Substituted benzopyranobenzothiazinones. Synthesis and estrogenic activity on 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-ones 3a-f were synthesized. These compounds were readily prepared by the addition of 2-aminothiophenol 2 to substituted 4-hydroxycoumarin derivatives 1a-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 antiestrogenic compound. Among the compounds tested, 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one 3e and 6,12-dihydro-3-hydroxy-1-benzopyrano[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 defined by their binding properties and their mechanism of action by computational modelling studies.
Jacquot
Y
Y
Equipe de Chimie Therapeutique, Faculté de Médecine et de Pharmacie, Place Saint-Jacques, F-25030, Besançon, France.
Bermont
L
L
Giorgi
H
H
Refouvelet
B
B
Adessi
G L
GL
Daubrosse
E
E
Xicluna
A
A
D001578:Benzopyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D045166:Estradiol Congeners / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism; D013843:Thiazines / Q000138:chemical synthesis / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001578:Benzopyrans; D045166:Estradiol Congeners; D011960:Receptors, Estrogen; D013843:Thiazines