polymerase-dNTP-and-DNA.jpg)
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![Fig. (2). Structures of DNA polimerase and DNA [14].](profile/Carlos-Pungitore-2/publication/233541698/figure/fig2/AS:669082345033730@1536533070138/Fig-2-Structures-of-DNA-polimerase-and-DNA-14_Q320.jpg)
This review article tries to summarize investigation about natural products with the ability to inhibit enzymes that play a crucial role in DNA metabolism such as replication, transcription, recombination, and chromosome segregation during mitosis. The focus is placed on DNA polymerases, topoisomerases and reverse transcriptase inhibitors because t...
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... I enzymes has been the topic of extensive biochemical and structural studies [9]. The first crystal structure of a member of this family of proteins, the large fragment (Klenow) of Escherichia coli DNA Pol I, showed that the polymerase domain has a shape evocative of a right hand in which the palm, fingers and thumb form the DNA-binding crevice (Fig. (1)) [10,11]. The active site, conformed of three acidic residues, is positioned at the palm which forms the base of the crevice. Besides, complexes of this protein segment with DNA described the enzyme in its editing form. On the basis of the arrangement of the binding partners at the 3'5' exonuclease active site, it was pro- jected that ...
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... isocoumarins (49-52) are natural compounds isolated from cultures of fungi (Nodulisporium sp.) and their struc- tures were determined by spectroscopic analyses. These compounds show activity against DNA polymerase [27] ( Fig. ...
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... (67-70), vitamin E compounds that have an unsaturated side chain with three double bonds, selectively inhibited the activity of mammalian DNA polymerase in vitro [46] (Fig. ...
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... the 60s, two rational problems relating to DNA struc- ture became evident. The first was that the unwinding of Fig. (11). Others natural ...
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... of one double-stranded DNA to allow the pas- sage of a second double helical strand through the breakage point [52]. The structural characterization of the complexes between short DNA duplexes and human topoisomerase I provided a basis to explain the extraordinary efficiency of the trans- esterification reaction catalyzed by topoisomerase I (Fig. (12)) [53]. The attack of the phosphodiester bond by the 5'- OH DNA (reverse) or tyrosine (forward) nucleophile is con- siderably activated by precise contacts between the non bridging scissile phosphodiester oxygens and the side chains of two arginines (Arg 488 and Arg 590 ), a lysine (Lys 532 ) and a histidine (His 632 ) residues. These ...
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... (71-72) is an important topoisomerase I inhibitor, and was isolated in the 1960s from the Chinese tree Camptotheca acuminate. Water soluble camptothecin derivatives (73-74) have been introduced in the clinic for colon and ovarian carcinoma [58,60] (Fig. ...
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... (75) is an anthracycline anticancer agent that is used clinically in the treatment of acute myelocytic leu- kemia. Aclarubicin is a strong DNA intercalating agent that prevents the binding of topoisomerase II to DNA, so it is antagonistic to classical topoisomerase II poisons [62]. Iso- Fig. (14). Anthracycline and ...
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... is an anti- cancer drug candidate. This compound has significant in vitro and in vivo activity against malignant tumor cells. This anticancer activity of salvicine is associated with its ability to induce tumor cell apoptosis and also acts as a topoi- somerase II inhibitor, generating its effects by trapping en- zyme-DNA cleavage complexes [66] (Fig. ...
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... triterpenoids isolated from bark of Phyllanthus flexuosus were screened from human topoisomerase I and II inhibitory activities. Olean-12-en-3,15-diol (83), olean-12-en- 3,15,24-triol (84), lupeol (85) and betulin (86) were found to be selective catalytic inhibitors of human topoisomerse II with IC 50 values in the range of 10-39 μM [68]. (Fig. ...
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... interaction with DNA and dual topoisomerase I and II inhibi- tion [69]. Rebeccamycin (90), a microbial metabolite, iso- lated from cultures of Saccharothrix aerocolonigenes, pos- sessing a maleimide indolo [2,3-]carbazole framework with a carbohydrate moiety attached to one of the indole nitro- gens, is a well-known topoisomerase I inhibitor [66] (Fig. (16) Fig. (16). Pyrrol ...
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... with DNA and dual topoisomerase I and II inhibi- tion [69]. Rebeccamycin (90), a microbial metabolite, iso- lated from cultures of Saccharothrix aerocolonigenes, pos- sessing a maleimide indolo [2,3-]carbazole framework with a carbohydrate moiety attached to one of the indole nitro- gens, is a well-known topoisomerase I inhibitor [66] (Fig. (16) Fig. (16). Pyrrol ...
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... compounds represent a structural class of organic cations that induce topoisomerase I-mediated DNA cleavage, a behavior termed topoisomerase I poisoning [67] (Fig. (17)). ...
