Abstract
Background: The discovery of new chemotherapeutic agents still remains a continuous goal to achieve. DNA polymerases and topoisomerases act in nucleic acids metabolism modulating different processes like replication, mitosis, damage repair, DNA topology and transcription. It has been widely documented that Polymerases serve as molecular targets for antiviral and antitumoral chemotherapy. Furthermore, telomerase is a ribonucleoprotein with exacerbated activity in most of the tumor cell lines, becoming as an emergent target in Cancer treatment.
Methods: We undertook an exhaustive search of bibliographic databases for peer-reviewed research literature related to the last decade. The characteristics of screened bibliography describe structure activity relationships and show the principal moieties involved. This work tries to summarize the investigation about natural and semi-synthetic products with natural origin with the faculty to inhibit key enzymes that play a crucial role in DNA metabolism.
Results: Eighty-five data references were included in this review, showing natural products widely distributed throughout the plant kingdom and their bioactive properties such as tumor growing inhibitory effects, and anti-AIDS activity.
Conclusion: The findings of this review confirm the importance to find new drugs and biologically active natural products, and their potential medicinally useful benefits.
Keywords: DNA polymerases, telomerases, topoisomerases, inhibition, molecular target, chemotherapy.
Graphical Abstract
[1]
Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007; 70: 461-77.
[2]
Cordell GA. Changing strategies in natural products chemistry. Phytochemistry 1995; 40: 1585-12.
[3]
Shan C, Tan JE, Ou TM, Huang ZS. Natural products and their derivatives as G-quadruplex binding ligands. Sci China Chem 2013; 56: 1351-63.
[4]
Gokbulut A, Kartal-Yandim M, Iskender G, Baran Y. Agents targeting bioactive sphingolipids for the treatment of cancer. Curr Med Chem 2013; 20: 108-22.
[5]
Morceau F, Chateauvieux S, Orsini M, Trécul A, Dicato M, Diederich M. Novel natural compounds and pharmaceuticals reprogram leukemia cell differentiation pathways. Biotechnol Adv 2015; 33: 785-97.
[6]
da Costa JP, Carvalhais V, Amado F, et al. Anti-tumoral activity of human salivary peptides. Peptides 2015; 71: 170-8.
[7]
Bosch-Barrera J, Menendez JA. Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat Rev 2015; 41: 540-6.
[8]
Cragg GM, Newman DJ. Natural products: A continuing source of novel drug leads. Biochim Biophys Acta 2013; 1830: 3670-95.
[9]
Pungitore CR. Natural products, synthetic and non-nucleoside compounds as inhibitors of enzymes related to DNA. Curr Enzym Inhib 2014; 10: 13-38.
[10]
Garro HA, Pungitore CR. Coumarins as potential inhibitors of DNA polymerases and reverse transcriptases. Searching new antiretroviral and antitumoral drugs. Curr Drug Discov Technol 2015; 12: 66-79.
[11]
Barakat K, Gajewski M, Tuszynski J. DNA polymerase beta (pol β) inhibitors: A comprehensive overview. Drug Discov Today 2012; 17: 913-20.
[12]
Mentegari E, Kissova M, Bavagnoli L, Maga G, Crespan E. DNA Polymerases λ and β: The Double-Edged Swords of DNA Repair. Genes 2016; 7: 1-17.
[16]
Tseng CK, Chen KJ, Lin CK, Hsu SH, Lee JC. An in vitro coupled transcription/translation reporter system for hepatitis C virus RNA-dependent RNA polymerase. Anal Biochem 2011; 418: 50-7.
[17]
Crespan E, Garbelli A, Amoroso A, Maga G. Exploiting the nucleotide substrate specificity of repair DNA polymerases to develop novel anticancer agents. Molecules 2011; 16: 7994-8019.
[18]
Tuominen A. Defensive strategies in Geranium sylvaticum, Part 2: Roles of water-soluble tannins, flavonoids and phenolic acids against natural enemies. Phytochemistry 2013; 95: 408-20.
[19]
Seleem D, Pardi V, Mendonça-Murata R. Review of flavonoids: A diverse group of natural compounds with anti-Candida albicans activity in vitro. Arch Oral Biol 2017; 76: 76-83.
[20]
Sawadjoon S, Kittakoop P, Kirtikara K, Vichai V, Tanticharoen M, Thebtaranonth Y. Myristinin is a bioflavonoid isolated from Myristica cinnamomea. J Org Chem 2002; 67: 5470-5.
