%0 Journal Article
%A Briel, Detlef
%A Pohlers, Dirk
%A Uhlig, Mathias
%A Vieweg, Silke
%A Scholz, Gerhard H.
%A Thormann, Michael
%A Hofmann, Hans-Jörg
%D 1999
%T 3-Amino-5-phenoxythiophenes: Syntheses and Structure−Function Studies of a
Novel Class of Inhibitors of Cellular l-Triiodothyronine Uptake
%U https://acs.figshare.com/articles/journal_contribution/3-Amino-5-phenoxythiophenes_Syntheses_and_Structure_Function_Studies_of_a_Novel_Class_of_Inhibitors_of_Cellular_l-Triiodothyronine_Uptake/3683859
%R 10.1021/jm980288r.s006
%2 https://acs.figshare.com/ndownloader/files/5774214
%K concept
%K dicyanoketenedithiolate
%K dose
%K phenolate
%K receptor model show
%K uptake
%K compound
%K prerequisite
%K series
%K thiophene
%K phenoxythiophene
%K benzoyl
%K malodinitrile
%K methylsulfonyl groups
%K inhibition studies
%K HepG 2 hepatoma cells
%K Novel Class
%K orientation
%K transthyretin
%K derivatives show
%K Synthese
%K postulate
%K carbon disulfide
%K Inhibitor
%K Replacement
%K inhibitor
%K binding
%K halogen methanes
%K Uptake
%K cyclization
%K ring systems
%K Cellular
%K Thorpe
%K potency
%K Amino
%K Docking studies
%X A series of substituted 3-amino-5-phenoxythiophenes was synthesized starting from malodinitrile and carbon disulfide. The resulting dicyanoketenedithiolate reacts via Thorpe−Dieckmann cyclization with halogen methanes bearing electron-withdrawing groups to give
thiophene-2-thiolates, which can be transformed into 3-amino-5-(methylsulfonyl)thiophene-4-carbonitriles. Replacement of the methylsulfonyl groups by substituted phenolates provides
the substituted 3-amino-5-phenoxythiophenes. Some of the derivatives show a considerable
inhibitory potency for the l-T3 uptake in inhibition studies on human HepG2 hepatoma cells
with maximum values of about 60% at a dose of 10-5 M for the most potent 2-benzoyl derivatives.
The structure of the phenoxythiophenes fits well into a general concept derived for other classes
of l-T3 uptake inhibitors, which postulates an angular and perpendicular orientation of the
ring systems in these compounds as a prerequisite for an inhibitory potency. Docking studies
for the phenoxythiophenes with transthyretin as a receptor model show their preferred attack
at the l-T4/l-T3 binding channel.
%I ACS Publications