Molecular Diversity

, Volume 19, Issue 4, pp 725–736 | Cite as

Synthesis of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-ones, their lipophilicity and anticancer activity in vitro

  • Joanna Matysiak
  • Małgorzata Juszczak
  • Monika M. Karpińska
  • Ewa Langner
  • Katarzyna Walczak
  • Marta K. Lemieszek
  • Alicja Skrzypek
  • Andrzej Niewiadomy
  • Wojciech Rzeski
Full-Length Paper


A new one-step synthesis of novel biologically active 2-substituted 2,4-dihydroxyphenyl-4\(H\)-thieno[3,2-\(d\)][1,3]thiazin-4-ones and 4\(H\)-thieno[2,3-\(d\)][1,3]thiazin-4-ones has been elaborated and described. The compounds were prepared by the reaction of aryl-modified sulfinylbis [(2,4-dihydroxyphenyl)methanethione]s and the corresponding aminothiophenecarboxamides. The derivatives showed anticancer activity in vitro. These compounds inhibited the proliferation and viability of lung cancer A549, colon cancer HT-29 and glioma C6 cells in a concentration-dependent manner. Some of the derivatives had no influence on normal skin fibroblasts culture viability. Moreover, one compound (1b) showed the ability to inhibit DNA synthesis in cancer cells, especially in C6 cells, and was not toxic for normal oligodendrocytes and hepatocytes. Using reversed phase RP 18 HPLC and immobilised artificial membrane (IAM) chromatography the phase affinity of the compounds was determined. The influence of lipophilicity on the activity of compounds has been discussed.


Anticancer agents Antiproliferative activity Cytotoxicity Lipophilicity Thieno-1,3-thiazin-4-ones Resorcinols 



This project was financed from the funds of the National Science Centre in Poland allocated on the basis of the decision number DEC-2011/01/B/NZ4/05005.

Supplementary material

11030_2015_9599_MOESM1_ESM.pdf (3.4 mb)
Supplementary material 1 (pdf 3503 KB)


