Biopolym. Cell. 2019; 35(4):321-330.
Bioorganic Chemistry
Anticancer activity evaluation of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines and thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine derivatives
1Shyyka O. Ya., 1Pokhodylo N. T., 2Finiuk N. S.
  1. Ivan Franko National University of Lviv
    4, Hrushevskoho Str., Lviv, Ukraine, 79005
  2. Institute of Cell Biology, NAS of Ukraine
    14/16, Drahomanov Str., Lviv, Ukraine, 79005


Aim. In vitro evaluation of anticancer activity of synthesized thieno[3,2-e][1,2,3]triazolo[1,5-a] pyrimidines and thieno[2,3-e][1,2,3]triazolo[1,5-a] pyrimidines. Methods. Organic synthesis, in vitro cytotoxicity assay, MTT assay, spectrophotometry, statistical analysis. Results. The isomeric thienotriazolopyrimidines synthesized were tested for their anticancer activity in the NCI-60 cancer cell line panel, a group of 60 human cancer cell lines. The selective influence of 5-oxo-4,5,6,7,8,9-hexahydrobenzo[4,5]thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine-3-carboxamide on melanoma cell line SK-MEL-5 with (GP = –31,50 %) was observed. Two compounds possessed a significant activity on CNS and breast cancer cells. Conclusions. Several thienotriazolopyrimidines were found to possess antitumor activity with a selective effect on a single cell line. These results are interesting for further structure optimization to increase selectivity and anticancer activity of fused pyrimidines.
Keywords: thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines, thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines, thienotriazolopyrimidines, anticancer activity, fused pyrimidines


[1] Shyyka O. Methods for the preparation of azolo-fused systems with thiophene core. Visn Lviv Univ. Ser Chem. 2018; 59(2): 239-3.
[2] Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem. 2011; 54(8): 2529-91.
[3] Brown N. Bioisosteres in medicinal chemistry: 54 (Methods and principles in medicinal chemistry). Weinheim: Wiley-VCH, 2012. 238 p.
[4] Zhang Y, Luo L, Han C, Lv H, Chen D, Shen G, Wu K, Pan S, Ye F. Design, Synthesis, and Biological Activity of Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine Derivatives as Anti-Inflammatory Agents. Molecules. 2017;22(11). pii: E1960. doi: 10.3390/molecules22111960.
[5] Fyfe TJ, Zarzycka B, Lim HD, Kellam B, Mistry SN, Katrich V, Scammells PJ, Lane JR, Capuano B. A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D(2) Receptor. J Med Chem. 2019;62(1):174-206. doi: 10.1021/acs.jmedchem.7b01565.
[6] Shyyka O, Pokhodylo N, Finiuk N, Matiychuk V, Stoika R, Obushak M. Anticancer Activity Evaluation of New Thieno[2,3-d]pyrimidin-4(3H)-ones and Thieno[3,2-d]pyrimidin-4(3H)-one Derivatives. Sci Pharm. 2018;86(3). pii: E28. doi: 10.3390/scipharm86030028.
[7] Lauria A, Abbate I, Patella C, Martorana A, Dattolo G, Almerico AM. New annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines, with potent anticancer activity, designed through VLAK protocol. Eur J Med Chem. 2013;62:416-24. doi: 10.1016/j.ejmech.2013.01.019.
[8] Ivachtchenko AV, Golovina ES, Kadieva MG, Koryakova AG, Kovalenko SM, Mitkin OD, Okun IM, Ravnyeyko IM, Tkachenko SE, Zaremba OV. Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists. Bioorg Med Chem. 2010;18(14):5282-90. doi: 10.1016/j.bmc.2010.05.051.
[9] Kim J, Kwon J, Lee D, Jo S, Park DS, Choi J, Park E, Hwang JY, Ko Y, Choi I, Ju MK, Ahn J, Kim J, Han SJ, Kim TH, Cechetto J, Nam J, Ahn S, Sommer P, Liuzzi M, No Z, Lee J. Synthesis and biological evaluation of triazolothienopyrimidine derivatives as novel HIV-1 replication inhibitors. Bioorg Med Chem Lett. 2013;23(1):153-7. doi: 10.1016/j.bmcl.2012.10.134.
[10] Pokhodylo NT, Shyyka OYa, Matiychuk VS. Synthesis and anticancer activity evaluation of new 1,2,3-triazole-4-carboxamide derivatives. Med Chem Res. 2014; 23(5): 2426-38.
[11] Pokhodylo N, Shyyka O, Matiychuk V. Synthesis of 1,2,3-Triazole Derivatives and Evaluation of their Anticancer Activity. Sci Pharm. 2013;81(3):663-76. doi: 10.3797/scipharm.1302-04. Print 2013.
