3-amino-5-phenoxythiophenes: Syntheses and structure-function studies of anovel class of inhibitors of cellular L-triiodothyronine uptake

A series of substituted 3-amino-5-phenoxythiophenes was synthesized startin g from malodinitrile and carbon disulfide. The resulting dicyanoketenedithi olate reacts via Thorpe-Dieckmann cyclization with halogen methanes bearing electron-withdrawing groups to give thiophene-2-thiolates, which can be tr ansformed into 3-amino-5-(methylsulfonyl)thiophene-4-carbonitriles. Replace ment of the methylsulfonyl groups by substituted phenolates provides the su bstituted 3-amino-5-phenoxythiophenes. Some of the derivatives show a consi derable inhibitory potency for the L-T-3 uptake in inhibition studies on hu man 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 phenox ythiophenes fits well into a general concept derived for other classes of L -T-3 uptake inhibitors, which postulates an angular and perpendicular orien tation of the ring systems in these compounds as a prerequisite for an inhi bitory potency. Docking studies for the phenoxythiophenes with transthyreti n as a receptor model show their preferred attack at the L-T-4/L-T-3 bindin g channel.