  1. 1.
    Butin AV, Tsiunchik FA, Abaev VT, Gutnov AV, Cheshkov DA (2009) Aryl ring migration reaction in the synthesis of 2,4-diaryl-4\(H\)-3,1-benzothiazines. Synthesis, pp 2616–2626. doi: 10.1055/s-0029-1217399
  2. 2.
    Abaev VT, Tsiunchik FA, Gumov AV, Butin AV (2008) Synthesis of 2,4-difuryl-4\(H\)-3,1-benzothiazines via a furan ring migration reaction. J Heterocycl Chem 45:475–481. doi: 10.1002/jhet.5570450227 CrossRefGoogle Scholar
  3. 3.
    Fernandes MA, Reid DH (2003) Synthesis of 3,1-benzothiazines by cyclisation of 2-thioformylaminodiphenylacetylenes. Synlett 14:2231–2233. doi: 10.1055/s-2003-42078 Google Scholar
  4. 4.
    Niewiadomy A, Matysiak J, Karpińska MM (2011) Synthesis and anticancer activity of new 2-aryl-4\(H\)-3,1-benzothiazines. Arch Pharm 344:224–230. doi: 10.1002/ardp.201000228 CrossRefGoogle Scholar
  5. 5.
    Leistner S, Gütschow M, Wagner G (1987) The facile synthesis of 2-aminothieno[2,3-\(d\)][1,3]thiazin-4-ones, in some cases 5,6-anellated. Synthesis, pp 466–470Google Scholar
  6. 6.
    Neumann U, Gütschow M (1995) 3,1-Benzothiazin-4-ones and 3,1-benzoxazin-4-ones - highly different activities in chymotrypsin inactivation. Bioorg Chem 23:72–88. doi: 10.1006/bioo.1995.1006 CrossRefGoogle Scholar
  7. 7.
    Ottersbach PA, Elsinghorst PW, Hacker HG, Gütschow M (2010) Direct formation of ring-fused 1,3-thiazine-2,4-dithiones from aromatic o-amino carboxylic acids: observation of a carbon disulfide mediated thionation. Org Lett 12:3662–3665. doi: 10.1021/ol101471g CrossRefPubMedGoogle Scholar
  8. 8.
    Leistner S, Gütschow M, Wagner G, Grupe R, Bohme B (1988) One-step synthesis of 2-aminothieno [2,3-\(d\)][1,3]thiazin-4-ones in some cases 5,6-anellated from ethyl 2-benzoylthioureidothiophen-3-carboxylates and evaluation of their antiallergy activity. Pharmazie 43:466–470PubMedGoogle Scholar
  9. 9.
    Matysiak J (2006) Synthesis, antiproliferative and antifungal activities of some 2-(2,4-dihydroxyphenyl)-4\(H\)-3,1-benzothiazines. Bioorg Med Chem 14:2613–2619. doi: 10.1016/j.bmc.2005.11.053 CrossRefPubMedGoogle Scholar
  10. 10.
    Matysiak J, Łoś R, Malm A, Karpińska MM, Glaszcz U, Rajtar B, Polz-Dacewicz M, Trojanowska-Wesołowska M, Niewiadomy A (2012) Synthesis and antibacterial activity of novel fused 1,3-thiazoles and 1,3-thiazines incorporating a 2,4-dihydroxyphenyl residue. Arch Pharm 345:303–313. doi: 10.1002/ardp.201100251 CrossRefGoogle Scholar
  11. 11.
    Gütschow M, Schlenk M, Gaeb J, Paskaleva M, Alnouri MW, Scolari S, Iqbal J, Mueller CE (2012) Benzothiazinones: a novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives. J Med Chem 55:3331–3341. doi: 10.1021/jm300029s CrossRefPubMedGoogle Scholar
  12. 12.
    Häcker HG, Grundmann F, Lohr F, Ottersbach PA, Zhou J, Schnakenburg G, Gütschow M (2009) 2-Amino- and 2-alkylthio-4\(H\)-3,1-benzothiazin-4-ones: synthesis, interconversion and enzyme inhibitory activities. Molecules 14:378–402. doi: 10.3390/molecules14010378 CrossRefPubMedGoogle Scholar
  13. 13.
    Makarov V, Manina G, Mikusova K, Moellmann U, Ryabova O, Saint-Joanis B, Dhar N, Pasca MR, Buroni S, Lucarelli AP, Milano A, De Rossi E, Belanova M, Bobovska A, Dianiskova P, Kordulakova J, Sala C, Fullam E, Schneider P, McKinney JD, Brodin P, Christophe T, Waddell S, Butcher P, Albrethsen J, Rosenkrands I, Brosch R, Nandi V, Bharath S, Gaonkar S, Shandil RK, Balasubramanian V, Balganesh T, Tyagi S, Grosset J, Riccardi G, Cole ST (2009) Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324:801–804. doi: 10.1126/science.1171583 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Manina G, Bellinzoni M, Pasca MR, Neres J, Milano A, Ribeiro ALdJL, Buroni S, Skovierova H, Dianiskova P, Mikusova K, Marak J, Makarov V, Giganti D, Haouz A, Lucarelli AP, Degiacomi G, Piazza A, Chiarelli LR, De Rossi E, Salina E, Cole ST, Alzari PM, Riccardi G (2010) Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance. Mol Microbiol 77:1172–1185. doi: 10.1111/j.1365-2958.2010.07277.x CrossRefPubMedGoogle Scholar
  15. 15.
