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 1...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2001-02, Vol.36 (2), p.127-136
Main Authors: Jacquot, Yves, Bermont, Laurent, Giorgi, Hervé, Refouvelet, Bernard, Adessi, Gerard.L, Daubrosse, Edwige, Xicluna, Alain
Format: Article
Language:English
Subjects:
2D-NMR
benzopyranobenzothiazinones
Benzopyrans - chemical synthesis
Benzopyrans - pharmacology
binding assay
Biological and medical sciences
Breast Neoplasms - pathology
Carcinogenesis, carcinogens and anticarcinogens
Cell Division - drug effects
Chemical agents
Dose-Response Relationship, Drug
Estradiol Congeners - chemical synthesis
Estradiol Congeners - pharmacology
estrogenic activity
Female
Humans
Medical sciences
Models, Molecular
Protein Binding
Receptors, Estrogen - metabolism
SAR
Thiazines - chemical synthesis
Thiazines - pharmacology
Transcriptional Activation - drug effects
Tumor Cells, Cultured - drug effects
Tumors
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Summary: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.
ISSN:0223-5234
1768-3254
DOI:10.1016/S0223-5234(00)01207-1