Arzneimittelforschung 2012; 62(12): 637-643
DOI: 10.1055/s-0032-1329952
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Synthesis, Anti-hypertensive Effect of a Novel Angiotensin II AT1 Receptor Antagonist and its Anti-tumor Activity in Prostate Cancer

Y.-J. Da
1   Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China
,
W.-D. Yuan
1   Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China
,
L.-F. Zhu
1   Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China
,
Z.-L. Chen
1   Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China
› Author Affiliations
Further Information

Publication History

received 16 July 2012

accepted 15 October 2012

Publication Date:
30 November 2012 (online)

Abstract

Since the first non-peptide Ang II receptor antagonist was originally reported, it has become the most common target in the development of new treatments for hypertension. In recent years, all components of the classical RAS have been reported in the prostate, these results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer. In this study, a new compound 2-(4-((2-propyl-5-nitro-1H-benzo[d]imidazol-1-yl) methyl)-1H-indol-1-yl) benzoic acid was synthesized and evaluated as a novel angiotensin II AT1 receptor antagonist by radioligand binding assays, anti-hypertensive assays in vivo and oral acute toxicity test. MTT assays and tests in nude mice were used to demonstrate its anti-tumor activity. This new compound showed high affinity to AT1 receptor and anti-hypertensive activity in spontaneously hypertensive rats and renal hypertensive rats. Moreover, in human prostate cancer cells and in athymic nude mice bearing human prostate cancer cells, we observed this new compound had an efficient antiproliferative activity in vitro and anti-tumor activity in vivo. The preliminary pharmacological characteristics with oral acute toxicity test suggested that this new compound can be considered as a candidate for both anti-hypertensive and anti-tumor drug.

Supporting information

 
  • References

  • 1 Wexler RR, Greenlee WJ, Irvin JD et al. Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy. J Med Chem 1996; 39: 625
  • 2 Kirch W, Horn B, Schweizer J. Comparison of angiotensin II receptor antagonists. Eur J Clin Invest 2001; 31: 698-706
  • 3 Jin Y-X, Yi Z, Qian R et al. Synthesis and biological activity of 2-alkylbenzimidazoles bearing a N-phenylpyrrole moiety ad novel angiotensin II AT1 receptor antagonists. Bioorg Med Chem Lett 2007; 17: 2921-2926
  • 4 Uemura H, Kubota Y. Application of angiotensin II receptor blocker in prostate cancer. Nippon Rinsho 2009; 67: 807-811
  • 5 Fujimoto Y, Sasaki T, Tsuchida A et al. Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist. FEBS Lett 2001; 495: 197-200
  • 6 Fujita M, Hayashi I, Yamashina S et al. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun 2002; 441-447
  • 7 Rivera E, Arrieta O, Guevara P et al. AT1 receptor is present in glioma cells; its blockage reduces the growth of rat glioma. Br J Cancer 2001; 85: 1396-1399
  • 8 Uemura H, Ishiguro H, Kubota Y. Angiotensin II receptor blocker: possibility of antitumor agent for prostate cancer. Mini Rev Med Chem 2006; 6: 835-844
  • 9 Chow L, Rezmann L, Catt KJ et al. Role of the rennin-angiotensin system in prostate cancer. Mol Cell Endocrinol 2009; 302: 219-229
  • 10 Poss MA. Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives: E.P. Patent 0,488,532 1992
  • 11 Poss MA. Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives: U.S. Patent 5,208,235 1993
  • 12 Poss MA, Atwal KS. Indole and benzimidazole-substituted dihydropyrimidine derivatives: U.S. Patent 5,212,177 1993
  • 13 Spiegel S, Desai NN, Poss MA. Antihypertensive indole- and benzimidazole- substituted imidazole and bezimidazole derivatives. U.S. Patent 5,374,615 1994
  • 14 Kubo K, Kohara Y, Imamiya E et al. Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids. J Med Chem 1993; 36: 2182-2195
  • 15 Kohara Y, Kubo K, Imamiya E et al. Total Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. J Med Chem 1996; 39: 5228-5235
  • 16 Daljit S, Dhanoa S, Bagley W et al. Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles. J Med Chem 1993; 36: 4230-4238
  • 17 olguin L, Jimenez-Estrada M, Barzana E et al. Baker’s yeast-mediated regioselective reduction of 2, 4-dinitroacylanilines: synthesis of 2-substituted 6-nitrobenzimidazoles. Synlett 2005; 2: 340-342
  • 18 Xingping L, Qing L, Yanshan Z et al. Culture and Identification of Rat Vascular Smooth Muscle Cells. J Shantou Uni Med Col 2008; 21: 137-140
  • 19 Scatchard G. The attraction of proteins for small molecules and ions. Ann N Y Acad Sci 1949; 51: 660-672
  • 20 Hiroji U, Hitoshi I, Noboru N et al. Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: A possibility of tyrpsine kinase inhibitor of growth factor. Mol Cancer Ther 2003; 2: 1139-1147
  • 21 Kim S, Ohta K, Hamaguchi A et al. Angiotensin II type 1 receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995; 273: 509-515
  • 22 Kaur M, Velmurgan B, Rajamanikam S et al. Gallic Acid, an Active Constituent of Grape Seed Extract, Exhibits Anti-proliferative, Pro-apoptotic and Anti-tumorigenic Effects against Prostate Carcinoma Xenograft Growth in Nude Mice. Pharm Res 2009; 26: 2133-2140
  • 23 Samir KP. Ras regulation of DNA-methylation and cancer. Exp Cell Res 2008; 341: 1193-1201