Pharmacological Profile of 6,12-Dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one, a Novel Human Estrogen Receptor Agonist.

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  • Jacquot Yves
    Laboratoire de Chimie Thérapeutique, Faculté de Médecine et de Pharmacie
  • Cleeren Anny
    Laboratoire de Cancérologie Mammaire, Institut Jules Bordet
  • Laios Ioanna
    Laboratoire de Cancérologie Mammaire, Institut Jules Bordet
  • Ma Yan
    Laboratoire de Cancérologie Mammaire, Institut Jules Bordet
  • Boulahdour Athem
    Laboratoire de Biophysique, Faculté de Médecine et de Pharmacie
  • Bermont Laurent
    Laboratoire d'Oncologie et d'Endocrinologie Moléculaire
  • Refouvelet Bernard
    Laboratoire de Chimie Thérapeutique, Faculté de Médecine et de Pharmacie
  • Adessi Gérard
    Laboratoire d'Oncologie et d'Endocrinologie Moléculaire
  • Leclercq Guy
    Laboratoire de Cancérologie Mammaire, Institut Jules Bordet
  • Xicluna Alain
    Laboratoire de Chimie Thérapeutique, Faculté de Médecine et de Pharmacie

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Abstract

Pharmacological studies were carried out to characterize further the endocrinological profile and the binding mode to the estrogen receptor (ER) of 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one (1). Binding experiments were conducted with highly purified recombinant human estrogen receptors hERα and β. Potent estrogenic activity of compound 1 was assessed by testing its ability to down-regulate ERs and to enhance estrogen receptor element (ERE)-dependent transcription. The latest step of our work dealt with the synthesis of the 9-fluorinated derivative 15 for ionic microscopy experiments to determine the intracellular localization of compound 1. Although 1 failed to compete with [3H]E2 for binding to both ER isoforms, evidence was reported that it interacted with hERα in MCF-7 cells (ER down-regulation/ERE-dependent luciferase induction). Hence, an appropriate conformation of the hormone binding domain, most probably conferred by co-regulators of ER, is required for the onset of an activity of the compound 1. Estrogenic activity was weak but on the order of magnitude of that of coumestrol (slightly weaker). The synthesis of the 9-methoxylated derivative 16 and its pharmacological evaluation led us to propose a binding mode of 1 on hERα. Compound 1 appears to interact with ERα mainly through interactions of its 3-methoxy substituent with the residue His-524 of the hormone binding domain.

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