Medicinal Chemistry, 2011, 7, 561-571 561 1573-4064/11 $58.00+.00 © 2011 Bentham Science Publishers Syntheses of 2,3-Diarylated 2H-Benzo[e][1,2]Thiazine 1,1-Dioxides and their 3,4-Dihydro Derivatives, and Assessment of their Inhibitory Activity Against MCF-7 Breast Cancer Cells Yuan-Yuan Shan a , Cheng-Mei Zhang a , Long-Qiang Tang a , Zhao-Peng Liu a, *, Nicole R. Bearss b , Jeffrey G. Sarver b , Amarjit Luniwal b and Paul W. Erhardt b a School of Pharmaceutical Sciences, Shandong University, Jinan 250012, P. R. China b Center for Drug Design and Development, University of Toledo College of Pharmacy, 2801 West Bancroft Street, Toledo, Ohio 43606-3390, USA Abstract: A practical synthesis of 2,3-diarylated 2H-benzo[e][1,2]thiazine 1,1-dioxides and their 3,4-dihydro derivatives was developed. ortho-Methyl lithiation of N-aryl-o-toluenesulfonamide followed by reaction with aryl aldehydes gave carbinol sulfonamides, which were either converted directly, or first oxidized to their ketones and converted, to 2,3-diarylated six-membered benzosultams via a TMSCl-NaI-MeCN mediated cyclization. A library of benzosultams was synthesized and evaluated for inhibitory activity against MCF-7 cells. Compound 3 in the 3,4-dihydro (saturated) series and compound 8 in the unsaturated series exhibited the highest potencies with growth inhibition (GI 50 ) values of 0.8 and 18.0 μM, respectively. Molecular modeling studies suggest that these compounds can associate with the colchicine binding site on microtubules. However, experimental assessments of that and other mechanistic possibilities are still ongoing. Keywords: TMSCl-NaI-MeCN, cyclization, benzo[e][1,2]thiazines, benzosultams, MCF-7 cells, anticancer. 1. INTRODUCTION A common structural motif found in nature consists of two, polyoxygenated aromatic rings connected by various carbon and heteroatom linkages, an overall relationship that can be designated as an Ar-n-Ar system. The polyphenolic flavonoids typify this scaffold. Their simplest members are the chalcones which have a pair of substituted benzene rings joined by an alpha-beta unsaturated ketone. In that case, both of the Ar rings are C6 and n equals C3 such that the designation becomes C6-C3-C6. Over 4,000 flavonoids are widely distributed across numerous materials that are com- ponents of the human diet. These agents can display a re- markable spectrum of biological activities including antial- lergenic, anti-inflammatory, antioxidant and anticancer, as well as modulation of enzyme activity and cell signaling pathways [1-4]. Genistein (Fig. 1) is a well known isofla- vonoid found in soybean that has a C6-C2-C6 arrangement. It exhibits significant anticancer activity, although the latter has not been able to be utilized clinically due to other side- effect toxicities also displayed by this molecule [5]. As shown in Fig. (1), the Ar-n-Ar motif can be found in many other natural products having anticancer activity such as col- chicine (C6-0-C7), podophyllotoxin (C6-C1-C6) and com- brestastatin A4 (C6-C2-C6). These particular agents were selected as examples because they all inhibit microtubule *Address correspondence to these authors at the School of Pharmaceutical Sciences, Shandong University, Jinan 250012, P. R. China; Tel: +86-531- 88382006; Fax: +86-531-88382548; E-mail: liuzhaop@sdu.edu.cn assembly by binding to the so-called ‘colchicine site.’ As a result they interrupt cancer cell division (mitosis) and ulti- mately prompt cell death by apoptosis [6]. Alternatively, sulfonamide-containing compounds are only rarely found in nature. However, because they can demonstrate potentially interesting therapeutic properties, many agents containing this structural moiety have been pre- pared and likewise investigated by medicinal chemists. The benzensulfonamide antibiotics represent one example of an extremely important class of these types of compounds [7-9]. ABT-751 (Fig. 1) is a sulfonamide-containing derivative that, similar to the natural products mentioned above, acts as an antimitotic agent by binding to the colchicine site on mi- crotubules. After showing antitumor activity against a broad spectrum of tumor cell lines including those resistant to con- ventional chemotherapies, ABT-751 is undergoing clinical investigation as an orally bioavailable anticancer agent [10,11]. As part of our synthetic chemistry efforts directed toward devising convenient methods for the assembly of cyclic sul- fonamides, also referred to as ‘sultams’ [12-15], we realized that our novel systems can combine the classical Ar-n-Ar scaffold and the key sulfonamide pharmacophore within semi-rigid frameworks that then display the components in distinct three-dimensional arrangements. Fig. (1) demon- strates the importance of the latter by depicting just two of the numerous conformations afforded to the completely flexible ABT-751 molecule, namely a ‘folded’ and an ‘ex- tended’ version of the sulfonamide’s immediately adjacent