Design, Synthesis, and Cytotoxicity of Novel 3-Arylidenones Derived from Alicyclic Ketones Vijay Satam 1 , Ravi K. Bandi 2 , Ajaya K. Behera 2 , Bijay K. Mishra 2 , Samuel Tzou 1 , Olivia Brockway 1 , Balaji Babu 1 , Matthias Zeller 3 , Cara Westbrook 4 , Susan L. Mooberry 4,5 , Moses Lee 1, * and Hari Pati 2 1 Division of Natural and Applied Sciences and Department of Chemistry, Hope College, Holland, MI 49423, USA 2 Department of Chemistry, Sambalpur University, Jyoti Vihar-768019, Sambalpur, Orissa, India 3 Department of Chemistry, Youngstown State University, Youngstown, OH 44555, USA 4 Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA 5 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA *Corresponding author: Moses Lee, lee@hope.edu Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investi- gated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) con- tains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active com- pounds 5j, 11j, 15j, and 12h produced IC 50 values from 4.4 to 15 lM against both cell lines. A single- crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly ’twisted’ conformation similar to that of combretastatin A-4. At a concentration of 30 lM, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action. Key words: 3-aryl-2-propenoyl, chalcones, combretastatin A-4, cyclopentanone, cytotoxicity, tubulin Despite recent advances in the understanding of the biological pro- cesses leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under con- trol. Among the recently identified antitumor agents, combretasta- tins and chalcones represent important classes of molecules. Combretastatin A-4 (CA-4 or 1 as shown in Figure 1) is a natural product, which consists of a core cis-stilbene moiety. It originates from the African willow tree, Combretum caffrum, and is known to inhibit tubulin polymerization via interaction with the colchicine binding site of tubulin (1–4). Like combretastatins, chalcones (2, Figure 1) also derive their antitumor properties through the inhibi- tion of tubulin polymerization (5–8). Chalcones differ from combre- tastatin by having a trans-enone moiety between the aromatic rings (Figure 1). This 1,3-diarylprop-1-enone system is essential for chal- cones to elicit their cytotoxic properties. The ease of synthesis of chalcones, from substituted benzaldehydes and acetophenones, makes them an attractive drug scaffold. Many of the chalcone ana- logs exhibit powerful anticancer activities, causing renewed interest in this class of molecules (9–15). Structurally, chalcones are open-chained molecules bearing two aro- matic rings linked by a three-carbon enone pharmacophore. We envisaged that the attachment of this 3-aryl-2-propenoyl pharmaco- phore to alicyclic scaffolds would lead to additional series of com- pounds, which may exhibit cytotoxic activities against malignant cells. This rationale was inspired by several reports that described superior cytotoxic effects of the cyclic chalcone analogs (3, Figure 2) (16–21). Some of these analogs were found to display sig- nificant CYP1A inhibitor activity (22,23). This study was aimed at preparing analogs that contained a 3-aryl- 2-propenoyl core structure 4 (Figure 2) and at investigating their ability to inhibit the proliferation of cancer cells in culture. A diverse group of compounds were included in this study because earlier structure–activity studies on cyclic chalcone analogs have revealed that the cytotoxicity of these compounds was influenced by the shape of the molecules (22,23). Accordingly, four structurally divergent series of compounds, each differing significantly in the substitution pattern of cyclic ketone moiety, were synthesized and evaluated for their cytotoxic activity against murine B16 and L1210 cancer cell lines. Selected molecules were also assayed in compari- son with a known tubulin inhibitor, CA-4, for their ability to cause microtubule depolymerization in A-10 cells. Material and Methods Solvents and organic reagents were purchased from Aldrich and used without further purification. Melting points (mp) were determined using a Büchi B-545 melting point apparatus, and the results were uncorrected. Infrared (IR) spectra were recorded on a Midac M1700 FT-IR instrument as films on KBr disks, unless stated otherwise. Proton NMR spectra were recorded on a Varian INOVA 700 Chem Biol Drug Des 2011; 78: 700–708 Research Letter ª 2011 John Wiley & Sons A/S doi: 10.1111/j.1747-0285.2011.01176.x