title: 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.
authors.affiliation: Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: M S
authors.initials: MS
authors.lastname: El-Said
authors.forename: M G
authors.initials: MG
authors.lastname: El-Gazzar
authors.forename: M S
authors.initials: MS
authors.lastname: Al-Dosari
authors.forename: M M
authors.initials: MM
authors.lastname: Ghorab
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005720:Gamma Rays; D056945:Hep G2 Cells; D006801:Humans; D007202:Indicators and Reagents; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011728:Pyridones; D011838:Radiation-Sensitizing Agents; D004317:Doxorubicin