Download PDF
Arzneimittelforschung 2012; 62(02): 63-74
DOI: 10.1055/s-0031-1295483
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Design, Synthesis and Evaluation of Novel Benzimidazoles, Benzothiazoles and Benzofurans Incorporating Pyrazole Moiety as Antiangiogenic Agents

S. M. Rida
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
,
A. M. Youssef
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
,
M. H. Badr
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
,
A. Malki
2   Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
,
Z. A. Sherif
3   Department of Oncology, Georgetown University Medical Center, Washington DC, USA
,
A. S. Sultan
2   Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
3   Department of Oncology, Georgetown University Medical Center, Washington DC, USA
› Author Affiliations
Further Information

Publication History

received 12 August 2011

accepted 07 November 2011

Publication Date:
16 February 2012 (online)

   Permissions and Reprints

Abstract

Novel benzimidazoles, benzothiazoles and benzofurans incorporating pyrazole moiety have been synthesized and screened for their antiangogenic activities, by testing their ability to inhibit human umbilical vein endothelial cell (HUVEC) proliferation, cord formation and migration in response to chemoattractant. 3 compounds 19, 23 and 26 showed antiangiogenic activities at non-cytotoxic concentrations. Compound 19 was the most active with chemotaxis activity data nearly comparable to that of the positive control, TNP-470. Compound 42 showed a significant cytotoxic effect on the tested cancer cell lines and less antiangiogenesis activity compared to compounds 19, 23 and 26. All the tested compounds, in contrary to TNP-470, interfered with the migratory function of HUVECs in response to vascular endothelial growth factor rather than the endothelial cells proliferation or cord formation. Moreover, a docked pose of compounds 19 and 26 was obtained bound to kinase insert domain receptor using Molecular Operating Environment module.

Key words

Benzimidazole - benzothiazole - benzofuran and pyrazole derivatives - human umbilical vein endothelial cell (HUVEC) - vascular endothelial growth factor receptor (VEGF-2) - Antiangiogenic activity - Antiproliferative effect
 

  • References

  • 1 Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 2002; 29 (Suppl. 16) 10-14
    PubMedSearch in Google Scholar
  • 2 Fava GA. Affective disorders and endocrine diseases. New insights from psychosomatic studies. Psychosomatics 1994; 35: 341-353
    CrossrefPubMedSearch in Google Scholar
  • 3 Wash DA. Angiogenesis and arthritis. Rheumatology 1999; 38: 103-112
    CrossrefPubMedSearch in Google Scholar
  • 4 Detmar M. The role of VEGF and thrombospondins in skin angiogenesis. J Dermatol Sci 2000; 24 (Suppl. 01) S78-S84
    CrossrefPubMedSearch in Google Scholar
  • 5 Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999; 5: 1359-1364
    CrossrefPubMedSearch in Google Scholar
  • 6 Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29 (Suppl. 16) 15-18
    PubMedSearch in Google Scholar
  • 7 Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 1999; 56: 794-814
    CrossrefPubMedSearch in Google Scholar
  • 8 O’Reilly MS, Holmgren L, Shing Y et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315-328
    CrossrefPubMedSearch in Google Scholar
  • 9 Ishigami SI, Arii S, Furutani M et al. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 1998; 78: 1379-1384
    CrossrefPubMedSearch in Google Scholar
  • 10 Folkman J. Fighting cancer by attacking its blood supply. Scientific American 1996; 275: 150-153
    CrossrefPubMedSearch in Google Scholar
  • 11 Kerbel RS. Clinical trials of antiangiogenic drugs: opportunities, problems, and assessment of initial results. J Clin Oncol 2001; 19: 45s-51s
    PubMedSearch in Google Scholar
  • 12 Yoshida A, Anand-Apte B, Zetter BR. Differential endothelial migration and proliferation to basic fibroblast growth factor and vascular endothelial growth factor. Growth Factors 1996; 13: 57-64
    CrossrefPubMedSearch in Google Scholar
  • 13 Lang Z, Guerrera M, Li R et al. Ganglioside GD1a enhances VEGF-induced endothelial cell proliferation and migration. Biochem Biophys Commun 2001; 282: 1031-1037
    CrossrefPubMedSearch in Google Scholar
  • 14 Veikkola T, Karkkainen M, Claesson-Welsh L et al. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000; 60: 203-212
    PubMedSearch in Google Scholar
  • 15 Shinkaruk S, Bayle M, Lain G et al. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anti-Cancer Agents 2003; 3 () 95-117
    CrossrefPubMedSearch in Google Scholar
  • 16 Harris PA, Boloor A, Cheung M et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 2008; 51: 4632-4640
    CrossrefPubMedSearch in Google Scholar
  • 17 Loges S, Mazzone M, Hohensinner P et al. Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited. Cancer Cell 2009; 15 () 167-170
    CrossrefPubMedSearch in Google Scholar
  • 18 Douglas NC, Tang H, Gomez R et al. Vascular endothelial growth factor receptor 2 (VEGFR-2) functions to promote uterine decidual angiogenesis during early pregnancy in the mouse. Endocrinology 2009; 150 () 3845-3854
    CrossrefPubMedSearch in Google Scholar
  • 19 Kang KB, Zhu C, Yong SK et al. Enhanced sensitivity of celecoxib in human glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cycle arrest and autophagy. Mol Cancer 2009; 8: 66-81
    CrossrefPubMedSearch in Google Scholar
  • 20 Davies NM, Gudde TW, AWC de Leeuw M. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert opin Pharmacother 2001; 2: 139-152
    CrossrefPubMedSearch in Google Scholar
  • 21 Swamy MV, Herzog CR, Rao CV. Inhibition of COX-2 in colon cancer cell lines by celecoxib increases the nuclear localization of active p53. Cancer Res 2003; 63: 5239-5242
    PubMedSearch in Google Scholar
  • 22 Abadi AH, Eissa AAH, Hassan GS. Synthesis of novel 1,3,4-trisubstitutes pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents. Chem Pharm Bull 2003; 51: 838-844
    CrossrefPubMedSearch in Google Scholar
  • 23 Potashman MH, Bready J, Coxon A et al. Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial frowth factor-2 receptor tyrosine kinase inhibitors. J Med Chem 2007; 50: 4351-4373
    CrossrefPubMedSearch in Google Scholar
  • 24 Hasegawa M, Nishigaki N, Washio Y et al. Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors. J Med Chem 2007; 50: 4453-4470
    CrossrefPubMedSearch in Google Scholar
  • 25 Hori A, Imaeda Y, Kubo K et al. Novel benzimidazole derivatives selectively inhibit endothelial cell growth and supress angiogenesis in vitro and in vivo. Cancer Lett 2002; 183: 53-60
    CrossrefPubMedSearch in Google Scholar
  • 26 Amino N, Ideyama Y, Yamano M et al. YM-201627: An orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation. Cancer Lett 2006; 238: 119-127
    CrossrefPubMedSearch in Google Scholar
  • 27 Chen P. p-Nitrobenzohydrazide as a reagent for the identification of aldehydes and ketones. J Chin Chem Soc 1935; 3: 251-255
    PubMedSearch in Google Scholar
  • 28 Mahadevan KM, Kumar DB, Prakash GK et al. Synthesis and antimicrobial investigation of some novel phenylpyrazole, azetidinone and diazenyl ethanone derivatives of benzofurans. Indian J Chem B 2007; 46B: 336-343
    PubMedSearch in Google Scholar
  • 29 Belotti D, Vergani V, Drudis T et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 1996; 2: 1843-1849
    PubMedSearch in Google Scholar
  • 30 Tarabolleti G, Micheletti G, Rieppi M et al. Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative. Clin Cancer Res 2002; 8: 1182-1188
    PubMedSearch in Google Scholar
  • 31 Sultan AS, Xie J, LeBaron MJ et al. Stat5 promotes homotypic adhesion and inhibits invasive characteristics of human breast cancer cells. Oncogene 2005; 24: 746-760
    CrossrefPubMedSearch in Google Scholar
  • 32 Bernard M, Hulley E, Molenda H et al. Azoles. 17. Beta-(4-pyrazol)acrylic and propionic acids and their anti-inflammatory activity. Pharmazie 1986; 41: 560-562
    PubMedSearch in Google Scholar
  • 33 Rathelot P, Azas N, El-Kashef H et al. 1,3-Diphenylpyrazoles: synthesis and antiparasitic activities of azomethine derivatives. Eur J Med Chem 2002; 37: 671-679
    CrossrefPubMedSearch in Google Scholar
  • 34 Rida SM, Saudi MNS, Youssef AM et al. Synthesis and biological evaluation of the pyrazole class of cyclooxygenase-2-inhibitors. Lett Org Chem 2009; 6: 282-288
    CrossrefPubMedSearch in Google Scholar
  • 35 Kira MA, Abdel-Rahman MO, Gadalla KZ. The Vilsmeier reaction-III, cyclization of hydrazones to pyrazoles. Tetrahedron Lett 1969; 10: 109-110
    CrossrefPubMedSearch in Google Scholar
  • 36 Elliott ED. The preparation and properties of 2-vinylbenzofuran. J Am Chem Soc 1951; 73: 754-
    CrossrefPubMedSearch in Google Scholar
  • 37 Molecular Operating Environment (MOE) 2009.10, Chemical Computing Group Inc., 1010 Sherbrooke Street West, Suite 910, Montréal, H3A 2R7, Canada < http://www.chemcomp.com/ >
    PubMed