Biopolym. Cell. 2020; 36(4):279-293.
http://dx.doi.org/10.7124/bc.000A2C
Bioorganic Chemistry
Spirocyclic thienopyrimidines: synthesis, new rearrangements under Vilsmeier conditions and in silico prediction of anticancer activity
1Kovtun A. V., 1Tokarieva S. V., 1Varenichenko S. A., 1Farat O. K., 2Mazepa A. V., 3, 4Dotsenko V. V., 1Markov V. I.
  1. Ukrainian State University of Chemical Technology
    8, Gagarina Ave., Dnipro, Ukraine, 49005
  2. A. V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine
    86, Lustdorfskaya Road, Odesa, Ukraine, 65080
  3. Kuban State University
    149 Stavropolskaya Str., Krasnodar, Russian Federation, 350040
  4. North Caucasus Federal University
    1a Pushkina Str., Stavropol, Russian Federation, 355017

Abstract

Aim. To find novel anticancer lead molecules among easily available spiro-fused thieno[2,3-d]pyrimidines. Methods. Organic synthesis, spectral methods and molecular docking. Results. New spiro heterocycles were synthesized by condensation of 2-aminothiophene-3-carbonitriles with cyclic ketones via Gevald reaction . Other model spirocyclic compounds were prepared by the reaction of 3-aminothieno[2,3-b]pyridine-2-carboxamides with cyclohexanone under acidic conditions. According to the docking studies against the EGFRWT the synthesized compounds revealed good binding energies ranging from -8.4 to -10.2 kcal/mol. The compounds were tested as inhibitors of protein kinase CK; 7’,8’,9’,10’-tetrahydro-1’H-spiro[cyclohexane-1,2’-pyrimido[4’,5’:4,5]thieno[2,3-b]quinolin]-4’(3’H)-one showed the best binding energy while be bound by a hydrogen bond to Val66 amino acid residue. This compound also showed good results as a potential inhibitor of B-Raf kinase. Conclusion. New spiro-fused thieno[2,3-d]pyrimidines have been synthesized. The inhibition activity of novel compounds as potential inhibitors of the EGFR, CK2, FGFR1 and B-raf kinases was examined. We found that spiro-fused thieno[2,3-d]pyrimidines undergo the rearrangement under Vilsmeier-Haack conditions to afford hitherto undescribed thienopyrimidines and –quinolines. The docking studies revealed that the rearranged products do not tend to form hydrogen bonds with the kinase amino acid residues and show moderate binding energies. Therefore, in contrast to the spiro-fused thieno[2,3-d]pyrimidines, the rearranged products cannot be considered as perspective targets for further screening.
Keywords: thieno[2,3-d]pyrimidines, thieno[2,3-b]pyridines, spiroheterocycles, Vilsmeier-Haack reaction, docking studies, anticancer activity, kinase inhibitors
Full text: (PDF, in English)

References

[1] Lin L, Yan L, Liu Y, Yuan F, Li H. Incidence and death in 29 cancer groups in 2017 and trend analysis from 1990 to 2017 from the Global Burden of Disease Study. J Hematol Oncol. 2019;12(1):374-89.
[2] Bonomi P. Erlotinib: a new therapeutic approach for non-small cell lung cancer. Expert Opin Investig Drugs. 2003; 12(8):1395-401.
[3] Vansteenkiste J. Gefitinib (Iressa): a novel treatment for non-small cell lung cancer. Expert Rev Anticancer Ther. 2004; 4(1):5-17.
[4] Dominguez I, Sonenshein GE, Seldin DC. Protein kinase CK2 in health and disease: CK2 and its role in Wnt and NF-kappa B signaling: Linking development and cancer. Cell Mol Life Sci. 2009;66(0):1850-7.
[5] The AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov. 2017;7(8):818-31
[6] Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N. at all. Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-54.
[7] Riesco-Eizaguirre G, Gutiérrez-Martínez P, García-Cabezas MA, Nistal M, Santisteban P. The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr Relat Cancer. 2006;13(1):257-69/
[8] Pedretti A, Villa L, Vistoli G. VEGA - An open platform to develop chemobioinformatics applications, using plugin architecture and script programming. J.C.A.M.D. 2004; 18: 167-73.
[9] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDock-Tools4: Automated docking with selective receptor flexibility. J. Comput Chem. 2009; 30 (16): 2785-91.
[10] Gewald K, Schinke E, Böttcher H. Heterocyclen aus CH‐aciden nitrilen, VIII. 2‐amino‐thiophene aus methyle-naktiven nitrilen, carbonylverbindungen und Schwefel. Chem Ber. 1966; 99:94-100.
[11] Kamal El‐Dean AM, Shaker R, Abo El‐Hassan AA, Abdel Latif FF. Synthesis of some thieno-tetrahydro quinoline derivatives. J Chin Chem Soc. 2004; 51(2):335-45.
