[1,2,4]triazines – as potential drugs in cancer chemotherapy
Anna Szymanowska 1 , Agnieszka Gornowicz 1 , Anna Bielawska 1 , Krzysztof Bielawski 2Abstract
Cancers are a high risk for humanity. In 2018, approximately 18 million new cancer cases were diagnosed in the world. The choice of treatment depends on the type of cancer and its stage at diagnosis. The treatment of cancer consists mainly of surgical methods, radiotherapy, immunotherapy, hormone therapy and chemotherapy. Cytotoxic drugs can be used both in monotherapy and combination therapy. In 2009-2018, the US. Food and Drug Administration (FDA) approved about 356 new drugs for cancer therapy. However, it should be noted that despite the increasing availability of modern drugs, this disease is the second leading cause of death in the world. Research on the development of a cytotoxic drug is aimed at designing a compound structure, whose action is directed at cancer cells while not affecting normal cells. Triazine derivatives might be the chemical structure with potential anticancer activity. This scaffold has been used in oncological therapy since 1965. Depending on the location of the nitrogen atoms in the ring, three isomers can be distinguished: [1,2,3]triazines, [1,2,4]triazines, [1,3,5]triazines. Modification of the structure of the [1,2,4]triazine derivatives should provide stronger cytotoxic properties and reduce the side effects of the novel drug. Designing new preparations also aims to improve the patient’s quality of life. This review will briefly present how the modification of the chemical structure of [1,2,4]triazine derivatives increases their cytotoxic activity against cancer and why these compounds may be better tolerated than current therapy.
References
- 1. Abi-Jaoudeh N.: TATE Versus TACE, an open-label randomizedstudy comparing trans arterial tirapazamine embolization versustrans arterial chemo embolization in intermediate stagehepatocellular carcinoma. https://clinicaltrials.gov/ct2/show/NCT03145558 (12.12.2019)
Google Scholar - 2. Ali R.S., Saad H.A.: Synthesis and pharmacological studies ofunprecedented fused pyridazino[3’,4’:5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine derivatives. Molecules, 2018; 23: 1024
Google Scholar - 3. Al-Temimay I.A., Al-Jibouri M.H., Hassan A.A., MohammadF.I.: Test the cytotoxicity of pleurotin extracted from and ediblemushroom Pleurotus osteratus against three human carcinomacell line. Iraqi J. Sci., 2015; 56: 2773–2781
Google Scholar - 4. Anjomshoa M., Fatemi S.J., Torkzadeh-Mahani M., HadadzadehH.: DNA- and BSA-binding studies and anticancer activity againsthuman breast cancer cells (MCF-7) of the zinc(II) complex coordinatedby 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine, Spectrochim.Acta A Mol. Biomol. Spectrosc., 2014; 127: 511–520
Google Scholar - 5. Anjomshoa M., Hadadzadeh H., Fatemi S.J., Torkzadeh-MahaniM.: A mononuclear Ni(II) complex with 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine: DNA- and BSA-binding and anticanceractivity against human breast carcinoma cells. Spectrochim. ActaA Mol. Biomol. Spectrosc., 2015; 136: 205–215
Google Scholar - 6. Anjomshoa M., Hadadzadeh H., Torkzadeh-Mahani M., FatemiS.J., Adeli-Sardou M., Rudbari H.A., Nardo V.M.: A mononuclearCu(II) complex with 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine:Synthesis, crystal structure, DNA- and BSA-binding, molecularmodeling, and anticancer activity against MCF-7, A-549, and HT- 29 cell lines. Eur. J. Med. Chem., 2015; 96: 66–82
Google Scholar - 7. Arpino G., Wiechmann L., Osborne C.K., Schiff R.: Crosstalkbetween the estrogen receptor and the HER tyrosine kinase receptorfamily: Molecular mechanism and clinical implicationsfor endocrine therapy resistance. Endocr. Rev., 2008; 29: 217–233
