Skip to main content
SpringerLink
Log in

Design, synthesis and in vitro antitumor evaluation of novel diaryl urea derivatives bearing sulfonamide moiety

  • Articles
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

A novel series of diaryl urea derivatives bearing sulfonamide moiety have been designed and synthesized. Their in vitro antitumor effect against human cancer cell lines MX-1, A375, HepG2, Ketr3 and HT-29 was screened and evaluated by the standard MTT assay with sorafenib as the positive control. Some of the compounds showed significant inhibitory activity against multiple cell lines compared to sorafenib. In particular, 2,6-dimethyl-4-{6-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]naphthalen-2-yl}sulfonyl morpholine (10d) was found to be the most potent against A375, HepG2 and Ketr3 with IC50 values of 0.65–0.97 μmol/L, which were 5–20-fold more potent than sorafenib. Compound 10d emerged as a valuable lead for further optimization.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S. Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov, 2006, 5(10): 835–844

    Article  CAS  Google Scholar 

  2. Spangenberg HC, Thimme R, Blum HE. Targeted therapy for hepatocellular carcinoma. Nat Rev Gastro Hepat, 2009, 6(7): 423–432

    Article  CAS  Google Scholar 

  3. Dai Y, Hartandi K, Ji Z, Ahmed AA, Albert DH, Bauch JL, Bouska JJ, Bousquet PF, Cunha GA, Glaser KB, 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. 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, 2007, 50(7): 1584–1597

    Article  CAS  Google Scholar 

  4. Menard D, Niculescu-Duvaz I, Dijkstra HP, Niculescu-Duvaz D, Suijkerbuijk BMJM, Zambon A, Nourry A, Roman E, Davies L, Manne HA, Friedlos F, Kirk R, Whittaker S, Gill A, Taylor RD, Marais R, Springer CJ. Novel potent BRaf inhibitors: Toward 1 nM compounds through optimization of the central phenyl ring. J Med Chem, 2009, 52(13): 3881–3891

    Article  CAS  Google Scholar 

  5. Potashman MH, Bready J, Coxon A, DeMelfi TMJ, DiPietro L, Doerr N, Elbaum D, Estrada J, Gallant P, Germain J, Gu Y, Harmange JC, Kaufman SA, Kendall R, Kim JL, Kumar GN, Long AM, Neervannan S, Patel VF, Polverino A, Rose P, Plas S, Whittington D, Zanon R, Zhao H. Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors. J Med Chem, 2007, 50(18): 4351–4373

    Article  CAS  Google Scholar 

  6. Ramurthy S, Subramanian S, Aikawa M, Amiri P, Costales A, Dove J, Fong S, Jansen JM, Levine B, Ma S, McBride CM, Michaelian J, Pick T, Poon DJ, Girish S, Shafer CM, Stuart D, Sung L, Renhowe PA. Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors. J Med Chem, 2008, 51(22): 7049–7052

    Article  CAS  Google Scholar 

  7. Jung MH, Kim H, Choi WK, El-Gamal MI, Park JH, Yoo KH, Sim TB, Lee SH, Baek D, Hah JM, Cho JH, Oh CH. Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line. Bioorg Med Chem Lett, 2009, 19(23): 6538–6543

    Article  CAS  Google Scholar 

  8. Sun M, Wu X, Chen J, Cai J, Cao M, Ji M. Design, synthesis, and in vitro antitumor evaluation of novel diaryl ureas derivatives. Eur J Med Chem, 2010, 45(6): 2299–2306

    Article  CAS  Google Scholar 

  9. Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Cancer Genome Project, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R. Mechanism of activation of the Raf-ERK signaling pathway by oncogenic mutations of B-Raf. Cell, 2004, 116(6): 855–867

    Article  CAS  Google Scholar 

  10. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer, 2009, 9(1): 28–39

    Article  Google Scholar 

  11. Dietrich J, Hulme C, Hurley LH. The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec®, Nexavar®, and BIRB-796. Bioorg Med Chem, 2010, 18(15): 5738–5748

    Article  CAS  Google Scholar 

  12. Tang J, Hamajima T, Nakano M, Sato H, Dickerson SH, Lackey KE. Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors. Bioorg Med Chem Lett, 2008, 18(16): 4610–4614

    Article  CAS  Google Scholar 

  13. Khire UR, Bankston D, Barbosa J, Brittelli DR, Caringal Y, Carlson R, Dumas J, Gane T, Heald SL, Hibner B, Johnson JS, Katz ME, Kennure N, Kingery-Wood J, Lee W, Liu XG, Lowinger TB, McAlexander I, Monahan MK, Natero R, Renick J, Riedl B, Rong H, Sibley RN, Smith RA, Wolanin D. Omega-carboxypyridyl substituted ureas as Raf kinase inhibitors: SAR of the amide substituent. Bioorg Med Chem Lett, 2004, 14(3): 783–786

    Article  CAS  Google Scholar 

  14. Zhan W, Li Y, Huang W, Zhao Y, Yao Z, Yu S, Yuan S, Jiang F, Yao S, Li S. Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors. Bioorg Med Chem, 2012, 20(14): 4323–4329

    Article  CAS  Google Scholar 

  15. Anandan SK, Gless RD. Exploration of secondary and tertiary pharmacophores in unsymmetrical N,N′-diaryl urea inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett, 2010, 20(9): 2740–2744

    Article  CAS  Google Scholar 

  16. Kim MH, Kim M, Yu H, Kim H, Yoo KH, Sim T, Hah JM. Structure based design and syntheses of amino-1H-pyrazole amide derivatives as selective Raf kinase inhibitors in melanoma cells. Bioorg Med Chem, 2011, 19(6): 1915–1923

    Article  CAS  Google Scholar 

  17. Song HB, Cao SL, Zheng XL. Advances in sulfonamides as antitumor agents. Chin New Drug J, 2009, 18(2): 108–115

    CAS  Google Scholar 

  18. Hu LX, Li ZR, Wang YM, Wu YB, Jiang JD, Boykin DW. Novel pyridinyl and pyrimidinylcarbazole sulfonamides as antiproliferative agents. Bioorg Med Chem Lett, 2007, 17(5): 1193–1196

    Article  CAS  Google Scholar 

  19. Bankston D, Dumas J, Natero R, Riedl B, Monahan MK, Sibley R. A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer. Org Proc Res Dev, 2002, 6(6): 777–781

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation; Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100050, China

    Can Luo, Ke Tang, Yan Li, DaLi Yin, XiaoGuang Chen & HaiHong Huang

Authors
  1. Can Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ke Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. DaLi Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. XiaoGuang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. HaiHong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to XiaoGuang Chen or HaiHong Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, C., Tang, K., Li, Y. et al. Design, synthesis and in vitro antitumor evaluation of novel diaryl urea derivatives bearing sulfonamide moiety. Sci. China Chem. 56, 1564–1572 (2013). https://doi.org/10.1007/s11426-013-4903-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-013-4903-z

Keywords

Search

Navigation