Short communication Cell cycle disruption and apoptotic activity of 3-aminothiazolo[3,2-a] benzimidazole-2-carbonitrile and its homologues Abdelwareth A.O. Sarhan a , Abdullah Al-Dhfyan b , Maha A. Al-Mozaini b, c , Chaker N. Adra b, d , Tarek Aboul-Fadl e, f, * a Department of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt b Stem Cell Therapy Program, King Faisal Specialized Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia c Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA d Transplantation Research Center (TRC), Brigham & Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA, USA e Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt f Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia article info Article history: Received 8 September 2009 Received in revised form 26 January 2010 Accepted 9 February 2010 Available online 16 February 2010 Keywords: 3-Aminothiazolo[3,2-a]benzimidazole-2- carbonitrile Cytotoxic activity Cell cycle disruption G2/M phase Apoptosis abstract 3-Aminothiazolo[3,2-a]benzimidazole-2-carbonitrile (2) was prepared and upon hydrolysis using concentrated sulfuric acid or phosphoric acid resulted in the corresponding 3-aminothiazolo[3,2-a] benzimidazole-2-carboxamide derivative (3). Cyclization of the 2 using acetic anhydride or formic acid gave the corresponding pyrimido[4 0 ,5 0 :4,5]thiazolo[3,2-a]benzimidazol-4(3H)-one (5) in good yields. Acetylation of 2 with acetic anhydride in pyridine afforded N-acetylaminothiazolo[3,2-a]benzimidazole- 2-carbonitrile (6). In vitro antiproliferative activities of synthesized compounds were investigated at The National Cancer Institute (NCI), USA, according to their applied protocol. Compound 6 revealed signifi- cant antiproliferative activity, however, weak activity was shown by the other derivatives. Cell cycle disruption and apoptotic activity of 6 were studied, interestingly, 6 has the ability to arrest G2/M phase and it can induce apoptosis in time dependant manner. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Unlimited and uncontrolled cell proliferation is characteristic of tumor cells [1,2]. Disruption of cell cycle has a crucial role in cancer progression [3], as a result of this carcinogenesis can be controlled by agent which have an effect of cell proliferation. Thus various natural and synthetic agents are gaining widespread attention due to their cell cycle regulation and modulation activity [4e17]. In fact, all the suspected contributory factors for oncogenesis and muta- gens, such as viruses and inherited predisposing factors e have been shown to impair 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 which most cytotoxic cancer treatments cause. The G2 cell cycle checkpoint is rarely used by normal cells, which makes a cell cycle G2 checkpoint abrogation strategy attractive against cancer [18,19]. From a medicinal chemistry point of view, synthetic small molecule modulators of the G2/M checkpoint are of particular interest. Several clinically important anticancer compounds, such as vinca alkaloids and taxanes, which act as prominent inhibitors of G2/M transition, can be an effective for controlling some cancer types. Nonetheless, all of these compounds disrupt tubulin directly and they have complex chemical structures that restrict chemical modification. In addition, several prominent disrupters of tubulin, such as nocodazole and colchicine, lack antitumor efficacy. There- fore, novel chemical structures that block G2/M phase transition are valuable as pharmacological probes and as lead structures for future therapeutic agents [20]. The antitumor activity of thiazolo [3,4-a]benzimidazoles on human T-lymphoblastic CEM leukemia cells has been reported [21e24]. According to these reports thia- zolobenzoimidazole derivatives exert their antitumor effect by activating the programmed cell death pathway (apoptosis). Thia- zolo[3,4-a]benzimidazoles were also shown to effect the P-glyco- protein mechanism in the HL60R cells, thus suggesting that they are not suitable substrates for the multidrug transporter. In * Corresponding author. Current address: Department of Pharmaceutical Chem- istry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Tel.: þ966 146 77341; fax: þ966 146 76220. E-mail addresses: fadl@aun.edu.eg, fadl@ksu.edu.sa (T. Aboul-Fadl). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.02.025 European Journal of Medicinal Chemistry 45 (2010) 2689e2694