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; Cheng-Mei      Zhang; Long-Qiang      Tang; Zhao-Peng      Liu; Nicole      R. Bearss; Jeffrey      G. Sarver; Amarjit      Luniwal; Paul      W. Erhardt

doi:10.2174/157340611797928307

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 (GI50) 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, synthesis of 2,3-diarylated, 2H-benzo[e][1,2]thiazine, microtubules, 3,4-dihydro (saturated)