Full Paper New Pyrimidinone and Fused Pyrimidinone Derivatives as Potential Anticancer Chemotherapeutics Aymn E. Rashad 1,2 , Ahmed H. Shamroukh 1,3 , Nabil M. Yousif 1 , Mowafia A. Salama 1 , Hatem S. Ali 4 , Mamdouh M. Ali 5 , Abeer E. Mahmoud 5 , and Mahmoud El-Shahat 1 1 National Research Center, Photochemistry Department, Dokki, Cairo, Egypt 2 Faculty of Science and Human Studies, Chemistry Department, Hurraiymla, Shaqra University, Saudi Arabia 3 Faculty of Science, Chemistry Department, Hail University, Saudi Arabia 4 Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, Saudi Arabia 5 National Research Center, Division of Genetic Engeneering and Biotechnology, Biochemistry Department, Dokki, Cairo, Egypt A series of novel substituted pyrimidinones and fused pyrimidinones (compounds 3–18) were synthesized starting with oxiranylmethanone 2. The in vitro cytotoxicity against a human breast adenocarcinoma (MCF-7) cell line was investigated and most of the tested compounds showed potent cytotoxic activity against the MCF-7 cell line comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF-7 cells with increasing doses (2, 5, 10, and 20 mg/mL) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF-7 cells. In general, derivatives 11 and 16 revealed the highest anticancer activity among the tested compounds. Keywords: Anticancer / Fused pyrimidinones / MCF-7 cells / Oxiranylmethanone / Pyrimidinone Received: March 25, 2012; Revised: April 28, 2012; Accepted: April 29, 2012 DOI 10.1002/ardp.201200119 Introduction Pyrimidinone and fused pyrimidinone derivatives are well known for their pharmacological properties [1, 2]. These com- pounds have therapeutic applications, as anticancer [3–10], interferon inducer [11], antiviral [12–15], anti-hypertensive [16, 17], hypoglycaemic [18, 19], anticonvulsive [20], anti-hista- minic [21], analgesic, and antiinflammatory drugs [22–25]. As cited above, the pyrimidinone and their analogue derivatives are present in many anticancer agents. In fact, it has been reported that these substances were proven to have significant activities against different types of human cancers, namely: leukemia, lung, liver, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer [3–10]. Because of the aforemen- tioned pharmacological potential of this class of compounds, our research group has been involved in synthesizing and testing the pharmacological activities of pyrimidinone and fused pyrimidinone derivatives, hoping that they could have some chemical and biological interest [4, 5, 14, 15, 26, 27]. Results and discussion Chemistry (2E)-1,3-Bis(4-chlorophenyl)-2-propen-1-one (1) was synthe- sized by the Claisen–Schmidt condensation method [28], which was performed with hydrogen peroxide in alkaline medium to produce (4-chlorophenyl)[3-(4-chlorophenyl)- oxiranyl]methanone (2) (Scheme 1). Analytical and spectral data of compound 2 are in agreement with the proposed structure (cf. Experimental section). Compound 2, as a typical epoxide, was utilized as a key starting material in the syn- thesis of many pyrimidinone derivatives. Thus, heating a Correspondence: Dr. Aymn E. Rashad, National Research Center, Photochemistry Department, Dokki, 12311 Cairo, Egypt. Faculty of Science and Human Studies, Chemistry Department, Hurraiymla, Shaqra University, Saudi Arabia E-mail: aymnelzeny@yahoo.com Fax: þ20 20337 0931 Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10 1 ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim