Advertisement

Medicinal Chemistry Research

, Volume 25, Issue 4, pp 728–737 | Cite as

The novel coumarin[3,2-c]thiophene and its hydroxamic acid and ureido derivatives: synthesis and cytostatic activity evaluations

  • Karlo Wittine
  • Ivana Ratkaj
  • Krešimir Benci
  • Tomislav Suhina
  • Leo Mandić
  • Nataša Ilić
  • Sandra Kraljević Pavelić
  • Krešimir Pavelić
  • Mladen MintasEmail author
Original Research

Abstract

In the present paper, we report on the synthesis and in vitro antitumour effects of novel hydroxamic acid (compounds 4 and 5) and ureido (compounds 711) derivatives containing coumarin[3,2-c]thiophene moiety. The results of antiproliferative assays performed on a panel of selected human tumour cell lines revealed stronger concentration-dependent antiproliferative activity of coumarin[3,2-c]thiophene (711) ureido derivatives in comparison with coumarin[3,2-c]thiophene hydroxamic acid derivatives (4 and 5). Nevertheless, compounds 710 were cytotoxic on normal human fibroblasts as well. Importantly, the ureido derivative 11 and hydroxamic acid derivatives 4 and 5 showed pronounced and selective inhibitory activity towards cervical carcinoma (HeLa) cell line with concomitant low or no cytotoxicity on normal human fibroblasts. These compounds can therefore be considered as potential antitumour lead compounds for further structural optimization.

Graphical Abstract

Keywords

Coumarin[3,2-c]thiophene Urea Hydroxamic acid Antitumour 

Notes

Acknowledgments

Support for this study was provided by the Ministry of Science, Education and Sports of the Republic of Croatia (Grant Nos. 125-0982464-2922, 335-0982464-239, 335-0000000-3532) and University of Rijeka research Grants 13.11.1.1.11 and 13.11.1.2.01.