[12] Pokhodylo NT, Shyyka OYa, Tupychak MA, Obushak MD. Selectivity in domino-reaction of ortho-carbonyl azides with malononitrile dimer leading to [1,2,3]triazolo[1,5-a]pyrimidines. Chem Heterocycl Compd. 2018; 54 (2): 209-12.
[13] Shyyka OYa, Pokhodylo NT, Slyvka YuI, Goreshnik EA, Obushak MD. Understanding the tetrazole ring cleavage reaction with hydrazines: Structural determination and mechanistic insight. Tetrahedron Lett. 2018; 59 (12): 1112-5.
[14] Pokhodylo NT, Shyyka OYa. New cascade reaction of azides with malononitrile dimer to polyfunctional[1,2,3]triazolo[4,5-b]pyridine. Synth Comm. 2017; 47 (11): 1096-101.
[15] Pokhodylo NT, Shyyka OY, Matiychuk VS, Obushak MD. New Convenient Strategy for Annulation of Pyrimidines to Thiophenes or Furans via the One-pot Multistep Cascade Reaction of 1H-Tetrazoles with Aliphatic Amines. ACS Comb Sci. 2015;17(7):399-403. doi: 10.1021/co5001376.
[16] Pokhodylo NT, Shyyka OYa, Obushak MD. Facile and efficient one-pot procedure for thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines preparation. Synth Commun. 2014; 44 (7): 1002-6.
[17] Pokhodylo NT, Shyyka OYa, Savka RD, Obushak MD. Novel selected tandem transformations of the amino and carbonyl/nitrile groups in the gewald thiophenes. Phosphorus Sulfur Silicon Relat Elem. 2010; 185 (10): 2092-100.
[18] Pokhodylo NT, Matiychuk VS. Synthesis of new 1,2,3-triazolo[1,5-a]quinazolinones. J Heterocyclic Chem. 2010; 47(2): 415-40.
[19] Pokhodylo NT, Matiychuk VS, Obushak MD. Synthesis of 3-Aryl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7- thiones as building blocks for potentially biologically active compounds. Phosphorus, Sulfur, Silicon Relat Elem. 2010; 185 (3): 578-81.
[20] Pokhodylo NT, Matiychuk VS, Obushak MD. Synthesis of the new heterocyclic system - pyrido[3',2':4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine. Chem Heterocycl Compd. 2009; 45 (7): 881-3.
[21] Pokhodylo NT, Matiichuk VS, Obushak ND. Synthesis of the new heterocyclic system - pyrido[3',2':4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine-ones. Tetrahedron. 2009; 65 (13): 2678-83.
[22] Pokhodylo NT, Matiychuk VS, Obushak MD. Synthesis of [1,2,3]triazolo-[4',5':4,5]pyrimido[1,6-a]benzimidazole, a new heterocyclic system. Chem Heterocycl Compd. 2009; 45 (2): 245-7.
[23] Pokhodylo NT, Matiychuk VS, Obushak MD. A convenient method for the synthesis of a new heterocyclic system - thiopyrano[4,3-c]quinoline. Chem Heterocycl Compd. 2009; 45 (1): 121-2.
[24] Pokhodylo NT, Matiychuk VS, Obushak MD. (Arylsulfonyl)acetones and -acetonitriles: New activated methylenic building blocks for synthesis of 1,2,3-triazoles. Synthesis 2009; 14: 1297-300.
[25] Pokhodylo NT, Matiychuk VS, Obushak MD. Synthesis of the 1H-1,2,3-triazole derivatives by the cyclization of arylazides with 1-(1,3-benzothiazol-2-yl)acetone, 1,3-benzothiazol-2-ylacetonitrile and (4-aryl-1,3-thiazol-2-yl)acetonitrile. Chem Heterocycl Compd. 2009; 45 (4): 483-8.
[26] Pokhodylo NT, Matiychuk VS, Obushak MD. New convenient synthesis of 2,3-diaminothieno[2,3-d]pyrimidin-4(3H)-one derivates from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-carboxylates. Tetrahedron. 2008; 64(7): 1430-4.
[27] Liu X, Zu YG, Fu YJ, Yao LP, Gu CB, Wang W, Efferth T. Antimicrobial activity and cytotoxicity towards cancer cells of Melaleuca alternifolia (tea tree) oil. Eur Food Res Technol. 2009; 229: 247-53.
[28] Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991;83(11):757-66.
[29] Boyd MR, Paull KD. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev Res. 1995; 34(2): 91-109.
[30] Boyd MR. The NCI In vitro anticancer drug discovery screen. In: Ed. Teicher BA. Anticancer Drug Development Guide. Cancer Drug Discovery and Development. Totowa, NJ: Humana Press, 1997. 23-43.
[31] Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer. 2006;6(10):813-23. Review.