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... toxic marine microalga Dinoflagellate Gymnodinium sp. produces a polysaccharide (103) that shows inhibition of DNA topoisomerase I and II, and growth inhibition of hu- man cancer cell lines [73] (Fig. ...
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... the gene products, viral proteins and the viral RNA genome itself, packaged as new viruses. The RNA viruses that include reverse transcriptases are known as retroviruses. Many reverse transcriptases have two subunits, and . The pol gene encodes the subunit (Mr 90,000), and the subunit (Mr 65,000) is simply a prote- olytic portion of the subunit (Fig. (19)) [80]. Reverses transcriptases catalyze three different reactions: (1) RNA- dependent DNA synthesis, (2) RNA degradation, and (3) DNA-dependent DNA ...
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... The compounds 1-hydroxymaprounic acid 3-p- hydroxybenzoate (113) and 2-hydroxymaprounic acid 2,3- bis-p-hydroxybenzoate (114) were obtained from Maprounea africana, they inhibited HIV-I RT and HIV-2 RT with IC 50 values close to 4 μM and 50 μM, respectively. M. africana is a Congolese traditional medicinal plant with antiamoebic activity [89] (Fig. ...
Citations
... As part of a program to determine biological activities of natural products and derivatives (Pungitore 2008;Martin et al. 2011;Garro et al. 2015), 23 naphthoquinones were tested as antibiofilm agents (Fig. 1). ...
The capacity of different naphthoquinones to inhibit and eradicate Yersinia enterocolitica biofilm was investigated and possible mechanisms of action were evaluated. Inhibition of biofilm formation and cell viability, quorum sensing (QS) inhibition and oxidative stress generation of 23 naphthoquinones were assayed against Yersinia enterocolitica. The best anti-biofilm agents at 100 µmol l⁻¹ were compounds 3, 11 and 13, which showed biofilm inhibition higher than 75%. Compound 3 was the most effective against biofilm forming capacity of Y. enterocolitica WAP 314 with a minimum biofilm inhibitory concentration (MBIC) of 25 µmol l⁻¹; while against Y. enterocolitica CLC001, the lowest MBIC was 6.1 µmol l⁻¹ for compound 11. Acyl-homoserine lactones production was decreased with compound 13. We showed that the oxidative stress influence biofilm growth, by means of ROS and RNI increment. All treatments increased ROS and RNI values in the biofilm of both strains; while in planktonic cells, the increase was lesser. Additionally, Y. enterocolitica WAP 314 biofilm treated with compounds 11 and 13 showed above 80% of SOD consumption. In Y. enterocolitica CLC001 biofilm all compounds induced above 90% of SOD consumption. The SOD activity was higher in biofilm than in planktonic cells. In conclusion, this is the first study to demonstrate that naphthoquinones are able to inhibit biofilm formation of Y. enterocolitica without critical disturbing its planktonic growth. Naphthoquinones as anti-biofilm agents might potentially be useful in the treatment of biofilm-associated infections in the future.
Graphic abstract
... Category I DNA topoisomerases break and rejoin only one of the two strands during catalysis, while type II DNA topoisomerases break and rejoin both strands for each DNA strand-passing reaction. Topoisomerase I seems to be associated with actively transcribed genes, whereas topoisomerase II is required for DNA replication and for successful traverse of mitosis [4]. Through these two different mechanisms, DNA topoisomerases change the topological states of DNA, which facilitate various DNA transactions such as DNA replication, RNA transcription, recombination, chromosome condensation/decondensation, and chromosome segregation [1][2][3]. ...
... Through these two different mechanisms, DNA topoisomerases change the topological states of DNA, which facilitate various DNA transactions such as DNA replication, RNA transcription, recombination, chromosome condensation/decondensation, and chromosome segregation [1][2][3]. Numerous inhibitors have been used in clinical trials including dideoxynucleotides, phospholipids, fatty acids, flavonoids, iridoids, triterpenoids, camptothecines, anthacyclines, aminoacridines and ellipticines [4,5]. However, more active compounds are still necessary. ...
