3-Amino-5-phenoxythiophenes: syntheses and structure-function studies of a novel class of inhibitors of cellular L-triiodothyronine uptake.
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.
Briel
D
D
Institute of Pharmacy, Faculty of Biosciences, Pharmacy, and Psychology, University of Leipzig, Brüderstrasse 34, D-04103 Leipzig, Germany.
Pohlers
D
D
Uhlig
M
M
Vieweg
S
S
Scholz
G H
GH
Thormann
M
M
Hofmann
H J
HJ
D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014284:Triiodothyronine / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D013876:Thiophenes; D014284:Triiodothyronine