Substituted benzopyranobenzothiazinones. Synthesis and estrogenic activityon MCF-7 breast carcinoma cells

In the search for new agents with estrogenic activity mediated by estrogen receptors (ER), six 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-on es 3a-f were synthesized. These compounds were readily prepared by the addi tion of 2-aminothiophenol 2 to substituted 4-hydroxycoumarin derivatives la -e. The estrogenic effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells and the specificity of described compounds was evaluated by the inhibition of their effect by ICI 182,780, an antiestrogen ic compound. Among the compounds tested, 6,12-dihydro-3-methoxy-1-benzopyra no[3,4 b][1,4]benzothiazin-6-one 3e and 6,1 2-dihydro-3-hydroxy-1-benzopyra no[3,4-b][1,4]benzothiazin-6-one 3f exhibited an ER-dependent proliferation and a high binding affinity to ER, but a moderate capacity to activate the transcription of a reporter gene. Their pharmacological profiles are defin ed by their binding properties and their mechanism of action by computation al modelling studies. (C) 2001 Editions scientifiques et medicales Elsevier SAS.