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

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.

Evaluation of 1,2-Benzothiazine 1,1-Dioxide Derivatives In Vitro Activity towards Clinical-Relevant Microorganisms and Fibroblasts

“…It has been shown that chemically modified 1,2-benzothiazine 1,1-dioxides are potent anti-inflammatory agents and their use does not correlate with ulcerogenicity occurrence [10]. In several studies, the chemopreventive, antioxidant and antimicrobial activity of the 1,2-benzothiazines was already shown [11][12][13]. In game-changing work by Soheili et al it was suggested that 1,2-benzothiazine-based drugs can be developed and used as potential inhibitors of the Pseudomonas aeruginosa, one of the most resistant and common opportunistic pathogen in nosocomial setting [14].…”

Discovery of Oral Anticancer 1,2-Bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazine Hybrids That Inhibit Angiogenesis and Induce DNA Cross-Links

“…Structural modification leading to improved chemical stability and pharmacological versatility is an essential medicinal approach to improve the bioavailability of lead compounds. − Benzology is one of the often used approaches to derive new compounds with improved bioavailability and enhanced biological activity. , Intriguingly, several reports have revealed the potent biological activities of phthalazine derivatives obtained by benzology. For example, imidazole-based benzo­[ g ]­phthalazine derivatives were revealed to display potent leishmanicidal activity mediated by the inhibition of Leishmania Fe-superoxide dismutase (SOD) but not human CuZn-SOD. , For anticancer studies, the synthetic di- O -acetyl of (±)- cis -1,2-dihydroxy-1,2-dihydroacronycinebenzo­[ b ]­acronycine ( 6 ) was more potent than the corresponding di- O -acetate of the naturally occurring antitumor (±)- cis -1,2-dihydroxyacronycine ( 7 ) in inhibiting P388 leukemia and colon 38 adenocarcinoma in xenograft models .…”