[12] Dotsenko VV, Krivokolysko SG, Chernega AN, Litvinov VP. Anilinomethylidene derivatives of cyclic 1,3-dicarbonyl compounds in the synthesis of new sulfur-containing pyridines and quinolines. Russ Chem Bull. 2002; 51(8):1556-61.
[13] Shvedov VI, Sycheva TP, Sakovich TV. Research on thienopyridines and pyridothienopyrimidines. 1. Synthesis of some substituted 3-aminothieno[2,3-b]pyridines. Chem Heterocycl Compds. 1979; 15(10):1070-4.
[14] Seck P, Thomae D, Kirsch G. Synthesis of Substituted Amino-Cycloalkyl[b]thieno [3,2-e]Pyridines. J. Hetero-cyclic Chem., 2008;45:853-7.
[15] Ibrahim YA., Elwahy AHM., Kadry AM. Thienopyrimidines: synthesis, reactions, and biological activity. Adv. Heterocycl. Chem. 1996; 65:235-81.
[16] Varvounis G, Giannopoulos T. Synthesis, chemistry, and biological properties of thienopyrimidines. Adv. Heterocycl. Chem. 1996; 66:193-283.
[17] Litvinov VP. Thienopyrimidines: synthesis, properties, and biological activity. Russ Chem Bull. 2004; 53(3):487-516.
[18] Litvinov VP. The chemistry of thienopyrimidines Adv. Heterocycl. Chem. 2006; 92:83-143.
[19] Noravyan AS, Paronikyan EG, Sirakanyan SN, Hakobyan ShF. [Synthesis and conversion of condensed thie-no[2,3-d]- and thieno[3,2-d]pyrimidines]. Chem J Arm. 2012; 65(4):447-73.
[20] Aly AA, Ishak EA, Ramadan M, Germoush MO, El‐Emary TI, Al‐Muaikel NS. Recent Report on Thie-no[2,3‐d]pyrimidines. Their Preparation Including Microwave and Their Utilities in Fused Heterocycles Synthesis. J Heterocycl Chem 2013; 50(3):451-72.
[21] Bozorov K, Zhao JY, Elmuradov B, Pataer A, Aisa HA. Recent developments regarding the use of thie-no[2,3-d]pyrimidin-4-one derivatives in medicinal chemistry, with a focus on their synthesis and anticancer properties. Eur J Med Chem. 2015; 102:552-73.
[22] Wilding B, Klempier N. Newest developments in the preparation of thieno[2,3-d]pyrimidines. Org Prep Proced Int. 2017; 49(3);183-215.
[23] Ali EMH, Abdel-Maksoud MS, Oh CH. Thieno[2,3-d]pyrimidine as a promising scaffold in medicinal chemistry: Recent advances. Bioorg Med Chem. 2019; 27(7):1159-94.
[24] Khripak SM, Slivla MV, Lendel VG. Synthesis and reactions of thieno[2,3-d]pyrimidines. Uzhgorod: "Patent", 2009; 132 p.
[25] Vlasov SV, Zhuravel' IO, Chernykh VP. Anticancer activity study of 6-hetarylthieno[2,3-d]pyrimidine derivatives. Ukrainian biopharmaceutical journal. 2015; 4(39):46-51.
[26] Gunda SR, Lingala S, Allenki V. Synthesis and anticancer activity of some novel 3-[(2-substituted-6,7,8,9-tetrahydro-5Hcyclohepta[b]thieno[2,3-d]pyrimidin-4-yl)amino]propan-1-ol derivatives. Eur J Pharm Med Res. 2017; 4(6):481-84.
[27] Amawi H, Karthikeyan C, Pathak R, Hussein N, Christman R, Robey R, Ashby CR, Trivedi P, Malhotra A, Tiwari AK. Thienopyrimidine derivatives exert their anticancer efficacy via apoptosis induction, oxidative stress and mi-totic catastrophe. Eur J Med Chem. 2017; 138:1053-65.
[28] Elrazaz EZ, Serya RA, Ismail NS, El Ella DAA, Abouzid KA. Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents. Future J Pharm Sci. 2015; 1(2):33-41.
[29] Ghith A, Ismail NS, Youssef K, Abouzid KA. Medicinal attributes of thienopyrimidine based scaffold targeting tyrosine kinases and their potential anticancer activities. Arch Pharm. 2017; 350(11):1700242.
[30] Mghwary AES, Gedawy EM, Kamal AM, Abuel-Maaty SM. Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile. J Enzyme Inhib Med Chem. 2019; 34(1):838-52.
