%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