Arch Pharm Res Vol 35, No 1, 35-49, 2012 DOI 10.1007/s12272-012-0104-0 35 3,5-Disubstituted Thiadiazine-2-thiones: New Cell-Cycle Inhibitors Awwad A. Radwan 1,5 , Abdullah Al-Dhfyan 2 , Mohammed K. Abdel-Hamid 3 , Abdullah A. Al-Badr 4 , and Tarek Aboul-Fadl 3,4 1 Pharmaceutical Technology Center, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia, 2 Stem Cell Therapy Program, King Faisal Specialized Hospital and Research Center, Riyadh 11211, Saudi Arabia, 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt, and 4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia, and 5 Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt (Received May 17, 2011/Revised July 25, 2011/Accepted July 26, 2011) Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H- 1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position- 3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC 50 = 8.98 µM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was gener- ated with a good correlation with the observed activity. Key words: Tetrahydro-2H-1,3,5-thiadiazine-2-thiones, Cell-cycle inhibitors, Antiproliferative, Apoptosis, Pharmacophore, Molecular modeling INTRODUCTION Unlimited and uncontrolled cell proliferation is a characteristic of tumor cells (Lopez-Saez et al., 1998; Rew and Wilson, 2000). Interruption of cell cycle has a crucial role in cancer progression (Hartwell and Kastan, 1994). As a result, carcinogenesis can be controlled by agents that can affect cell proliferation. Various natural and synthetic agents are gaining widespread attention due to their cell cycle regulation and modulation activities (Agarwal, 2000; Agarwal et al., 2000; Weinstein, 2000; Chinni et al., 2001; Moragoda et al., 2001; Donato et al., 2002; Katdare et al., 2002; Lin, 2002; Lin et al., 2002; Park et al., 2002; Singh et al., 2002; Sun et al., 2002; Tyagi et al., 2002; Chinami et al., 2005). In fact, all the suspected contributory factors for oncogenesis and mutagens, such as viruses and inherited predisposing factors, impair the G1 checkpoint function. Consequently, more than half of all human cancer cells with impaired G1 checkpoint function rely on the G2 checkpoint to survive against the DNA damage caused by most cytotoxic cancer treatments. The G2 cell cycle checkpoint is rarely used by normal cells, which makes a cell cycle G2 checkpoint abrogation strategy attractive against cancer (Dixon and Norbury, 2002; Kawabe, 2004). From a medicinal chemistry point of view, synthetic small molecule modulators of the G2/M checkpoint are of particular interest. Several clinically important anticancer com- pounds, such as vinca alkaloids and taxanes, are effec- tive in controlling some cancer types through their prominent inhibition of G2/M transition. Nonetheless, all these compounds can disrupt tubulin directly; they have complex chemical structures that restrict possible chemical modifications. In addition, several prominent disrupters of tubulin, such as nocodazole and colchicine, lack antitumor efficacy. Therefore, novel chemical struc- tures that block G2/M phase transition are valuable Correspondence to: Tarek Aboul-Fadl, Department of Pharma- ceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia Tel: 966-1-467-7341, Fax: 966-1-467-6220 E-mail: fadl@ksu.edu.sa