    Lechartier B, Hartkoorn RC, Cole ST (2012) In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 56:5790–5793. doi: 10.1128/aac.01476-12 PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Kaneko C, Hara S, Matsumoto H, Takeuchi T, Mori T, Ikeda K, Mizuno Y (1991) A series of novel acyclic nucleosides. 4. Synthesis of N1-sulfur analogs of acyclovir, directed toward improved antiviral activities. Chem Pharm Bull 39:871–875. doi: 10.1248/cpb.39.871 CrossRefGoogle Scholar
  17. 17.
    Hara S, Kaneko C, Matsumoto H, Nishino T, Takeuchi T, Mori T, Mizuno Y, Ikeda K (1992) Synthesis of 6-sulfur analogs of oxanosine and closely related derivatives thereof. Nucleos Nucleot 11:571–582. doi: 10.1080/07328319208021726 CrossRefGoogle Scholar
  18. 18.
    Luk K-C, Moore DW, Keith DD (1994) A novel synthesis of oxanosine and 1-thiaguanosine. Tetrahedron Lett 35:1007–1010. doi: 10.1016/S0040-4039(00)79951-5 CrossRefGoogle Scholar
  19. 19.
    Gütschow M, Leistner S, Pink M (1992) Polycyclic azines with heteroatoms in the 1-position and 3-position. 27. One-pot synthesis of 4-acylimino-2-aminothieno[2,3-\(d\)][1,3]-thiazines from 2-thioureidothiophene-3-carbonitriles. J Heterocycl Chem 29:279–282. doi: 10.1002/jhet.5570290201 CrossRefGoogle Scholar
  20. 20.
    Gütschow M, Leistner S (1995) Synthesis of 2-acetonyl-substituted, 2-phenacyl-substituted, and 2-(dioxocycloalkyl)-substituted thieno[2,3-\(d\)][1,3]thiazin-4-ones. Liebigs Ann, pp 445–448Google Scholar
  21. 21.
    Matysiak J, Karpińska MM, Niewiadomy A, Wietrzyk J, Kłopotowska D (2012) One-pot synthesis of new (1,3-thiazolo[5,4-\(b\)]pyridin-2-yl)benzenediols and their antiproliferative activities against human cancer cell lines. Chem Biodivers 9:48–57. doi: 10.1002/cbdv.201100007 CrossRefPubMedGoogle Scholar
  22. 22.
    Rzeski W, Matysiak J, Kandefer-Szerszeń M (2007) Anticancer, neuroprotective activities and computational studies of 2-amino-1,3,4-thiadiazole based compound. Bioorg Med Chem 15:3201–3207. doi: 10.1016/j.bmc.2007.02.041 CrossRefPubMedGoogle Scholar
  23. 23.
    Juszczak M, Matysiak J, Szeliga M, Pożarowski P, Niewiadomy A, Albrecht J, Rzeski W (2012) 2-Amino-1,3,4-thiadiazole derivative (FABT) inhibits the extracellular signal-regulated kinase pathway and induces cell cycle arrest in human non-small lung carcinoma cells. Bioorg Med Chem Lett 22:5466–5469. doi: 10.1016/j.bmcl.2012.07.036 CrossRefPubMedGoogle Scholar
  24. 24.
    Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KMJ, Collins I, Davies NGM, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wrightt L (2008) 4,5-Diarylisoxazole HSP90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51:196–218. doi: 10.1021/jm701018h CrossRefPubMedGoogle Scholar
  25. 25.
    Smith NF, Hayes A, James K, Nutley BP, McDonald E, Henley A, Dymock B, Drysdale MJ, Raynaud FI, Workman P (2006) Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors. Mol Cancer Ther 5:1628–1637. doi: 10.1158/1535-7163.mct-06-0041 CrossRefPubMedGoogle Scholar
  26. 26.
    Cikotiene I, Kazlauskas E, Matuliene J, Michailoviene V, Torresan J, Jachno J, Matulis D (2009) 5-Aryl-4-(5-substituted-2,4-dihydroxyphenyl)-1,2,3-thiadiazoles as inhibitors of Hsp90 chaperone. Bioorg Med Chem Lett 19:1089–1092. doi: 10.1016/j.bmcl.2009.01.003 CrossRefPubMedGoogle Scholar
  27. 27.
    Gopalsamy A, Shi M, Golas J, Vogan E, Jacob J, Johnson M, Lee F, Nilakantan R, Petersen R, Svenson K, Chopra R, Tam MS, Wen Y, Ellingboe J, Arndt K, Boschelli F (2008) Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90. J Med Chem 51:373–375. doi: 10.1021/jm701385c CrossRefPubMedGoogle Scholar
  28. 28.
    Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A, Cozens R, Drysdale MJ, Garcia-Echeverria C, Chene P (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10:1–12CrossRefGoogle Scholar
  29. 29.
    Lin T-Y, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London C (2008) The novel Hsp90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors. Exp Hematol 36:1266–1277. doi: 10.1016/j.exphem.2008.05.001 CrossRefPubMedGoogle Scholar
  30. 30.