[21]
Maloney DJ, Deng JZ, Starck SR, Gao Z, Hecht SM. (+)-myristinin A, a naturally occurring DNA polymerase â inhibitor and potent DNA-damaging agent. JACS Comm 2005; 127: 4140-1.
[22]
Merlo S, Basile L, Giuffrida ML, Sortino MA, Guccione S, Copani A. Identification of 5-methoxyflavone as a novel DNA polymerase-beta inhibitor and neuroprotective agent against beta-amyloid toxicity. J Nat Prod 2015; 78: 2704-11.
[23]
Gerhauser C, Alt A, Heiss E, Gamal-Eldeen A, Klimo K, Knauft J. Cancer chemopreventive activity of xanthohumol, a natural product derived from hop. Mol Cancer Ther 2002; 1: 959-69.
[24]
Coulerie P, Nour M, Maciuk A, et al. Structure-Activity Relationship Study of Biflavonoids on the Dengue Virus Polymerase DENV-NS5 RdRp. Planta Med 2013; 79: 1313-8.
[25]
Reta G, Chiaramello A, García C, et al. Derivatives of grindelic acid: From a non-active natural diterpene to synthetic antitumor derivatives. Eur J Med Chem 2013; 67: 28-38.
[26]
Manayi A, Nabavi SM, Daglia M, Jafari S. Natural terpenoids as a promising source for modulation of GABAergic system and treatment of neurological diseases. Pharmacol Rep 2016; 68: 671-9.
[27]
Dvora H, Koffas MAG. In: Microbial production of flavonoids and
terpenoids. Microbial Production of Food Ingredients, Enzymes
and Nutraceuticals. Ed.; Woodhead Publishing Series in Food Science,
Technology and Nutrition 2013; 10: 234-61.
[28]
Yaoita Y, Kikuchi M, Machida K. In: Studies in Natural Products
Chemistry; Atta-ur-Rahman. Ed.; Elsevier Science B.V: Amsterdam
2015; 44: 1-32.
[29]
Houghton P, Mensah A, Iessa N, Hong L. Terpenoids in Buddleja: relevance to chemosystematics, chemical ecology and biological activity. Phytochemistry 2003; 64: 385-93.
[30]
Mizushina Y, Tanaka N, Yagi H, et al. Fatty acids selectively inhibit eukaryotic DNA polymerase activities in vitro. Biochim Biophys Acta 1996; 1308: 256-62.
[31]
Mizushina Y, Miyazaki S, Ohta K, Hirota M, Sakaguchi K. Novel anti-in£ammatory compounds from Myrsine seguinii, terpeno-benzoic acids, are inhibitors of mammalian DNA polymerases. Biochim Biophys Acta 2000; 1475: 1-4.
[32]
Deng JZ, Starck SR, Sun DA, Sabat M, Hecht SM. A new 7,8-euphadien-type triterpenoid from Brackenridgea nitida and Bleasdalea bleasdalei that inhibits DNA Polymerase. J Nat Prod 2000; 63: 1356-60.
[33]
Gao Z, Maloney DJ, Dedkova LM, Hecht SM. Inhibitors of DNA polymerase β: activity and mechanism. Bioorg Med Chem 2008; 16: 4331-40.
[34]
Bartnik PC, Delgoda R, Facey M. In: Glycosides Pharmacognosy;
Ed.; Academic Press: Boston 2017; 101-61.
[35]
Gerwig G, Poele E, Dijkhuizen L, Kamerling J. Stevia glycosides: Chemical and enzymatic modifications of their carbohydrate moieties to improve the sweet-tasting quality. Adv Carbohydr Chem Biochem 2016; 73: 1-72.
[36]
Martin OA, Garro HA, Kurina-Sanz MB, Pungitore CR, Tonn CE. In silico study of the inhibition of DNA polymerase by a novel catalpol derivative. J Mol Model 2011; 17: 2717-23.
[37]
Pungitore CR, Juri-Ayub M, Borkowsky E, Tonn CE, Ciuffo GM. Inhibition of Taq DNA polymerase by catalpol. Cell Mol Biol 2004; 50: 767-72.
[38]
Pungitore CR, Leon L, García C, Martín V, Tonn CE, Padrón JM. Novel antiproliferative analogs of the Taq DNA polymerase inhibitor catalpol. Bioorg Med Chem Lett 2007; 17: 1332-5.
[39]
Garro HA, García C, Martín V, Tonn CE, Pungitore CR. A new iridoid, verbascoside and derivatives with inhibitory activity against Taq DNA polymerase. Bioorg Med Chem Lett 2015; 25: 914-8.
