Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2583–2591 | Cite as

Synthesis and biological evaluation of novel N-(5-phenyl-1H-pyrazol-3-yl)benzenesulfonamide derivatives as potential BRAFV600E inhibitors

  • Zhen-Hua Gong
  • Jian Yao
  • Jian-Feng Ji
  • Jun Yang
  • Tie Xiang
  • Chang-Kai Zhou
Original Research


A series of novel N-(5-phenyl-1H-pyrazol-3-yl)benzenesulfonamide derivatives (5a5l) were synthesized and developed as potential BRAFV600E inhibitors. Among them, compound 5l exhibited the most potent inhibitory activity with an IC50 value of 0.18 μM for BRAFV600E. Antiproliferative assay results indicated that compound 5l have higher antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 1.58 and 2.04 μM, respectively, which were comparable with the positive control vemurafenib. Molecular docking of 5l into the BRAFV600E active site was performed to determine the probable binding mode.


BRAFV600E inhibitor Pyrazole Molecular docking Antiproliferative 



The authors are very much grateful to Nantong University, for providing laboratory facility.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Beck TW, Huleihel M, Gunnell M, Bonner TI, Rapp UR (1987) The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucleic Acids Res 15:595–609CrossRefPubMedPubMedCentralGoogle Scholar
  2. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMedGoogle Scholar
  3. Dong J, Li Q, Wang S, Li C, Zhao X, Qiu H et al. (2013) Synthesis, biological evaluation and molecular docking of novel 5-phenyl-1 H-pyrazol derivatives as potential BRAF V600E inhibitors. Org Biomol Chem 11:6328–6337CrossRefPubMedGoogle Scholar
  4. Garnett MJ, Marais R (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6:313–319CrossRefPubMedGoogle Scholar
  5. Ghorab MM, Ragab FA, Alqasoumi SI, Alafeefy AM, Aboulmagd SA (2010) Synthesis of some new pyrazolo [3, 4-d] pyrimidine derivatives of expected anticancer and radioprotective activity. Eur J Med Chem 45:171–178CrossRefPubMedGoogle Scholar
  6. Gray-Schopfer V, Wellbrock C, Marais R (2007) Melanoma biology and new targeted therapy. Nature 445:851–857CrossRefPubMedGoogle Scholar
  7. Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD, Vojtek AB (2000) Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem 275:27354–27359PubMedGoogle Scholar
  8. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedPubMedCentralGoogle Scholar
  9. Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J et al. (2009) Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res 69:3042–3051CrossRefPubMedGoogle Scholar
  10. Huebner K, Griffin CA, Isobe M, Kozak C, Emanuel BS, Nagarajan L et al. (1986) Actively transcribed genes in the raf oncogene group, located on the X chromosome in mouse and human. Proc Natl Acad Sci USA 83:3934–3938CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hwang K, Park K, Lee C, Kim B (2002) Novel benzoylurea derivatives as potential antitumor agents; synthesis, activities and structure-activity relationships. Arch Pharm Res 25:781–785CrossRefPubMedGoogle Scholar
  12. Ikawa S, Fukui M, Ueyama Y, Tamaoki N, Yamamoto T, Toyoshima K (1988) B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol Cell Biol 8:2651–2654CrossRefPubMedPubMedCentralGoogle Scholar
  13. Imielinski M, Cha S, Rejtar T, Richardson EA, Karger BL, Sgroi DC (2012) Integrated proteomic, transcriptomic, and biological network analysis of breast carcinoma reveals molecular features of tumorigenesis and clinical relapse. Mol Cell Proteom 11:M111–14910CrossRefGoogle Scholar
  14. Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351:289–305CrossRefPubMedPubMedCentralGoogle Scholar
  15. Lee JH, Lee ES, Kim YS (2007) Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid. Cancer 110:38–46CrossRefPubMedGoogle Scholar
  16. Li Q, Li C, Lu X, Zhang H, Zhu H (2012) Design, synthesis and biological evaluation of novel (E)-α-benzylsulfonyl chalcone derivatives as potential BRAF inhibitors. Eur J Med Chem 50:288–295CrossRefPubMedGoogle Scholar
  17. Li Y, Nakamura M, Kakudo K (2009) Targeting of the BRAF gene in papillary thyroid carcinoma (Review). Oncol Rep 22:671–681PubMedGoogle Scholar
  18. Liu X, Cui P, Song B, Bhadury PS, Zhu H, Wang S (2008) Synthesis, structure and antibacterial activity of novel 1-(5-substituted-3-substituted-4, 5-dihydropyrazol-1-yl) ethanone oxime ester derivatives. Bioorg Med Chem 16:4075–4082CrossRefPubMedGoogle Scholar
  19. McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J et al. (2007) Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci 104:19936–19941CrossRefPubMedPubMedCentralGoogle Scholar
  20. Peyssonnaux C, Eychène A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62CrossRefPubMedGoogle Scholar
  21. Suijkerbuijk BM, Niculescu-Duvaz I, Gaulon C, Dijkstra HP, Niculescu-Duvaz D, Ménard D et al. (2010) Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group. J Med Chem 53:2741–2756CrossRefPubMedGoogle Scholar
  22. Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H et al. (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712CrossRefPubMedPubMedCentralGoogle Scholar
  23. Tuveson DA, Weber BL, Herlyn M (2003) BRAF as a potential therapeutic target in melanoma and other malignancies. Cancer Cell 4:95–98CrossRefPubMedGoogle Scholar
  24. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM et al. (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867CrossRefPubMedGoogle Scholar
  25. Wang S, Zhu Y, Zhu P, Makawana JA, Zhang Y, Zhao M, Lv P, Zhu H (2014) Design, synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAF V600E inhibitors. Bioorg Med Chem 22:6201–6208CrossRefPubMedGoogle Scholar
  26. Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Bio 5:875–885CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Zhen-Hua Gong
    • 1
  • Jian Yao
    • 1
  • Jian-Feng Ji
    • 1
  • Jun Yang
    • 1
  • Tie Xiang
    • 1
  • Chang-Kai Zhou
    • 1
  1. 1.Department of Burn and Plastic SurgeryThe First People Hospital of NantongNantongChina

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