1. Nehad A. El Sayed, Amal A. H. Eissa, Reem K. Arafa and Ghada F. El Masry* Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University 1- Abstract DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL QUINAZOLINE DERIVATIVES AS ANTINEOPLASTIC AGENTS. 3- Synthesis Methodology Cancer is continuing to be a major health problem worldwide. Quinazolines have been exploited as protein kinase inhibitors effective as cytotoxic agents. In the present study two isosteric series of quinazoline derivatives viz 6-iodo-2-(pyridin-3-yl)-3-substitutedquinazolin-4(3 H )-one and their 2- (pyridin-4-yl) counterparts were synthesized and evaluated for their in-vitro antitumor activity employing a 60 cell lines panel assay. The target compounds were found to be active against ABL and ALK kinases displaying IC 50 values ranging from 17 to 323 nM. 4- Biological Evaluation 4- SAR The novel synthesized quinazoline derivatives were tested against 150 kinases and were found to be active against ABL. They were also screened against 60 cancer cell lines, CCRF-CEM and K562 were most responsive to the tested compounds. Docking showed that these compounds bind well in the active site of ABL. Rational approach and biological findings enabled the understanding of the pharmacophoric requirement for quinazoline derivatives. The overall outcome of these findings revealed that: (i) the quinazoline ring is satisfactory backbone for antitumor activity, (ii) the presence of hydrophobic group at 3 position of quinazoline enhances the activity. These preliminary encouraging results of biological screening of the tested compounds could offer an excellent framework in this field that may lead to discovery of potent antitumor agents.. 6- Conclusion 6- References Enzyme inhibition assay was conducted for screening of the targeted quinazolinone compounds 8a-l, 9a-n against a panel of 150 kinases and their IC 50 values were determined against the most sensitive kinase in this study which was ABL. The synthesized target compounds were also evaluated for their antitumor activity against 60 cell lines from which CCRF-CEM and K562 cell lines were the most responsive as expected from their known over-expression of ABL. ( Table1 ) As shown in Table1, all the targeted quinazolinone compounds 8a-l, 9a-n displayed moderate to high cytotoxic activity against CCRF-CEM and K562 cancer cell lines. Concerning quinazolinone derivatives 8a-l : replacement of the pyridin-3-yl moiety (8a-f ) with pyridin-4-yl moiety (8g-l) didn’t cause significant effect on the antitumor activity against leukemia cell lines. Regarding the effect of substitution pattern on the ureido/ thioureido moiety (CCRF-CEM cell line), the cyclohexyl derivatives (8c and 8i) exhibited higher activity compared to their phenyl counter parts (8e and 8K). On the contrary the cyclohexyl derivatives (8b and 8h) did not display increased cytotoxicity in comparison with the phenyl derivatives (8d and 8j), this might be attributed to the replacement of the thioxo moiety in compounds (8c and 8i) with the carbonyl moiety (compounds 8b and 8h). Exploring the effect of different substituents at position 4 on the 3-(benzylidene)amino moiety of the 6-iodo-2-(pyridin-3-yl)quinazoline scaffold (9a-g), revealed that the introduction of 2-chloro benzylideneamine group at 3 position of quinazoline markedly increased the activity that results into the potent compound 9b. 2-Introduction and aim Protein kinase has been identified as interesting target for medicinal chemistry programs especially in cancer therapy. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. Kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction. Deregulated kinase activity or kinase over expression has been associated with a number of cancers, including non-small cell lung, breast, ovarian and colon cell cancers [1] Much attention has been paid to the development of kinase inhibitors as anticancer agents. Among the KIs, different quinazoline derivatives have been intensively studied, leading to a number of active molecules [2]. In this investigation two isosteric series of quinazoline derivatives with tyrosine kinase inhibitory effect viz 6-iodo-2-(pyridin-3-yl)-3-substituted quinazolin-4(3 H )-one and their 2-(pyridin- 4-yl) counterparts were synthesized and evaluated for their antitumor activity. Compound Number IC 50 (nM) Compound Number IC 50 (nM) ABLCCRF-CEMK562ABLCCRF-CEMK562 8a54 57.5069.6 9b24 13.5515.65 8b43 48.4087 9c35 44.3446.7 8c66 39.5076.5 9d39 24.4625.5 8d76 48.6065 9e48 33.4336.6 8e68 56.7954 9f26 34.4737.8 8f43 46.6050.5 9g20 35.4775.5 8g44 57.9034.4 9h36 54.6695.34 8h33 45.7023.5 9i18 45.5884.34 8i26 33.5036.67 9j21 43.5475.54 8j32 34.4047.8 9k46 56.5754.45 8k47 45.5048.4 9l39 45.6665.45 8l55 46.8045.5 9m40 54.4556.67 9a17 25.4626.87 9n55 47.8843 Table1 5-Molecular Modeling against ABL Molecular docking was performed in the active site of ABL ((PDB ID: 2HZI) and the compounds were found to recognize the active site amino acids of ABL as indicated in Figure1(3D interaction of compound 9b) and Figure2 (2D interaction of compound 9b). 1- Manning, G., Whyte, D. B., Martinez, R., Hunter, T., Sudarsanam, S., Science, 2002, 298 ; 1912-1934. 2- Lü, S., Zheng, W., Ji, L., Luo, Q., Hao, X., Li, X., Wang, F., Eur J Med Chem, 2012, 61; 84-94. 2D