JCT  Vol.1 No.1 , March 2010
Synthesis, Characterization and Anti-Angiogenic Effects of Novel 5-Amino Pyrazole Derivatives on Ehrlich Ascites Tumor [EAT] Cells in-Vivo
Abstract: In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multi-stage carcinogenesis, we synthesized a series of novel 5-amino pyrazole derivatives 11(a-h) by a nucleophilic substitution reaction and characterized by 1H nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting Ehrlich ascites tumor [EAT] cells in-vivo. In the present study we designed, synthesized, characterized and investigate the anti-angiogenic effects of these compounds, on Ehrlich ascites tumor [EAT] cells in-vivo. The compounds were subsequently tested for their ability to inhibit neovascularisation in chorio allantoin membrane (CAM) model. From the Structure Activity Relationship (SAR) studies, it reveals that, the substitution at N-terminal in pyrazole ring plays key role in the antitumor and anti-angiogenic effects.
Cite this paper: H. Raju, S. Chandrappa, M. Ramakrishna, T. Nagamani, H. Ananda, S. Byregowda and K. Rangappa, "Synthesis, Characterization and Anti-Angiogenic Effects of Novel 5-Amino Pyrazole Derivatives on Ehrlich Ascites Tumor [EAT] Cells in-Vivo," Journal of Cancer Therapy, Vol. 1 No. 1, 2010, pp. 1-9. doi: 10.4236/jct.2010.11001.

[1]   A. W. Griffioen and G. Molema, “Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation,” Pharmacol Reviews, Vol. 52, No. 2, pp. 237–268, 2000.

[2]   T. Vaios, Karathanos, and I. Mourtzinos, “Study of the solubility, antioxidant activity and structure of inclusion complex of vanillin with β-cyclodextrin,” Food Chemistry, Vol. 101, pp. 652–658, 2007.

[3]   A. Soumyakanti, I. P. Kavirayani, and T. Mukherjee, “Physico-chemical studies on the evaluation of the antioxidant activity of herbal extracts and active principles of some indian medicinal plants,” Journal of Clinical Biochemistry Nutrition, Vol. 40, No. 3, pp. 174–183, 2007.

[4]   L. Kriengsak, K. Jan-Peter, and S. Tuangporn, “Vanillin suppresses metastatic potential of human cancer cells through PI3K inhibition and decreases angiogenesis in vivo,” Journal of Agricultural and Food Chemistry, Vol. 57, No. 8, pp. 3055–3063, 2009.

[5]   C. Keshava, N. Keshava, O. Tong-man, and N. Joginder, “Protective effect of vanillin on radiation-induced micronuclei and chromosomal aberrations in V79 cells,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 397, pp. 149–159, 1998.

[6]   T. S. Daniel, S. Woodrow, and M. D. David, “The antimutagenic effect of vanillin and cinnamaldehyde on spontaneous mutation in Salmonella TA104 is due to a reduction in mutations at GC but not AT sites,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 480, pp. 55–69, 2001.

[7]   M. Baba, H. Konno, and S. B. Nakamura, “Relationship of p53 and vascular endothelial growth factor expression to clinicopathological factors in human scirrhous gastric cancer,” European Surgical Research, Vol. 30, pp. 130– 137, 1998

[8]   E. Akbas and I. Berber, “Antibacterial and antifungal activities of new pyrazolo [3, 4-d] pyridazin derivatives,” European Journal of Medicinal Chemistry, Vol. 40, pp. 401–408, 2005.

[9]   S. Y. Fulmer and O. C. Allen, “Synthesis, antileukemic activity, and stability of 3-(substituted-triazeno) pyrazole -4-carboxylic acid esters and 3-(substituted-triazeno) pyrazole-4-carboxamides,” Journal of Pharmaceutical Science , Vol. 60, No. 4, pp. 554–560. 1970.

[10]   Z. Ozdemir, H. B. Kandilici, B. Gumusel, U. Calis, and A. Bilgin, “Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives,” European Journal of Medicinal Chemistry, Vol. 42, pp. 373–379, 2007

[11]   B. S. Priya, C. Anil Kumar, S. NanjundaSwamy, Basappa., S. Naveen, J. ShashidharaPrasad, and K. S. Rangappa, “2-(2-(2-Ethoxybenzoyl amino)-4-chlorophenoxy)-N-(2-ethoxybenzoyl) benzamine inhibits EAT cell induced angiogenesis by down regulation of VEGF secretion,” Bioorganic & Medicinal Chemistry Letters, Vol. 17, pp. 2775–2780, 2007.

[12]   A. C. Sharada, F. E. Solomon, P. U. Devi, N. Udupa, and K. Srinivasan, “Antitumor and radiosensitizing effects of withaferin A on mouse ehrlich ascites carcinoma in vivo,” Acta Oncologica, Vol. 35, pp. 95–102, 1996.

[13]   G. Srinivas, R. JohnAnto, P. Srinivas, S. Vidyalakshmi, V. Priya Senan, and D. Karunagaran, “Emodin induces apoptosis of human cervical cancer cells through poly (ADP-ribose) polymerase cleavage and activation of caspase-9,” European Journal Pharmacol, Vol. 473, pp. 117– 125, 2003.

[14]   C. AnilKumar, Basappa, P. S. Bharathi, and K. S. Rangappa, “Pro-apoptotic activity of imidazole derivatives mediated by up-regulation of Bax and activation of CAD in Ehrlich Ascites Tumor cells,” Invest New Drugs, Vol. 25, pp. 343–350. 2007.

[15]   Z. Franco, P. Paola, P. Silvana, P. Graziella, S. Rosanna, and A. Federico, “Role of apoptotic response in cellular resistance to cytotoxic agents,” Pharmacology & Therapeutics, Vol. 76, No. 1, pp. 177–185, 1997.

[16]   K. Tetsuro, S. Kazunari, K. Hideaki, and M. Yukihisa, “Enhanced suppression of tumor growth by combination of angiogenesis inhibitor O-(Chloroacetyl-carbamoyl) fumagillol (TNP-470) and cytotoxic agents in mice,” Cancer Research, Vol. 54, pp. 5143–5147, 1994.

[17]   B. A. Teicher, S. A. Holden, G. Ara, T. Korbut, and K. Manon, “Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in Lewis lung carcinoma,” Cancer Chemothe Pharmacol, Vol. 38, pp. 169– 177, 1996.

[18]   S. Chandrappa, H. Chandru, A. C. Sharada, K. Vinaya, C. S. AnandaKumar, N. R. Thimmegowda, P. Nagegowda, M. Karuna Kumar, and K. S. Rangappa, “Synthesis and in vivo anticancer and antiangiogenic effects of novel thioxothiazolidin-4-one derivatives against transplantable mouse tumor,” Medicinal Chemistry Research (In press), 2009.

[19]   T. Browder, C. E. Butterfield, B. M. Kraling, B. Shi, B. Marshall, S. Michael, M. S. O’Reilly, and Folkman, “Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer,” Journal of Cancer Research, Vol. 60, pp. 1878–1886, 2000.

[20]   J. W. Rak, B. D. St Croix, and R. S. Kerbel, “Consequences of angiogenesis for tumor progression, metastasis and cancer therapy,” Anticancer Drugs, Vol. 6, No. 1, pp. 3–18, 1995.

[21]   Z. J. Shang, Z. B. Li, and J. R. Li, “VEGF is up-regulated by hypoxic stimulation and related to tumour angiogenesis and severity of disease in oral squamous cell carcinoma: In vitro and in vivo studies,” International Journal of Oral and Maxillofacial Surgery, Vol. 35, pp. 533–538, 2006.