Background: DNA polymerases and topoisomerases are proteins that play a vital part in DNA metabolism such as replication, transcription, recombination, and chromosome segregation during mitosis. For this reason, these enzymes are appreciated targets for the development of cancer chemotherapeutic drugs. Method: All compounds evaluated in this work were obtained under the conditions and using the reagents described in the Schemes (1-3). Polymerase Chain Reaction (PCR): Sample stock solutions were prepared at a concentration of 10 mM in dimethyl sulfoxide (DMSO) using 1 ml as a final volume. The PCR master mix consisted of 2.5 μl of PCR Buffer (40 mM Tris-acetate, pH 8.3), 0.5 μl of MgCl2 at a concentration of 15 mM, 2.5 U Taq DNA polymerase, 2.5 μl of each oligonucleotide primer at a concentration of 100 mM, 0.5 μl of each deoxynucleotide triphosphates (dNTP) at a concentration of 10 mM and 0.1 μg/ml of DNA template. Topoisomerase I activity was determined by relaxation of super-coiled pBr 322 plasmid DNA. The reaction mixture in 20 ml contained 35 mM Tris-HCl, pH 8, 72 mM KCl, 5 mM MgCl2, 5 mM DTT, 5 mM spermidine, 0.01% bovine serum albumin, 0.64 mg/20 ml super-coiled pBr 322 DNA, 1.5 U human topoisomerase I and 1 ml of test compound diluted with DMSO. Results: Faithful replication of DNA molecules with the intervention of DNA polymerases and topoisomerases is essential for genome integrity and correct transmission of genetic information in all living organisms. For this reason, DNA polymerases and topoisomerases have emerged as important cellular targets for chemical intervention in the development of anti-cancer agents. Herein we report the semi-synthesis of resveratrol derivatives and similar compounds and their biological activity against Taq DNA polymerase and topoisomerases. Compound 4 was the most active against both enzymes with IC50 values equal to 18.56 and 28.37 μM, respectively. Additionally, compounds 3 and 5 showed interesting activity against Taq DNA polymerase with IC50 values equal to 76.89 and 71.65 μM, respectively. Conclusion: In summary, one compound (4) was found to have excellent inhibitory activity against human topoisomerase I and Taq DNA polymerase. This compound can be a leading molecule for the development of original anticancer treatment and an excellent instrument to explore DNA polymerase and topoisomerase activity.
... For example, it has been postulated that fatty acids, such as palmitic acid, play a key role in regulating the characteristic loss of homeostasis in cancer [4]. Numerous fatty acids, mainly of bacterial origin, also inhibit DNA polymerase and Topoisomerase I, and display anti-malarial and anti-viral activity [1,[7][8][9][10][11]. ...
... It is still necessary to develop new less cytotoxic antiretrovirals for the treatment of this disease. Natural products from various marine sources have been known to possess diverse biological activities including antiviral [11,31]. ...
The natural fatty acids (5Z)-5-pentacosenoic and (9Z)-9-pentacosenoic acids were synthesized for the first time in eight steps starting from either 4-bromo-1-butanol or 8-bromo-1-butanol and in 20-58 % overall yields, while the novel fatty acids 5-pentacosynoic and 9-pentacosynoic acids were also synthesized in six steps and in 34-43 % overall yields. The ∆(5) acids displayed the best IC50's (24-38 µM) against the HIV-1 reverse transcriptase (RT) enzyme, comparable to nervonic acid (IC50 = 12 µM). The ∆(9) acids were not as effective towards HIV-RT with the (9Z)-9-pentacosenoic acid displaying an IC50 = 54 µM and the 9-pentacosynoic acid not inhibiting the enzyme at all. Fatty acid chain length and position of the unsaturation was important for the observed inhibition. None of the synthesized fatty acids were toxic (IC50 > 500 µM) towards peripheral blood mononuclear cells. Molecular modeling studies indicated the structural determinants underlying the biological activity of the most potent compounds. These results provide new insights into the structural requirements that must be present in fatty acids so as to enhance their inhibitory potential towards HIV-RT.
... Enzymes involved in the metabolism of nucleic acids, such as polymerases, topoisomerases and girases, are molecular targets in the search for new antimicrobial drugs [17]. This strategy could be considered analogous to the screening of DNA polymerase inhibitors in the search of new potential anticancer compounds, which is now widely accepted. ...
Some members of a series of cinnamic acid derivatives possess promising inhibitory activities in cellular assays against fungi of the Aspergillus genus. In order to search for a possible molecular target of such compounds, their role as Taq polymerase I inhibitors was studied. Four of the compounds studied displayed IC50 values within the range of those considered active as DNA polymerase inhibitors when searching for new cytotoxic molecules. The results obtained in our molecular modeling study appear to show that the inhibitory activity depends on the presence of a stabilizing interaction between the phenylpropanoid derivatives and the residues Asp610, Thr664, Phe667, Tyr671, and Asp785 located in the active site of Taq polymerase I. Also, it is possible to assert that the polymerization of DNA would be the molecular target of cinnamic acid derivatives with antifungal activity, which correlates with the inhibition of Taq polymerase I and the quantitative descriptor for the lipophilia (ClogP).
Aims of the study:
The ability of Yersinia enterocolitica strains to form biofilms and the capacity of different alkaloids to inhibit biofilm formation were investigated.