[40]
Mizushina Y, Kamisuki S, Kasai N, et al. Petasiphenol: A DNA polymerase λ inhibitor. Biochem 2002; 41: 14463-71.
[41]
Islam M, Jackson P, Rahman K, Thurston D. Recent advances in targeting the telomeric G-quadruplex DNA sequence with small molecules as a strategy for anticancer therapies. Future Med Chem 2016; 10: 4155-86.
[42]
Aissaa K, Ebbenc J, Kadleca A, Beyera A. Friend or foe? Telomerase as a pharmacological target in cancer and cardiovascular disease. Pharmacol Res 2016; 11: 422-33.
[43]
Dominick P, Keppler B, Legassie J, Moon I, Jarstfer M. Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase. Bioorg Med Chem Lett 2004; 14: 3467-71.
[44]
Raymond E, Sun D, Chen SF, Windle B, Von Hoff D. Agents that target telomerase and telomeres. Curr Opin Biotechnol 1996; 7: 583-91.
[45]
Arora A, Kumar N, Agarwal T, Maiti S. Human telomeric G-quadruplex: targeting with small Molecules. FEBS J 2010; 277: 1345-61.
[46]
Zhou JL, Lu YJ, Ou TM, et al. Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase. J Med Chem 2005; 48: 7315-21.
[47]
Zhou JM, Zhu XF, Lu YJ, et al. Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines. Oncogene 2006; 25: 503-11.
[48]
Franceschin M, Rossetti L, D’Ambrosio A, et al. Natural and synthetic G-quadruplex interactive berberine derivatives. Bioorg Med Chem Lett 2006; 16: 1707-11.
[49]
Ma Y, Ou TM, Hou JQ. N-Substituted berberine derivatives: Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc. Bioorg Med Chem Lett 2008; 16: 7582-619.
[50]
Ghosh S, Dasgupta D. Quadruplex forming promoter region of c-myc oncogene as a potential target for a telomerase inhibitory plant alkaloid, chelerythrine. Biochem Biophys Res Commun 2015; 459: 75-80.
[51]
Li H, Zhanga S, Zhou J, Yang X. Specific binding of human telomeric G-quadruplex by homobarringtonie: An alkaloid from traditional Chinese medicine. Int J Mass Spectrom 2015; 379: 157-64.
[52]
Kadri T, Rouissi T, Brar SK, Cledon M, Sarma S, Verma M. Biodegradation of polycyclic aromatic hydrocarbons (PAHs) by fungal enzymes: A review. J Environ Sci 2017; 51: 52-74.
[53]
Wei C, Wang L, Jia G, Zhou J, Han G, Li C. The binding mode of porphyrins with cation side arms to (TG4T)4 G-quadruplex: Spectroscopic evidence. Biophys Chem 2009; 143: 79-84.
[54]
Franceschin M, Pascucci E, Alvino A, et al. New highly hydrosoluble and not self-aggregated perylene derivatives with three and four polar side-chains as G-quadruplex telomere targeting agents and telomerase inhibitors. Bioorg Med Chem Lett 2007; 17: 2515-22.
[55]
Franceschin M, Alvino A, Casagrande V, et al. Specific interactions with intra- and intermolecular G-quadruplex DNA structures by hydrosoluble coronene derivatives: A new class of telomerase inhibitors. Bioorg Med Chem Lett 2007; 15: 1848-58.
[56]
Saify ZS, Mushtaq N, Noor F, Takween S, Arif M. Role of quinone moiety as antitumor agents: a review. Pak J Pharm Sci 1999; 12: 21-31.
[57]
Tang WJ, Wang J, Tong X, Shi JB, Liu XH, Li J. Design and synthesis of celastrol derivatives as anticancer agents. Eur J Med Chem 2015; 95: 166-73.
[58]
Cai XH, Jin J, Huiyuan HM. Advances in structural modifications of celastrol. ARKIVOC 2016; (i): 172-82.
[59]
Soares J, Keppler B, Wanga X, Lee KH, Jarstfer M. ortho-Quinone tanshinones directly inhibit telomerase through an oxidative mechanism mediated by hydrogen peroxide. Bioorg Med Chem Lett 2011; 21: 7474-8.
[60]
Atkinsonab D, Brimble M. Isolation, biological activity, biosynthesis and synthetic studies towards the rubromycin family of natural products. Nat Prod Rep 2015; 32: 811-40.
[61]
Wilsdorf M, Reissig HU. A Convergent Total Synthesis of the Telomerase Inhibitor (±)-γ-Rubromycin. Angew Chem Int Ed 2014; 53: 1-6.
