S_NAr and Palladium‐Catalyzed Reactions of Deactivated Thiophene: Application to the Synthesis of Protein Farnesyltransferase Inhibitors

Abstract

To investigate the influence of the 5‐thioether moiety of our previously identified hit thiophene compound upon protein farnesyltransferase inhibition, we synthesized a new library of 3‐(4‐chlorophenyl)‐4‐cyanothiophene‐2‐carboxylic derivatives through the application of aromatic nucleophilic substitutions benefiting from a sulfone‐based leaving group and by direct palladium‐catalyzed reactions on a thioalkylthiophene. This small library of ester derivatives and their corresponding acids was then evaluated for protein farnesyltransferase inhibitory activity; some library members exhibited promising submicromolar activities.

Interplay between spin-crossover and luminescence in a multifunctional single crystal iron(ii) complex: towards a new generation of molecular sensors

“…The napht-trz molecule ( L1 ) and the potassium salt K(tcnsme) were prepared according to modified synthetic strategies (see ESI†). 12,13 Single crystals of [M(napht-trz) 6 ](tcnsme) 2 ·4CH 3 CN (M = Fe II ( C1 ); M = Cu II ( C2 )) have been prepared under aerobic conditions by refluxing acetonitrile solutions containing [M(BF 4 ) 2 ]· x H 2 O (M = Fe II ( C1 ); M = Cu II ( C2 )), napht-trz and K(tcnsme) in a 1 : 6 : 2 molar ratio. Details of the synthesis, NMR spectra (Fig.…”

Improvement of the trypanocidal activity of 3-arylthiophene farnesyltransferase inhibitors by modulation of their 3-aryl group

“…In the continuity of our investigation, we also modified the substituent in position 5 by S N Ar and Liebeskind-Srogl coupling. 8 The nature of the aromatic group in position 3 was first varied by means of an efficient three-step solid-phase synthesis including a Suzuki-Miyaura cross-coupling. 9 Because of the high hydrophobicity of the analogues synthesised through this method, inhibitory activities on protozoan parasites were not as high as expected.…”

Introduction of methionine mimics on 3-arylthiophene: influence on protein farnesyltransferase inhibition and on antiparasitic activity

“…Thus, interactions of analogues 15 and 16 in the FTase pocket seem to be similar to compound 2. 10 In contrast, addition of methionine to 3-polyhydroxyphenylthiophenes had no effect on their enzymatic activity. These results support our former hypothesis 12 that the binding mode or binding site of polyhydroxyphenylthiophenes differs from that of our hit compound 1.…”

“…Other structure-activity relationship (SAR) studies on our hit compound 1 were also carried out. Position 5 was modied by S N Ar or Liebeskind-Srogl coupling 10 and position 3 by solid-or liquid-phase Suzuki-Miyaura couplings. 11,12 These modications conrmed the potency of the thio-isopropyl moiety at position 5 and of bulky or polyoxygenated aromatic groups at position 3 showing low micromolar activities on T. brucei FTase (TbFTase).…”