ORIGINAL RESEARCH Docking study, in vitro anticancer screening and radiosensitizing evaluation of some new fluorine-containing quinoline and pyrimidoquinoline derivatives bearing a sulfonamide moiety Mostafa M. Ghorab • Fatma A. Ragab • Helmy I. Heiba • Reem K. Arafa • Ebaa M. El-Hossary Received: 4 November 2009 / Accepted: 16 February 2010 / Published online: 13 March 2010 Ó Springer Science+Business Media, LLC 2011 Abstract The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5- b]quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for carbonic anhydrase (CA) inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly syn- thesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 11 and 12 exhibited better activities than the reference drug doxorubicin (IC 50 = 71.8 lM) with IC 50 values of 52.6 lM and 67.3 lM, respectively. On the other hand, compounds 6, 10, and 13 showed IC 50 values (71.8 lM, 69.8 lM, and 70.8 lM, respectively) comparable to that of the reference drug doxorubicin. In addition, docking of the synthesized compounds into human carbonic anhydrase isozyme II (hCA II) active site was performed in order to predict the affinity and the ori- entation of these compounds at the isozyme active site. Also, the most active compounds, 11 and 12, were selected and evaluated for their ability to enhance the cell killing effect of c-radiation. Keywords Quinoline Á Fluorine Á Sulfonamide Á Carbonic anhydrase II Á Anticancer Á c-Radiation Introduction Sulfonamides posses many types of biological activities and many of them are widely used in therapy as antibac- terial (Drews, 2000), hypoglycemic (Boyd, 1988), diuretic (Supuran and Scozzafava, 2000; Maren, 1976), anti-car- bonic anhydrase (Supuran and Scozzafava, 2000; Supuran and Scozzafava, 2001), and antithyroid (Thornber, 1979) agents. Recently, a host of structurally novel sulfonamide derivatives have been reported to show substantial antitu- mor activity in vitro and/or in vivo (Abbate et al., 2004; Ghorab et al., 2006; Ismail et al., 2006; Rostom, 2006; Supuran et al., 2004). It has been known that aryl/heteroaryl sulfonamides may act as antitumor agents through a variety of mechanisms such as cell cycle perturbation in the G1 phase, disruption of microtubule assembly, angiogenesis inhibition, and functional suppression of the transcriptional activator NF-Y, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes (Casini et al., 2002). In addition, quinoline and fused quinoline derivatives are known to possess several biological activities including anticancer activity (Gopal et al., 2003; Kim et al., 2005; Zhao et al., 2005). Also, several reduced quinoline deriv- atives have shown significant anticancer activity (Liou et al., 2008). Also, the special properties of the fluorine atom, such as strong electronegativity, small size, and the low polariz- ability of the C–F bond, can have considerable impact on the behavior of a molecule in a biological environment (Be ´gue ´ and Delpon, 2006). The incorporation of fluorine into a drug allows simultaneous modulation of electronic, lipophilic, and steric parameters, all of which can critically influence both the pharmacodynamic and pharmacokinetic properties of drugs. Bioisosteric substitution for hydrogen M. M. Ghorab (&) Á H. I. Heiba Á E. M. El-Hossary Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of pharmacy, King Saud University, Riyadh, Saudi Arabia e-mail: mmsghorab@yahoo.com F. A. Ragab Á R. K. Arafa Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Cairo University, Cairo, Egypt 123 Med Chem Res (2011) 20:388–400 DOI 10.1007/s00044-010-9332-3 MEDICINAL CHEMISTR Y RESEARCH