    Jhaveri K, Chandarlapaty S, Lake D, Gilewski T, Robson M, Goldfarb S, Drullinsky P, Sugarman S, Wasserheit-Leiblich C, Fasano J, Moynahan ME, D’Andrea G, Lim K, Reddington L, Haque S, Patil S, Bauman L, Vukovic V, El-Hariry I, Hudis C, Modi S (2014) A phase II open-label study of ganetespib, a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer. Clin Breast Cancer 14:154–160. doi: 10.1016/j.clbc.2013.12.012 CrossRefPubMedGoogle Scholar
  31. 31.
    Kreusch A, Han SL, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ (2005) Crystal structures of human HSP90 alpha-complexed with dihydroxyphenylpyrazoles. Bioorg Med Chem Lett 15:1475–1478. doi: 10.1016/j.bmcl.2004.12.087 CrossRefPubMedGoogle Scholar
  32. 32.
    Matysiak J, Niewiadomy A (2006) Application of sulfinyl bis(2,4-dihydroxythiobenzoyl) in the synthesis of N-substituted 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles. Synth Commun 36:1621–1630. doi: 10.1080/00397910600591896 CrossRefGoogle Scholar
  33. 33.
    Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113Google Scholar
  34. 34.
    Ward RS, Davies J, Hodges G, Roberts DW (2003) Applications of immobilised artificial membrane chromatography to quaternary alkylammonium sulfobetaines and comparison of chromatographic methods for estimating the octanol-water partition coefficient. J Chromatogr A 1007:67–75. doi: 10.1016/s0021-9673(03)00947-6
  35. 35.
    Taillardat-Bertschinger A, Galland A, Carrupt PA, Testa B (2002) Immobilized artificial membrane liquid chromatography: proposed guidelines for technical optimization of retention measurements. J Chromatogr A 953:39–53. doi: 10.1016/s0021-9673(02)00119-x CrossRefGoogle Scholar
  36. 36.
    Soczewinski E, Wachtmeister CA (1962) The relation between the composition of certain ternary two-phase solvent systems and R\(_{\rm M}\) values. J Chromatogr 7:311–320CrossRefGoogle Scholar
  37. 37.
    Niewiadomy A, Żabińska A, Matysiak J, Różyło JK (1997) Influence of modifier and molecular structure of some dihydroxythiobenzanilides on retention in reversed-phase high-performance thin-layer chromatography. J Chromatogr A 791:237–243CrossRefGoogle Scholar
  38. 38.
    Janicka M, Kwietniewski L, Matysiak J (2000) A new method for estimating log k\(_{\rm w}\) values and solute biological activity. J Planar Chromatogr 13:285–289Google Scholar
  39. 39.
    Pidgeon C, Venkataram UV (1989) Immobilized artificial membrane chromatography - supports composed of membrane-lipids. Anal Biochem 176:36–47. doi: 10.1016/0003-2697(89)90269-8 CrossRefPubMedGoogle Scholar
  40. 40.
    Barbato F (2006) The use of immobilised artificial membrane (IAM) chromatography for determination of lipophilicity. Curr Comput-Aided Drug Des 2:341–352. doi: 10.2174/157340906778992319 CrossRefGoogle Scholar
  41. 41.
    Matysiak J (2007) Evaluation of electronic, lipophilic and membrane affinity effects on antiproliferative activity of 5-substituted-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles against various human cancer cells. Eur J Med Chem 42:940–947. doi: 10.1016/j.ejmech.2006.12.033 CrossRefPubMedGoogle Scholar
  42. 42.
    Ghose AK, Crippen GM (1987) Atomic physicochemical parameters for 3-dimensional-structure-directed quantitative structure-activity-relationships. 2. Modeling dispersive and hydrophobic interactions. J Chem Inf Comput Sci 27:21–35. doi: 10.1021/ci00053a005 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Joanna Matysiak
    • 1
  • Małgorzata Juszczak
    • 2
  • Monika M. Karpińska
    • 3
  • Ewa Langner
    • 2
    • 4
  • Katarzyna Walczak
    • 4
  • Marta K. Lemieszek
    • 2
  • Alicja Skrzypek
    • 1
  • Andrzej Niewiadomy
    • 1
    • 3
  • Wojciech Rzeski
    • 2
    • 5
  1. 1.Department of ChemistryUniversity of Life Sciences in LublinLublinPoland
  2. 2.Department of Medical BiologyInstitute of Rural Health in LublinLublinPoland
  3. 3.Institute of Industrial Organic Chemistry in WarsawWarsawPoland
  4. 4.Department of PharmacologyMedical University in LublinLublinPoland
  5. 5.Department of Virology and ImmunologyMaria Curie-Skłodowska University in LublinLublinPoland

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