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.
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.
School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
Yuan-Yuan
YY
Shan
Cheng-Mei
CM
Zhang
Long-Qiang
LQ
Tang
Zhao-Peng
ZP
Liu
Nicole R
NR
Bearss
Jeffrey G
JG
Sarver
Amarjit
A
Luniwal
Paul W
PW
Erhardt
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D013843:Thiazines