Google Scholar - 8. Ashour H.M., El-Wakil M.H., Khalil M.A., Ismail K.A., LaboutaI.M.: Synthesis of some (E)-6-[2-(furan-2-yl)ethenyl]-1,2,4-triazin-5-ones and their biological evaluation as antitumor agents. Med.Chem. Res., 2013; 22: 1909–1924
Google Scholar - 9. Branowska D., Ławecka J., Sobiczewski M., Karczmarzyk Z.,Wysocki W., Wolińska E., Olender E., Mirosław B., Perzyna A., BielawskaA., Bielawski K.: Synthesis of unsymmetrical disulfanes bearing1,2,4-triazine scaffold and their in vitro screening towardsanti-breast cancer activity. Monatsh Chem., 2018; 149: 1409-1420
Google Scholar - 10. Bray F., Jemal A., Grey N., Ferlay J., Forman D.: Global cancertransitions according to the Human Development Index (2008-2030): A population-based study. Lancet Oncol., 2012; 13: 790–801
Google Scholar - 11. Cascioferro S., Parrino B., Spanò V., Carbone A., MontalbanoA., Barraja P., Diana P., Cirrincione G.: Synthesis and antitumoractivities of 1,2,3-triazines and their benzo- and heterofused derivatives.Eur. J. Med. Chem., 2017; 142: 74–86
Google Scholar - 12. Cortez D., Reuther G., Pendergast A.M.: The Bcr-Abl tyrosinekinase activates mitogenic signaling pathways and stimulatesG1-to-S phase transition in hematopoietic cells. Oncogene, 1997;15: 2333–2342
Google Scholar - 13. Dinh Ngoc T., Moons N., Kim Y., De Borggraeve W., MashentsevaA., Andrei G., Snoeck R., Balzarini J., Dehaen W.: Synthesis of triterpenoidtriazine derivatives from allobetulone and betulonic acidwith biological activities. Bioorg. Med. Chem., 2014; 22: 3392–3300
Google Scholar - 14. Dziadziuszko R., Zyśk R.: Rak płuca – korzyści kliniczne leczeniainhibitorami ALK w świetle ograniczeń ekonomicznych w Polsce.Onkol. Prakt. Klin. Edu., 2015; 1: 54–64
Google Scholar - 15. El-All A.S., Hassan A.S., Osman S.A., Yosef H.A., Abdel-HadyW.H., El-Hashash M.A., Atta-Allah S.R., Ali M.M., El Rashedy A.A.:Synthesis, characterization and biological evaluation of new fusedtriazine derivatives based on 6-methyl-3-thioxo-1,2,4-triazin-5-one. Acta Pol. Pharm, 2016; 73: 79–92
Google Scholar - 16. El-All A.S., Osman S.A., Roaiah H.M., Abdalla M.M., El Aty A.A.,Abd El-Hady W.H.: Potent anticancer and antimicrobial activitiesof pyrazole, oxazole and pyridine derivatives containing 1,2,4-triazinemoiety. Med. Chem. Res., 2015; 24: 4093–4104
Google Scholar - 17. Ell-Wakil M.H., Ashour H.M., Saudi M.N., Hassan A.M., LaboutaI.M.: Design, synthesis and molecular modeling studies of newseries of antitumor 1,2,4-triazines with potential c-Met kinase inhibitoryactivity. Bioorg. Chem., 2018; 76: 154–165
Google Scholar - 18. Elsayed E.H., Radwan E.M.: New potential antitumor nitrogenheterocycles: Synthesis and cytotoxic evaluation. Der PharmaChemica, 2016; 8: 399–413
Google Scholar - 19. Fink B.E., Norris D., Mastalerz H., Chen P., Goyal B., Zhao Y., KimS.H., Vite G.D., Lee F.Y., Zhang H., Oppenheimer S., Tokarski J.S.,Wong T.W., Gavai A.V.: Novel pyrrolo[2,1-f][1,2,4]triazin-4-amines:Dual inhibitors of EGFR and HER2 protein tyrosine kinases. Bioorg.Med. Chem. Lett., 2011; 21: 781–785
Google Scholar - 20. Gao L.Z., Li T., Yu S.X., Huang W.L., Zhao H., Hu G.Q.: Design,synthesis, antibacterial and anti-cell proliferation activities of[1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acidderivatives. Acta Pharm. Sin., 2015; 50: 332–336
Google Scholar - 21. Garajová I., Giovannetti E., Biasco G., Peters G.J.: c-Met asa target for personalized therapy. Transl. Oncogenomics, 2015;7: 13–31