[62]
Ueno T, Takahashi H, Oda M, et al. Inhibition of human telomerase by rubromycins: implication of spiroketal system of the compounds as an active moiety. Biochemistry 2000; 39: 5995-6002.
[63]
Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 2006; 6: 789-802.
[64]
Baranello L, Kouzine F, Levens D. DNA topoisomerases: beyond the standard role. Transcription 2013; 4: 232-7.
[65]
Cheng B, Annamalai T, Sorokin E, Abrenica M, Aedo S, Tse-Dihn YC. Asp-To-Asn substitution at the first position of the DXD toprim motif of recombinant bacterial topoisomerase I is extremely lethal to E. coli. J Mol Biol 2009; 385: 558-67.
[66]
Ireton G, Stewart L, Parker L, Champoux J. Expression of human topoisomerase I with a partial deletion of the linker region yields monomeric and dimeric enzymes that respond differently to camptothecin. J Biol Chem 2000; 275: 25820-30.
[67]
Forterre P, Gribaldo S, Gadelle D, Serre MC. Origin and evolution of DNA topoisomerases. Biochimie 2007; 89: 427-46.
[68]
Teicher B. Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochem Pharmacol 2008; 75: 1262-71.
[69]
Reuveni D, Halperin D, Shalit I, Priel E, Fabian I. Quinolones as enhancers of camptothecin-induced cytotoxic and anti-topoisomerase I effects. Biochem Pharmacol 2008; 75: 1272-81.
[70]
Mizushina Y, Ikuta A, Endoh K. Inhibition of DNA polymerases and DNA topoisomerase II by triterpenes produced by plant callus. Biochem Biophys Res Commun 2003; 305: 365-73.
[71]
Wang GW, Lv C, Yuan X, et al. Lanostane-type triterpenoids from Abies faxoniana and their DNA topoisomerase inhibitory activities. Phytochemistry 2015; 116: 221-9.
[72]
Chen J, Sun Z, Zhang Y, et al. Synthesis of gibberellin derivatives with anti-tumor bioactivities. Bioorg Med Chem Lett 2009; 19: 5496-9.
[73]
Pezzuto JM, Antosiak SK, Messmer WM, Slaytor B, Honig GR. Interaction of the antileukemic alkaloid, 2-hydroxy-3,8,9-trimethoxy-5-methylbenzo-[c]-phenanthridine (fagaronine) with nucleic acids. Chem Biol Interact 1983; 43: 323-39.
[74]
Larsen AK, Grondard L, Couprie J, et al. The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II. Biochem Pharmacol 1993; 46: 1403-12.
[75]
Kluza J, Baldeyrou B, Colson P, et al. Cytotoxicity and DNA binding properties of the plant alkaloid burasaine. Eur J Pharm Sci 2003; 20: 383-91.
[76]
Basili S, Basso G, Faccio A, et al. Diazoniapolycyclic ions inhibit the activity of topoisomerase I and the growth of certain tumor cell lines. ChemMedChem 2008; 3: 1671-6.
[77]
Kumar A, Chowdhury SR, Sarkar T, et al. A new bisbenzylisoquinoline alkaloid isolated
from Thalictrum foliolosum, as a potent inhibitor of DNA
topoisomerase IB of Leishmania donovani. Fitoterapia 2016; 109:
25-30.
[78]
Figueiredo PO, Garcez FR, Matos MFC, et al. A New Cytotoxic β-Carboline Alkaloid from Galianthe thalictroides. Planta Med 2011; 77: 1852-4.
[79]
Figueiredo PO, Perdomo RT, Garcez FR, Matos MFC, de Carvalho JE, Garcez WS. Further constituents of Galianthe thalictroides (Rubiaceae) and inhibition of DNA topoisomerases I and IIa by its cytotoxic β-carboline alkaloids. Bioorg Med Chem Lett 2014; 24: 1358-61.
[80]
Li Y, Fang H, Xu W. Recent advance in the research of flavonoids as anticancer agents. Mini Rev Med Chem 2007; 7: 663-78.
[81]
López-Lázaroa M, Willmorea E, Austina C. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res 2010; 696: 41-7.
[82]
Hossion A, Zamami Y, Kandahary R, et al. Quercetin Diacylglycoside Analogues Showing Dual Inhibition of DNA. J Med Chem 2011; 54: 3686-703.
[83]
Tselepi M, Papachristou E, Emmanouilidi A, et al. Catalytic inhibition of eukaryotic topoisomerases I and II by flavonol glycosides extracted from Vicia faba and Lotus edulis. J Nat Prod 2011; 74: 2362-70.
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