Synthesis, Anticancer Activity and Radiosensitizing Evaluation of Some New 2-Pyridone Derivatives

Abstract

Based on the reported anticancer activity of 2-pyridone, a new series of 6-amino-5-cyano-1-(3-ethylphenyl)-2-oxo-4-substituted-1,2-dihydropyridine-3-carbo-nitriles 4a-p were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line and liver human tumor cell line (HEPG2). Radiosensitizing activity was also evaluated. The starting material 2-cyano-N-(3-ethylphenyl)-acetamide 3 was obtained via reaction of 3-ethyl aniline 1 with ethyl cyanoacetate under condition of fusion. Upon treatment of compound 3 with aromatic aldehyde and malononitrile in the presence of catalytic amount of piperidine yielded the corresponding 1,2-dihydropyridine derivative 4a-p. Also chromenes 5 and 6 were obtained in good yield via reaction of compound 3 with salicyladehyde under different condition. The chromene derivatives 5 and 6 were further reacted with malononitrile in NH₄OAc, afford the corresponding chromenopyridones 7 and 8. The structures of the synthesized compounds 3–8 were confirmed by analytical and spectral data. Compounds 4d, 4e, 5 and 6 showed higher anticancer activity against EAC cell line with IC₅₀ values (75.32, 20.77, 73.1 and 67.05 µM) compared to doxorubicin as positive control with IC₅₀ value (68.13 µM), moreover, these compounds showed potent activity on HEPG2 cell line with IC₅₀ values (26.5, 19.2, 39.3, 44.9 µM), respectively, compared to doxorubicin (CAS 29042-30-6) (38.46 µM) and their activity increased synergistically when combined with γ-radiation.

Key words

synthesis - 2-pyridone - anticancer - γ-radiation

• References

• 1 Abadi AH, Ibrahim TM, Abouzid KM et al. Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors. Bioorg Med Chem 2009; 17: 5974-5982
• 2 Cheney IW, Yan S, Appleby T et al. Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase. Bioorg Med Chem Lett 2007; 17: 1679-1683
• 3 Wendt MD, Sun C, Kunzer A et al. Discovery of a novel small molecule binding site of human survivin. Bioorg Med Chem Lett 2007; 17: 3122-3129
• 4 Aqui NA, Vonderheide RH. Survivin as a universal tumor antigen for novel cancer immunotherapy: functions of a killer clone. Cancer Biol Ther 2008; 7: 1888-1889
• 5 Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3: 917-921
• 6 Gary P, Soh JW, Mao Y et al. Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res 2000; 6: 4136-4141
• 7 Cheng J, Grande JP. Cyclic Nucleotide Phosphodiesterase (PDE) Inhibitors: Novel Therapeutic Agents for Progressive Renal Disease. Exp Biol Med. 2007. 232. 38-51
• 8 Murata T, Shimizu K, Narita M et al. Characterization of phosphodiesterase 3 in human malignant melanoma cell line. Anticancer Res 2002; 22: 3171-3174
• 9 Murata T, Sugatani T, Shimizu K et al. Phosphodiesterase 3 as a potential target for therapy of malignant tumors in the submandibular gland. Anticancer Drugs 2001; 12: 79-83
• 10 Moon E, Lee R, Near R et al. Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia. Clin Cancer Res 2002; 8: 589-595
• 11 Ghorab MM, Ragab FA, Hamed MM. Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety. Eur J Med Chem 2009; 44: 4211-4217
• 12 Al-Said MS, Ghorab MM, Al-qasoumi SI et al. Synthesis and in vitro anticancer screening of some novel 4-[2-amino-3-cyano-4-substituted-5,6,7,8-tetrahydroquinolin-1-(4H)-yl]benzenesulfonamides. Eur J Med Chem 2010; 45: 3011-3018
• 13 Al-qasoumi SI, Al-Taweel AM, Alafeey AM et al. Synthesis and biological evaluation of 2-amino-7,7-dimethyl 4-substituted-5-oxo-1-(3,4,5-trimethoxy)-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile derivatives as potential cytotoxic agents. Bioorg Med Chem Lett 2009; 19: 6939-6942
• 14 Ghorab MM, Ragab FA, Al-qasoumi SI et al. Synthesis of some new pyrazolo[3,4-d]pyrimidine derivatives of expected anticancer and radioprotective activity. Eur J Med Chem 2010; 45: 171-178
• 15 Al-gasouni SI, Al-Taweel AM, Al-afeefy AM et al. Novel quinolines and pyrimido[4,5-b]quinolines bearing biologically active sulfonamide moiety as a new class of antitumor agents. Eur J Med Chem 2010; 45: 738-744
• 16 Al-qasoumi SI, Al-Taweel AM, Alafeefy AM et al. Discovering some novel tetrahydroquinoline derivatives bearing the biologically active sulfonamide moiety as a new class of antitumor agents. Eur J Med Chem 2010; 45: 1849-1853
• 17 Devi PU, Solomon FE, Sharada AC. Plumbagin, a plant naphthoquinone with antitumor and radiomodifying properties. Pharm Biol 1999; 37 (03) 231-236
• 18 Brusick DJ. Cytogenetic Assays, Aberrations, and SCE Techniques in Carcinogenesis and Mutagenesis Testing. Human Press Inc.; Clifton, New Yersey: 1984. pp 265-276
• 19 Skehan P, Storeng R, Scudiero D et al. New calorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990; 82: 1107-1112
• 20 Nishimura Y. Rationale for chemoradiotherapy. Int J clin Oncol 2004; 9: 414-420