Google Scholar - 22. Gavai A.V., Fink B.E., Fairfax D.J., Martin G.S., Rossiter L.M.,Holst C.L., Kim S.H., Leavitt K.J., Mastalerz H., Han W.C., Norris D.,Goyal B., Swaminathan S., Patel B., Mathur A. i wsp.: Discovery andpreclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamicacid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selectiveand orally efficacious inhibitor of human epidermal growthfactor receptor 1 and 2 kinases. J. Med. Chem., 2009; 52: 6527–6530
Google Scholar - 23. Gazieva G.A., Izmest’ev A.N., Anikina L.V., Pukhov S.A., MeshchanevaM.E., Khakimov D.V., Kolotyrkina N.G., Kravchenko A.N.:The influence of substituents on reactivity and cytotoxicity ofimidazothiazolotriazinones. Mol. Divers., 2018; 22: 585–599
Google Scholar - 24. Gucký T., Fryšová I., Slouka J., Hajdúch M., Džubák P.: Cyclocondensationreaction of heterocyclic carbonyl compounds, PartXIII: Synthesis and cytotoxic activity of some 3,7-diaryl-5-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e][1,2,4]triazines. Eur. J. Med.Chem., 2009; 44: 891–900
Google Scholar - 25. Gucký T., ŘezníčkováE., Džubák P., Hajdúch M., Kryštof V.:Synthesis and anticancer activity of some 1,5-diaryl-3-(3,4,5-trihydroxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines. MonatshChem., 2010; 141: 709–714
Google Scholar - 26. Gumulec J., Balvan J., Sztalmachova M., Raudenska M., DvorakovaV., Knopfova L., Polanska H., Hudcova K., Ruttkay-NedeckyB., Babula P., Adam V., Kizek R., Stiborova M., Masarik M.: Cisplatin-resistant prostate cancer model: Differences in antioxidantsystem, apoptosis and cell cycle. Int. J. Oncol., 2014; 44: 923–933
Google Scholar - 27. Juszczyński P.: Nowe cele terapii ukierunkowanej w nowotworachukładu chłonnego z perspektywy ostatnich 5 lat badań.Hematologia, 2015; 6: 1–9
Google Scholar - 28. Karczmarzyk Z., Wysocki W., Urbańczyk-Lipowska Z., KalickiP., Bielawska A., Bielawski K., Ławecka J.: Synthetic approachesfor sulfur derivatives containing 1,2,4-triazine moiety: Their activityfor in vitro screening towards two human cancer cell lines.Chem. Pharm. Bull., 2015; 63: 531–537
Google Scholar - 29. Keane L.A.J., Mirallai S.I., Sweeney M., Carty M.P., ZissimouG.A., Berezin A.A., Koutentis P.A., Aldabbagh F.: Anti-cancer activityof phenyl and pyrid-2-yl 1,3-substituted benzo[1,2,4]triazin-7-ones and stable free radical precursors. Molecules, 2018; 23: 574
Google Scholar - 30. Koziński K., Dobrzyń A.: Szlak sygnałowy Wnt i jego rola wregulacji metabolizmu komórki. Postępy Hig. Med. Dośw., 2013;67: 1098–1108
Google Scholar - 31. Krzeminski P.: Receptory nukleotydowe w komórkach nowotworowych.Postępy Biochemii, 2014; 60: 490–505
Google Scholar - 32. Kwon Y.S., Nam J.H., Kim D.Y., Suh D.S., Kim J.H., Kim Y.M., KimY.T.: Hexamethylmelamine as consolidation treatment for patientswith advanced epithelial ovarian cancer in complete response afterfirst-line chemotherapy. J. Korean Med. Sci., 2009; 24: 679–683
Google Scholar - 33. Lee C.I., Huang C.M., Huang W.H., Lee A.R.: Synthesis, preferentiallyhypoxic apoptosis and anti-angiogenic activity of 3-amino-1,2,4-benzotriazine-1,4-dioxide bearing alkyl linkers with a3-amino-1,2,4-benzotriazine-1-oxide moiety. Anticancer AgentsMed. Chem., 2014; 14: 1428–1446
Google Scholar - 34. Li Q., Lescrinier E., Groaz E., Persoons L., Daelemans D.,Herdewijn P., De Jonghe S.: Synthesis and biological evaluationof pyrrolo[2,1-f][1,2,4]triazine c-nucleosides with a ribose,2’-deoxyribose,and 2’,3’-dideoxyribose sugar moiety. Chem. Med.Chem., 2018; 13: 97–104
Google Scholar - 35. Lou J., Zhou X., Weng Q., Wang D.D., Xia Q., Hu Y., He Q., YangB., Lou P.: XQ2, a novel TPZ derivative induced G2/M phase arrestand apoptosis under hypoxia in non-small cell lung cancer cells.Biosci. Biotechnol. Biochem., 2010; 74: 1181–1187
Google Scholar - 36. Makki M.S.I., Abdel-Rahman R.M., Khan K.A.: Fluorine substituted1,2,4-triazinones as potential anti-HIV-1 and CDK2 inhibitors.J. Chem., 2014; 2014: 430573