References

  1. Avendano C, Menendez JC (2008) Medicinal chemistry of anticancer drugs. Elsevier, AmsterdamGoogle Scholar
  2. Bezboruah P, Gogoi P, Gogoi J, Boruah RC (2013) KF/Al2O3/PEG-400: an efficient catalytic system for the fiesselmann-type synthesis of thiophene derivatives. Synthesis 45:1341–1348CrossRefGoogle Scholar
  3. Boland GM, Donnelly DMX (1998) Isoflavonoids and related compounds. Nat Prod Rep 15:241–260CrossRefGoogle Scholar
  4. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23(16):2825–2837CrossRefPubMedGoogle Scholar
  5. Dai Y, Hartandi K, Ji Z, Ahmed AA, Albert DH, Bauch JL, Bouska JJ, Bousquet PF, Cunha GA, Glaser KBC, Harris CM, Hickman D, Guo J, Li J, Marcotte PA, Marsh KC, Moskey MD, Martin RL, Olson AM, Osterling DJ, Pease LJ, Soni NB, Stewart KD, Stoll VS, Tapang P, Reuter DR, Davidsen SK, Michaelides MR (2007) Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N’-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J Med Chem 50(7):1584–1597CrossRefPubMedGoogle Scholar
  6. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391(6665):387–390CrossRefPubMedGoogle Scholar
  7. Fujita F, Fujita M, Inaba H, Sugimoto T, Okuyama Y, Taguchi T (1991) Combination chemotherapy of HO-221, a derivative of benzoylphenylurea with various anticancer agents against human cancer xenografts in nude mice. Gan To Kagaku Ryoho 18(13):2263–2270PubMedGoogle Scholar
  8. Gautam DR, Protopappas J, Fylaktakidou KC, Litinas KE, Nicolaides DN, Tsoleridis CA (2000) Unexpected one-pot synthesis of new polycyclic coumarin[4,3-c] pyridine derivatives via a tandem hetero-Diels–Alder and 1,3-dipolar cycloaddition reaction. Tetrahedron Lett 50(4):448–451CrossRefGoogle Scholar
  9. Gazivoda T, Raić-Malić S, Kristafor V, Makuc D, Plavec J, Bratulić S, Kraljević-Pavelić S, Pavelić K, Naesens L, Andrei G, Snoeck R, Balzarini J, Mintas M (2008) Synthesis, cytostatic and anti-HIV evaluations of the new unsaturated acyclic C-5 pyrimidine nucleoside analogues. Bioorg Med Chem 16(10):5624–5634CrossRefPubMedGoogle Scholar
  10. Gnewuch CT, Sosnovsky G (1997) A critical appraisal of the evolution of N-nitrosoureas as anticancer drugs. Chem Rev 97(3):829–1014CrossRefPubMedGoogle Scholar
  11. Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O’Connor PM, Piwnica-Worms H (2000) The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 275(8):5600–5605CrossRefPubMedGoogle Scholar
  12. Grese T, Pennington D, Sluka JP, Adrian MD, Cole HW, Fuson TR, Magee DE, Phillips DL, Rowley ER, Shetler PK, Short LL, Venugopalan M, Yang NN, Sato M, Glasebrook AL, Bryant HU (1998) Synthesis and pharmacology of conformationally restricted raloxifene analogues: highly potent selective estrogen receptor modulators. J Med Chem 41(8):1272–1283CrossRefPubMedGoogle Scholar
  13. Janetka JW, Almeida L, Ashwell S, Brassil PJ, Daly K, Deng C, Gero T, Glynn RE, Horn CL, Ioannidis S, Lyne P, Newcombe NJ, Oza VB, Pass M, Springer SK, Su M, Toader D, Vasbinder MM, Yu D, Yu Y, Zabludoff SD (2008) Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors. Bioorg Med Chem Lett 18(14):4242–4248CrossRefPubMedGoogle Scholar
  14. Jiang JD, Denner L, Ling YH, Li JN, Davis A, Wang Y, Li Y, Roboz JL, Wang LG, Roman PS, Marcelli M, Bekesi G, Holland JF (2002) Double blockade of cell cycle at G1-S transition and M phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. Cancer Res 62:6080–6088PubMedGoogle Scholar
  15. Kawabe T (2004) G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 3(4):513–519PubMedGoogle Scholar
  16. Kumar M, Hosur MV (2003) Adaptability and flexibility of HIV-1 protease. Eur J Biochem 270(6):1231–1239CrossRefPubMedGoogle Scholar
  17. Miski M, Jakupovic J (1990) Cyclic farnesyl-coumarin and farnesyl-chromone derivatives from Ferula communis subsp. communis. Phytochemistry 29:1995–1998CrossRefGoogle Scholar
  18. Morré DJ, Wu L-Y, Morré DM (1995) The antitumor sulfonylurea N-(4-methylphenyl sulfonyl)-N’-(4-chlorophenyl) urea (LY181984) inhibits NADH oxidase activity of HeLa plasma membranes. Biochim Biophys Acta 1240(1):11–17CrossRefPubMedGoogle Scholar
  19. Ohnuma S, Muraoka M, Ioriya K, Ohashi N (2004) Synthesis and structure-activity relationship studies on a novel series of naphthylidinoylureas as inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT). Bioorg Med Chem Lett 14(5):1309–1311CrossRefPubMedGoogle Scholar
  20. Okada H, Koyanagi T, Yamada N (1994) Synthesis and antitumor activities of prodrugs of benzoylphenylureas. Chem Pharm Bull 42(1):57–61CrossRefPubMedGoogle Scholar
  21. On KF, Chen Y, Ma HT, Chow JP, Poon RY (2011) Determinants of mitotic catastrophe on abrogation of the G2 DNA damage checkpoint by UCN-01. Mol Cancer Ther 10(5):784–794CrossRefPubMedGoogle Scholar
  22. Rappa G, Shyam K, Lorico A, Fodstad O, Sartorelli AC (2000) Structure-activity studies of novobiocin analogs as modulators of the cytotoxicity of etoposide (VP-16). Oncol Res 12(3):113–119CrossRefPubMedGoogle Scholar
  23. Šaban N, Bujak M (2009) Hydroxyurea and hydroxamic acid derivatives as antitumor drugs. Cancer Chemother Pharmacol 64(2):213–221CrossRefPubMedGoogle Scholar
  24. Schuster N, Christiansen C, Jakupovic J, Mungai M (1993) An unusual [2 + 2] cycloadduct of terpenoid coumarin from Ethulia vernonioides. Phytochemistry 34(4):1179–1181CrossRefGoogle Scholar
  25. Song EY, Kaur N, Park MY, Yin Y, Lee K, Kim G, Lee KY, Yang JS, Shin JH, Nam KY, No KT, Han G (2008) Synthesis of amide and urea derivatives of benzothiazole as Raf-1 inhibitor. Eur J Med Chem 43(7):1519–1524CrossRefPubMedGoogle Scholar
  26. Thaisrivongs S, Janakiraman MN, Chong KT, Tomich PK, Dolak LA, Turner SR, Strohbach JW, Lynn JC, Horng MM, Hinshaw RR, Watenpaugh KD (1996) Structure-based design of novel HIV protease inhibitors: sulfonamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent non-peptidic inhibitors. J Med Chem 39(12):2400–2410CrossRefPubMedGoogle Scholar
  27. Toth JE, Grindey GB, Ehlhardt WJ, Ray JE, Boder GB, Bewley JR, Klingerman KK, Gates SB, Rinzel SM, Schultz RM, Weir LC, Worzalla JF (1997) Sulfonimidamide analogs of oncolytic sulfonylureas. J Med Chem 40(6):1018–1025CrossRefPubMedGoogle Scholar
  28. Wang X, Bastow KF, Sun C, Lin Y, Yu H, Don M, Wu T, Nakamura S, Lee K (2004) Antitumor Agents. 239. Isolation, structure elucidation, total synthesis, and anti-breast cancer activity of neo-tanshinlactone from Salvia miltiorrhiza. J Med Chem 47(23):5816–5819CrossRefPubMedGoogle Scholar
  29. Yang EB, Zhao YN, Zhang K, Mack P (1999) Daphnetin, one of coumarin derivatives, is a protein kinase inhibitor. Biochem Biophys Res Commun 260(3):682–685CrossRefPubMedGoogle Scholar
  30. Zhao L, Brinton RD (2005) Structure-based virtual screening for plant-based ERbeta selective ligands as potential preventative therapy against age-related neurodegenerative diseases. J Med Chem 48(10):3463–3466CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Karlo Wittine
    • 2
  • Ivana Ratkaj
    • 2
  • Krešimir Benci
    • 1
  • Tomislav Suhina
    • 1
  • Leo Mandić
    • 1
  • Nataša Ilić
    • 2
  • Sandra Kraljević Pavelić
    • 2
  • Krešimir Pavelić
    • 2
  • Mladen Mintas
    • 1
    Email author
  1. 1.Department of Organic Chemistry, Faculty of Chemical Engineering and TechnologyUniversity of ZagrebZagrebCroatia
  2. 2.Department of BiotechnologyUniversity of RijekaRijekaCroatia

Personalised recommendations