Methods and results:
The capacity to form biofilm on polystyrene of 31 Y. enterocolitica strains was evaluated. Biofilm and quorum sensing (QS) inhibition of 17 alkaloids were assayed; furthermore, minimum biofilm inhibitory concentration (MBIC) was determined. The capacity to form biofilms among the examined strains seemed to be a strain-related feature. The best biofilm inhibitors at 100 µmol l-1 were oliverine (1), guatterine (3), liriodenine (4), oliveridine (5) and pachypodanthine (6), which showed biofilm inhibition higher than 87 %. Pachypodanthine (6) was the most effective compound with MBIC value of 12.5 µmol l-1 at sub-inhibitory concentration and also was able to inhibit QS system and reduce yenR expression at this concentration.
Conclusion:
This is the first study to demonstrate that oliverine, liriodenine, and pachypodanthine are able to inhibit biofilm formation of Y. enterocolitica without critical disturbing its growing capacity. At MBIC pachypodanthine inhibited biofilm formation and QS.
Significance and impact of the study:
The use of aporphinoid alkaloids as biofilms inhibitory agents might potentially be useful to treat biofilm-associated infections in the future.
This review article tries to be an update of 2008 Pungitore’s review. Again, this paper tries to summarize the investigation about natural products, synthetic and non-nucleoside compounds with the ability to inhibit enzymes that play a crucial role in DNA metabolism such as replication, transcription, retro-transcription, recombination, and chromosome segregation during mitosis. The focus is placed on DNA polymerases, topoisomerases and reverse transcriptase inhibitors because most of the literature emphasized on their inhibitory activity. A great diversity of chemical compounds encompassing triterpenes, flavonoids, chromones, lipids, iridoids, phytosterols, coumarins, anthracyclines, quinones, protoberberines, tannins, lignans, acetogenins, benzimidazoles and other natural products, produced by different species of organisms, have inhibitory activities against enzymes related to DNA metabolism allowing these enzymes to arise as important molecular targets for cancer and AIDS research.
Coumarin derivatives were prepared using natural products isolated from plants belonging in the Pterocaulon genus (Asteraceae) and commercial drugs. Some molecules have displayed interesting activity against myeloid murine leukemia virus-reverse transcriptase (MMLV-RT) (compounds 20 and 28 produced inhibition with IC50 values of 38.62 and 50.98μM, respectively) and Taq DNA polymerase (analogues 13 and 14 produced inhibition with IC50 values of 48.08 and 57.88μM, respectively). Such inhibitors may have importance as antiretroviral chemotherapeutic agents and also in the development of anticancer drugs.
Anthocyanins (Greek antos, flower and kyanos, blue) are part of a widespread group of plant constituents, col-lectively known as flavonoids, which occur in the western diet at relatively high concentrations and own a variety of pharmacological properties which make them potential anti-inflammatory and cancer agents. Besides their ability to scav-enge reactive oxygen species, anthocyanins exhibit anticancer effects through impaired expression and function of en-zymes, most of which are involved in abnormal activation of signaling pathways leading to cancer cell growth and pro-gression. Antiproliferative and antiangiogenetic properties of anthocyanins encompass inhibition of phosphorylation of receptor tyrosine kinases (EGFR, VEGFR, Met receptor, PDGFR) and down-regulation of downstream signaling cas-cades, impaired activity of cAMP-specific phosphodiesterases, chymotrypsin–like proteasome activity, ornithine decar-boxylase and cyclin-dependent kinases/cyclin complex. Transcription activity of NF-B, involved in the carcinogenesis process, is affected by anthocyanins through inhibition of the IB kinase complex phosphorylation. The antiproliferative activity is dependent on the presence of hydroxyl groups on ring B of the anthocyanin molecule. Anthocyanins influence cancer cell invasion as well, through the decrease of metalloproteinases and plasmin activity. Finally, inhibition of cy-clooxygenase activity may counteract a number of characteristics of tumor progression and metastasis. Conversely, one potential drawback of the anthocyanin's effect is their inhibitory activity on topoisomerases I and II. This review will deal with the current knowledge on the anthocyanins ability to hamper the expression and function of signaling pathway en-zymes involved in cancer development and discuss anthocyanins preventive/therapeutic potential against human cancers.
In this work, a novel catalpol derivative (6,10,2',6'-tetraacetyl-O-catalpol), which was previously obtained by our group and shown experimentally to inhibit a type of Taq DNA polymerase, was studied in silico. Studies of the interaction of 6,10,2',6'-tetraacetyl-O-catalpol with the Klentaq fragment of the Taq DNA polymerase I from Thermus aquaticus helped to elucidate the mechanism of inhibition of the enzyme, and offered valuable information that can be used to propose substrate structural modifications aimed at increasing the binding affinity. Classical and semi-empirical methods were used to characterize the conformational preferences of this organic compound in solution. Using docking simulations, the most probable binding mode was found, and the stabilities of the docked solutions were tested in a series of molecular dynamics experiments. Results indicated that the mechanism of inhibition may be competitive, which agrees with previous binding experiments done with 6,10,2',6'-tetraacetyl-O-catalpol.
