Novel Pyrazole Derivatives as Anticancer and Radiosensitizing Agents

Abstract

The present article describes the synthesis of some novel pyrrole, pyrazolo[4,3-d]oxazole, pyrrolo[2,3-b]pyridine, 1,2,3-triazole and oxoazetidin derivatives incorporating pyrazole moiety, the structures of which were confirmed by elemental analyses and spectral data. All the target compounds were subjected to in-vitro antitumor activity against liver and colon human tumor cell lines (HEPG2 and HCT), furthermore, the most potent compounds were evaluated for their ability to enhance the cell killing effect of γ-radiation (radiosensitizing evaluation). The results of in-vitro anticancer evaluation showed that compounds 3 and 16a were the most potent compounds on HEPG2 (IC₅₀=2.6 and 4.2 µg/ml) and compounds 2 and 10 were the most potent on HCT (IC₅₀=2.7 and 3.9 µg/ml) compared to vinblastine (IC₅₀=4.6 on HEPG2 and 2.6 µg/ml on HCT), while, the activity of the most potent compounds increased after combination with γ-radiation and they showed no toxicity on normal hepatocytes and colon cells at their effective concentrations.

Key words

pyrazoles - anticancer - radiosensitizing

• References

• 1 Wilson WL, Bottiglieri NG. Phase I studies with pyrazole. Cancer Chemother. Rep 1962; 21: 137-141
• 2 Foley HT, Shnider BI, Gold GL et al. Phase I studies with pyrazole (NSC-45410). Cancer Chemother Rep 1965; 44: 45-48
• 3 Ausman RK, Nadler S, Moore GE. thiocarzolamide (NSC-45409): A phase I study. Cancer Chemother. Rep 1963; 33: 41-43
• 4 Bouabdallah I, M’Barek LA, Zyad A et al. New pyrazolic compounds as cytotoxic agents. A. Nat Prod Res 2007; 21: 298-302
• 5 Havrylyuk D, Zimenkovsky B, Vasylenko O et al. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur J Med Chem 2009; 44: 1396-1404
• 6 Shaharyar M, Abdullah MM, Bakht MA et al. Pyrazoline bearing benzimidazoles: search for anticancer agent. Eur J Med Chem 2010; 45: 114-119
• 7 Lin R, Chiu G, Yu Y et al. Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors. Bioorg Med Chem Lett 2007; 17: 4557-4581
• 8 Pevarello P, Brasca MG, Amici R et al. 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. J Med Chem 2004; 47: 3367-3380
• 9 Kry V, Canka P, Fry-sová I et al. 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006. 49. 6500-6509
• 10 Squires MS, Feltell RE, Wallis NG et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Ther 2009; 8: 324-332
• 11 Moravcová D, Kry-stof V, Havlícek L et al. Pyrazolo[4,3-d]pyrimidines as new generation of cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett 2003; 13: 2989-2992
• 12 Regan J, Breitfelder S, Cirillo P et al. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J Med Chem 2002; 45: 2994-3008
• 13 Howard S, Berdini V, Boulstridge JA et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem 2009; 52: 379-388
• 14 Sawyer JS, Anderson BD, Beight DW et al. Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem 2003; 46: 3953-3956
• 15 Wasylyk C, Zheng H, Castell C et al. Inhibition of the Ras-Net (Elk-3) pathway by a novel pyrazole that affects microtubules. Cancer Res 2008; 68: 1275-1283
• 16 Ghorab MM, Ragab FA, Heiba HI et al. Synthesis of some new pyrazole and pyrimidine derivatives carrying a sulfonamide moiety of expected antitumor activity and study of the synergistic effect of gamma-irradiation. Arzneimittelforschung 2010; 60 (01) 48-55
• 17 Ghorab MM, Heiba HI, Hassan AA et al. Antimicrobial evaluation of novel pyrrole, pyrazole, pyrimidine and pyrrolo[2,3-d]pyrimidine derivatives bearing sulfonamide moiety. J Am Sci 2011; 7 (01) 1063-1073
• 18 Ghorab MM, Ragab FA, Heiba HI et al. Synthesis of Novel Pyrazole and Pyrimidine derivatives bearing Sulfonamide moiety as antitumor and radiosensitizing agents. Med Chem Res.
• 19 Aly HM. Synthesis and antitumor activity of some novel pyrazole and thienopyrimidine derivatives. Phosphorous. Sulfur and Silicon 2010; 185: 211
• 20 Aly HM. Novel Pyrrolidinone and Pyrazolo[1,5-a][1,3,5]triazine Derivatives Bearing Biologically Active Sulfamoyl Moiety as a New Class of Antitumor Agents. Monatsch. Chem 2011; 142: 935
• 21 Aly HM, Saleh NM, Elhady HA. Design and Synthesis of Some New Thiophene, Thienopyrimidine and Thienothiadiazine Derivatives of Antipyrine as Potential Antimicrobial Agents. Eur J Med Chem 2011; 46: 4566-
• 22 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol. Methods 1983; 65: 55-63
• 23 Vijayan P, Raghu C, Ashok G et al. Antiviral activity of medicinal plants of Nilgiris. Indian J Med Res 2004; 120: 24-29
• 24 Dong HS, Wang B. The synthesis and crystal structure of new 3,6-bis[1-(4-ethoxyphenyl)-5-methyl-1,2,3- triazol-4-yl]-s-triazolo[3,4-b]-1,3,4-thiadiazole. J Chem. Cryst 2005; 35 (01) 61-65
• 25 Pokhodylo NT, Matiychuk VS, Obushak MD. Synthesis of ethyl 4,5-disubstited 2-azido-3-thiophenecarboxylates and use in the synthesis of thieno[3,2-e][1,2,3-triazolo[1,5-a]pyrimidin-5(4H)-ones. Tetrahedron 2009; 65: 2678-2683
• 26 Noolvi M, Agrawal S, Patel H et al. Synthesis, antimicrobial and cytotoxic activity of novel azetidine-2-one derivatives of 1H-benzimidazole. Arabian Journal of Chemistry. 2011
• 27 Halve AK, Bhadauria D, Dubey R. N/C-4 substituted azetidin-2-ones: Synthesis and preliminary evaluation as new class of antimicrobial agents. Bioorg Med Chem Lett 2007; 17: 341-345
• 28 Kumar A, Rajput CS, Bhati SK. Synthesis of 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-[(substituted azetidinone/thiazolidinone)-aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory agent. Bioorg Med Chem 2007; 15: 3089-3096
• 29 Nishimura Y. Rationale for chemoradiotherapy. Int Clin Oncol 2004; 9: 414-420
• 30 Bartelink H, Schellens JHM, Verheij M. The combined use of radiotherapy and chemotherapy in the treatment of solid tumors. Eur J Cancer 2002; 38: 216-222