10.1021/jm980288r.s006
Detlef Briel
Detlef
Briel
Dirk Pohlers
Dirk
Pohlers
Mathias Uhlig
Mathias
Uhlig
Silke Vieweg
Silke
Vieweg
Gerhard H. Scholz
Gerhard H.
Scholz
Michael Thormann
Michael
Thormann
Hans-Jörg Hofmann
Hans-Jörg
Hofmann
3-Amino-5-phenoxythiophenes: Syntheses and Structure−Function Studies of a
Novel Class of Inhibitors of Cellular l-Triiodothyronine Uptake
American Chemical Society
1999
concept
dicyanoketenedithiolate
dose
phenolate
receptor model show
uptake
compound
prerequisite
series
thiophene
phenoxythiophene
benzoyl
malodinitrile
methylsulfonyl groups
inhibition studies
HepG 2 hepatoma cells
Novel Class
orientation
transthyretin
derivatives show
Synthese
postulate
carbon disulfide
Inhibitor
Replacement
inhibitor
binding
halogen methanes
Uptake
cyclization
ring systems
Cellular
Thorpe
potency
Amino
Docking studies
1999-04-30 00:00:00
Journal contribution
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
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-T<sub>3</sub> uptake in inhibition studies on human HepG2 hepatoma cells
with maximum values of about 60% at a dose of 10<sup>-5</sup> 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-T<sub>3</sub> 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-T<sub>4</sub>/l-T<sub>3</sub> binding channel.