[31] Kolomieitsev DO, Varenichenko SA, Astakhina VO, Markov VI, Kovalenko SI, Kharchenko OV. The direction of heterocyclization of 4-hydrazino-5,6,7,8-tetrahydro[1]benzotieno[2,3-d]pyrimidine in reaction with dicarboxylic acid anhydride. Voprosy khimii i khimicheskoi tekhnologii. 2016; 2(106):32-6.
[32] Kolomieitsev DO, Markov VI, Varenichenko SA, Astakhina VO, Kovalenko SI, Kharchenko OV, Mazepa AV. Dimroth rearrangement in the synthesis of substituted cyclopenta and cyclohexa[4,5]thieno[2',3': 4,5]pyrimido[1,6-b][1,2,4]triazines. Chem Heterocycl Compds. 2016; 52(7):498-502.
[33] Dotsenko VV, Krivokolysko SG, Litvinov VP. The Mannich reaction in the synthesis of N, S-containing hetero-cycles. 9. A new approach to thieno[2,3-d] pyrimidines. Russ Chem Bull. 2009; 58(7):1524-5.
[34] Kolomieitsev DO, Markov VI, Astakhina VO, Kovalenko SI, Varenichenko SA, Kharchenko OV. The synthesis, reactivity and the antimicrobial activity of substituted thieno[2,3-d]pyrimidine-4(3H)-thio(seleno)nes. Journal of Organic and Pharmaceutical Chemistry. 2015; 13(4):32-8.
[35] Paronikyan EG, Noravyan AS, Vartanyan SA. Synthesis, transformations, and pharmacological properties of thienopyridines. Pharm Chem J. 1987; 21(5):309-17.
[36] Bakhite EAG. Recent trends in the chemistry of thienopyridines. Phosphorus Sulfur Silicon Relat Elem. 2003; 178(5):929-92.
[37] Litvinov VP, Dotsenko VV, Krivokolysko SG. The chemistry of thienopyridines. Adv Heterocycl Chem. 2007; 93:117-78.
[38] Litvinov VP, Dotsenko VV, Krivokolysko SG. The chemistry of thienopyridines and related systems. Moscow: "Nauka", 2006; 407 p.
[39] Eurtivong C, Semenov V, Semenova M, Konyushkin L, Atamanenko O, Reynisson J, Kiselyov A. 3-Aminothieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells. Bioorg Med Chem 2017; 25(2):658-64.
[40] Abdelaziz ME, El-Miligy MM, Fahmy SM, Mahran MA, Hazzaa AA. Design, synthesis and docking study of pyridine and thieno[2,3-b]pyridine derivatives as anticancer PIM-1 kinase inhibitors. Bioorg Chem. 2018; 80:674-92.
[41] Feng L, Reynisdóttir I, Reynisson J. The effect of PLC-γ2 inhibitors on the growth of human tumour cells. Eur J Med Chem. 2012; 54:463-9.
[42] Arabshahi HJ., Leung E, Barker D, Reynisson J. The development of thieno[2,3-b]pyridine analogues as anti-cancer agents applying in silico methods. MedChemComm. 2014; 5(2):186-91.
[43] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. Autodock4 and AutoDock-Tools4: automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91.
[44] Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2):455-61.
[45] Park JH, Liu Y, Lemmon MA, Radhakrishnan R. Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem J. 2012; 448:417.
[46] Battistutta R, De Moliner E, Sarno S, Zanotti G, Pinna LA. Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole. Protein Sci. 2001; 10(11):2200-6.
[47] Li N, Batt D, Warmuth M. B-Raf kinase inhibitors for cancer treatment. Curr Opin Investig Drugs. 2007; 8:452-6.
[48] Markov VI, Farat OK, Varenichenko SA, Velikaya EV. Rearrangement of 5',6',7',8'-tetrahydro-1'H-spiro(cyclohexane-1,2'-quinazolin)-4'(3'H)-one during Vilsmeier reaction. Mendeleev Commun. 2012;22:101-2.
[49] Farat OK, Markov VI, Varenichenko SA, Dotsenko VV, Mazepa AV. The Vilsmeier-Haack formylation of 2,3-dihydro-4H-1,3-benzoxazin-4-ones and isomeric 1,2-dihydro-4H-3,1-benzoxazin-4-ones: an effective approach to functionalized 2H-/4H-Chromenes and Tetrahydroacridines. Tetrahedron. 2015; 71:5554-61.
[50] Farat OK, Ananyev IV, Varenichenko SA, Zaliznaya EV, Markov VI. A facile approach for the synthesis of novel xanthene derivatives with Vilsmeier-Haack reagent. Chem Heterocycl Compds. 2019; 55(1):38-46
[51] Farat OK, Varenichenko SA, Zaliznaya EV, Markov VI. Rearrangement of substituted 1,3-benzoxazines into xanthene-type compounds. Ukr Knim ZH. 2020; 86(2):111-22.