REV. CHIM. (Bucharest) ♦ 65♦ No.5 ♦ 2014 http://www.revistadechimie.ro 560 Antitumor Activity of Tetra-Substituted Zinc Phthalocyanines Containing 4(3H)-Quinazolinone Derivatives TAMER E. YOUSSEF 1,2 *, YAHIA A. ALHAMED 1 , SAAD S. AL-SHAHRANI 1 , KORANY A. ALI 2 1 Chemical & Materials Engineering Department ,Faculty of Engineering, King Abdulaziz University, P. O. Box 80204, Jeddah, 21589, Saudi Arabia. 2 Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt. Series of tetra-substituted zinc(II)phthalocyanines (ZnPcs) bearing four 4(3H) quinazolinone ring system units (qz) 4 ZnPcs 4a-c have been synthesized and characterized. They were screened for their in-vitro antitumor activity on Human lung adenocarcinoma (A549), human breast adenocarcinoma (MCF-7) and Hepatocellular carcinoma (HEPG2). Preliminary study of the structure–activity relationship showed that electronic factors in the 4(3H)-quinazolinone moiety that attached to the ZnPc skeleton had a magnificent effect on the antitumor activity of the newly synthesized (qz) 4 ZnPcs 4a-c. They showed promising anticancer activity against the tested human cancer cell lines. The detailed synthesis, characterization and biological screening data were reported. Keywords: 4(3H)-quinazolinone, zinc(II)phthalocyanines, hetero-substituted phthalocyanines, anticancer activity, biological targeting agents. Different series of Zinc phthalocyanines (ZnPcs) were used as valuable photosensitizers for photodynamic therapy of cancer (PDT) [1-5]. Until now, great variety of ZnPc derivatives functionalized with substituted heterocycles such as pyridyloxy, 4-pyridylmethyloxy [6] and oxyquinoline groups [7] have been offered potent PDT properties. Another derivatives of ZnPcs with multiple functional groups have been received attention as anticancer agents due to their photophysical and photochemical properties (e.g., tetracarboxy zinc phthalocyanine[8], pentalysine peptidyl moiety(ZnPc-(Lys) 5 ) [9], hexadecafluoro zinc phthalo- cyanine[10] and adamantylethoxy zinc phthalocyanines) [11]. Unfortunately, limitations of PDT of cancer have been found in previous studies [12] . It was shown that the ZnPc photosensitiser drugs require cellular oxygen to kill cancer cells via the formation of singlet oxygen. Moreover, they worked only on the area which was exposed to light. Therefore, when cancer spread in the body, it cannot be treated completely. In this regard, new hypoth has been studied in the present work dealing with the combinations of chemotherapy of ZnPcs and 4(3H)-quinazolinone derivatives (which will most likely result in the enhance of their anticancer efficiency for the treatment of metastasized and localized cancers).4(3 H )-Quina- zolinones are known to posses interesting drugs with diverse biological activities. They were used to modify the biological properties of several other compounds. The major effective biological activities and pharmacological properties of their derivatives include: anti-inflammatory activity [13-15], sedative [16], antimalarial [17], CNS depressant[18] analgesic [19], anticonvulsant [20], antidiabetic [21,22], antitubercular and antibacterial effects [23], antihypertensive[24], antiviral [25] and cancer chemotherapy [26-28]. The value of the 4(3H)- quinazolinone ring system derivatives as antitumor agents in drug design was also recognized [29-33]. Additionally, some researchers have reported the importance of different quinazolinone derivatives with potent antitumor activities * email: tamezzat@yahoo.com; Tel.: + 966538952007 such as, quinazolinones bearing thioureido[34] or thiazolidinone [35,36]. Earlier, Youssef et al. [37-42] have described novel symmetrically and asymmetrically Pcs with differently peripheral substitution and axial ligands for potential applications. The authors have also described the synthesis of NiPcs bearing heterocyclic moieties for pharmaceutical application [43]. In connection with a previous work and our current interest in the synthesis of organic compounds for biological evaluations [44-49]. We described herein a facile convenient synthesis of novel tetra substituted zinc phthalocyanines based on heterocyclic moiety (i.e 4(3H)-quinazolinone ring system, (qz) 4 ZnPcs (4a-c). To the best of our knowledge, this is the first report which aims to modify the structural activity of zinc(II)phthalocyanines by combining them with four 4(3H)-quinazolinone units and evaluates their parameters required for the structure-function relationship for cancer therapy. The biological screening results obtained for the newly (qz) 4 ZnPcs 4a-c showed a promising anticancer activity in vitro. Experimental part Materials and methods All reagents and solvents were commercial reagent grade and used without further purification. The following chemicals were purchased commercially from Aldrich and used as received: 4-nitrophthalonitrile, 2-Methyl-4(3H)- quinazolinone, 2-phenyl-4(3 H)-quinazolinone and 2- mercapto-4(3H)-quinazolinone. Solvents (GR grade) from Merck (Darmstadt, Germany) were distilled. Silica gel thin- layer chromatography (TLC) plates 250 microns from Analtech (Newark, DE, USA) were used. Physical characterizations Melting points were determined by the open capillary method and were uncorrected. Infrared spectra were recorded on a Nicolet Magna 560 spectrophotometer in the spectral range 4000–400 cm -1 using KBr pellets. 1 H NMR