Google Scholar - 37. Mojzych M.: Cytotoxic activity of some pyrazolo[4,3-e][1,2,4]triazines against human cancer cell lines. J. Chem. Soc. Pak., 2011;33: 123–128
Google Scholar - 38. Mojzych M., Bielawska A., Bielawski K., Ceruso M., SupuranC.T.: Pyrazolo[4,3-e][1,2,4]triazine sulfonamides as carbonic anhydraseinhibitors with antitumor activity. Bioorg. Med. Chem.,2014; 22: 2643–2647
Google Scholar - 39. Mojzych M., Šubertová V., Bielawska A., Bielawski K., BazgierV., Berka K., Gucký T., Fornal E., Kryštof V.: Synthesis and kinaseinhibitory activity of new sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazines. Eur. J. Med. Chem., 2014; 78: 217–224
Google Scholar - 40. Mojzych M., Tarasiuk P., Karczmarzyk Z., Juszczak M., RzeskiW., Fruziński A., Woźny A.: Synthesis, structure and antiproliferativeactivity of new pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazinederivatives. Med Chem., 2018; 14: 53–59
Google Scholar - 41. Nassar I.F.: Synthesis and antitumor activity of new substitutedmercapto-1,2,4-triazine derivatives, their thioglycosides, and acyclicthioglycoside analogs. J. Heterocyclic Chem., 2013; 50: 129–134
Google Scholar - 42. Ndagi U., Mhlongo N., Soliman M.E.: Metal complexes in cancertherapy – an update from drug design perspective. Drug Des.Devel. Ther., 2017; 11: 599–616
Google Scholar - 43. Noriega-Guerra H., Freitas V.M.: Extracellular matrix influencingHGF/c-MET signaling pathway: Impact on cancer progression.Int. J. Mol. Sci., 2018; 19: 3300
Google Scholar - 44. Ott G.R., Wells G.J., Thieu T.V., Quail M.R., Lisko J.G., MesarosE.F., Gingrich D.E., Ghose A.K., Wan W., Lu L., Cheng M., Albom M.S.,Angeles T.S., Huang Z., Aimone L.D., Ator M.A., Ruggeri B.A., DorseyB.D.: 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New variantof an old template and application to the discovery of anaplasticlymphoma kinase (ALK) inhibitors with in vivo antitumor activity.J. Med. Chem., 2011; 54: 6328–6341
Google Scholar - 45. Pastorekova S., Gillies R.J.: The role of carbonic anhydrase IXin cancer development: Links to hypoxia, acidosis and beyond.Cancer Metastasis Rev., 2019; 38: 65–77
Google Scholar - 46. Powis G.: Triazine and hydrazine derivatives. W: CancerGrowth and Progression: H.E. Kaiser. Kluwer Academic Publishers,Dordrecht Netherlands, 1989, 113–118
Google Scholar - 47. Ranjbar S., Edraki N., Khoshneviszadeh M., Foroumadi A., MiriR., Khoshneviszadeh M.: Design, synthesis, cytotoxicity evaluationand docking studies of 1,2,4-triazine derivatives bearing differentarylidene-hydrazinyl moieties as potential mTOR inhibitors. Res.Pharm. Sci., 2018; 13: 1–11
Google Scholar - 48. Reddy S.B., Williamson S.K.: Tirapazamine: A novel agent targetinghypoxic tumor cells. Expert Opin. Investig. Drugs, 2009;18: 77–87
Google Scholar - 49. Saad H.A., Moustafa A.H.: Synthesis and anticancer activity ofsome new s-glycosyl and s-alkyl 1,2,4-triazinone derivatves. Molecules,2011; 16: 5682–5700
Google Scholar - 50. Saad H.A., Youssef M.M., Mosselhi M.A.: Microwave assistedsynthesis of some new fused 1,2,4-triazines bearing thiophenemoieties with expected pharmacological activity. Molecules, 2011;16: 4937–4957
Google Scholar - 51. Safaie Qamsari E., Safaei Ghaderi S., Zarei B., Dorostkar R.,Bagheri S., Jadidi-Niaragh F., Somi M.H., Yousefi M.: The c-Metreceptor: Implication for targeted therapies in colorectal cancer.Tumour Biol., 2017; 39: 1010428317699118
Google Scholar - 52. Ścibor-Bentkowska D., Czeczot H.: Komórki nowotworowe astres oksydacyjny. Postępy Hig. Med. Dośw., 2009; 63: 58–72
Google Scholar - 53. Seibert W.: Uber den Mechanismus der Reaktion von Kishner-Wolff-Staudinger. I. Mildeilung. Chem. Ber., 1947; 80: 494–502
Google Scholar - 54. Shang S., Hua F., Hu Z.W.: The regulation of β-catenin activityand function in cancer: Therapeutic opportunites. Oncotarget,2017; 8: 33972–33989
Google Scholar - 55. Shnider B.I., Frei E., Tuohy J.H., Gorman J., Freireich E.J., BrindleyC.O.Jr., Clements J.: Clinical studies of 6-azauracil. Cancer Res.,1960; 20: 28–33
Google Scholar - 56. Showalter H.D., Turbiak A.J., Fearon E.R., Bommer G.T.: Pyrimidotriazinedionesand pyrimidopyrimidinediones and methods ofusing the same. Patent No. US 20110166144 A1, 2011
Google Scholar - 57. Smith A.B., Thoma G., Van Eis M.: Monocyclic heteroarylcycloalkyldiaminederivatives. WO 2013171690 A1, 2013
Google Scholar - 58. Soria J.C., Cortes J., Massard C., Armand J.P., De Andreis D.,Ropert S., Lopez E., Catteau A., James J., Marier J.F., Beliveau M.,Martell R.E., Baselga J.: Phase I safety, pharmacokinetic and pharmacodynamictrial of BMS-599626 (AC480), an oral pan-HER receptortyrosine kinase inhibitor, in patients with advanced solidtumors. Ann. Oncol., 2012; 23: 463–471
Google Scholar - 59. Spoerri L., Oo Z.Y., Larsen J.E., Haass N.K., Gabrielli B., PaveyS.: Cell cycle checkpoint and DNA damage response defects as anticancertargets: From molecular mechanisms to therapeutic opportunities.W: Stress Response Pathways in Cancer: G. Wondrak,Springer, 2015; 29–49
Google Scholar - 60. Stępień E., Jakubiak D.: Szlak Wnt jako potencjalny celoddziaływania nanocząstek na komórki. W: Nanocząstki inanomateriały, red.: J. Gromadzińska, W. Wąsowicz. Zarząd GłównyPolskiego Towarzystwa Toksykologicznego, Łódź 2013, 194–204
Google Scholar - 61. Sweeney M., Coyle R., Kavanagh P., Berezin A.A., Lo Re D., ZissimouG.A., Koutentis P.A., Carty M.P., Aldabbagh F.: Discovery ofanti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strongcorrelation to pleurotin and thioredoxin reductase inhibition.Bioorg. Med. Chem., 2016; 24: 3565–3570
Google Scholar - 62. Sztanke K., Pasternak K., Sztanke M., Kandefer-Szerszeń M.,Kozioł A.E., Dybała I.: Crystal structure, antitumour and antimetastaticactivities of disubstituted fused 1,2,4-triazinones. Bioorg.Med. Chem. Lett., 2009; 19: 5095–5100
Google Scholar - 63. Tadesse S., Caldon E.C., Tilley W., Wang S.: Cyclin-dependentkinase 2 inhibitors in cancer therapy: An update. J. Med. Chem.,2019; 62: 4233–4251
Google Scholar - 64. Voskoboynik O.Y., Kovalenko S.I., Shishkina S.V.: Benzo[e][1,2,4]triazino[2,3-c][1,2,3]triazin-2-ones electro-deficient heterocycliccompounds with promising anticancer activity. Heterocycl.Commun., 2016; 22: 137–141
Google Scholar - 65. Wittman M.D., Carboni J.M., Yang Z., Lee F.Y., Antman M., AttarR., Balimane P., Chang C., Chen C., Discenza L., Frennesson D.,Gottardis M.M., Greer A., Hurlburt W., Johnson W. i wsp.: Discoverof 2,4-disubstituted pyrrolo-[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase inclinical development. J. Med. Chem., 2009; 52: 7360–7363
Google Scholar - 66. Xin M., Zhang L., Tang F., Tu C., Wen J., Zhao X., Liu Z., ChengL., Shen H.: Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors.Bioorg. Med. Chem., 2014; 22: 1429–1440
Google Scholar - 67. Yang S.J., Liu M.C., Zhao Q., Hu D.Y., Xue W., Yang S.: Synthesisand biological evaluation of betulonic acid derivatives as antitumoragents. Eur. J. Med. Chem., 2015; 96: 58–65
Google Scholar - 68. Yurttaş L., Demirayak Ş., Ilgın S., Atlı Ö.: In vitro antitumoractivity evaluation of some 1,2,4-triazine derivatives bearing piperazineamide moiety against breast cancer cells. Bioorg. Med.Chem., 2014; 22: 6313–6323
Google Scholar - 69. Zeman E.M., Brown J.M., Lemmon M.J., Hirst V.K., Lee W.W.:SR-4233: A new bioreductive agent with high selective toxicity forhypoxic mammalian cells. Int. J. Radiat. Oncol. Biol. Phys., 1986;12: 1239–1242
Google Scholar