Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation.

Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4CRBN. Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs.

Acyl Fluorides from Carboxylic Acids, Aldehydes, or Alcohols under Oxidative Fluorination.

We describe a novel reagent system to obtain acyl fluorides directly from three different functional group precursors: carboxylic acids, aldehydes, or alcohols. The transformation is achieved via a combination of trichloroisocyanuric acid and cesium fluoride, which facilitates the synthesis of various acyl fluorides in high yield (up to 99%). It can be applied to the late-stage functionalization of natural products and drug molecules that contain a carboxylic acid, an aldehyde, or an alcohol group.

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD®/Olah's reagent under solvent-free conditions.

A new protocol enabling the formation of trifluoromethyl compounds from acyl fluorides has been developed. The combination of FLUOLEAD® and Olah's reagent in solvent-free conditions at 70 °C initiated the significant deoxyfluorination of the acyl fluorides and resulted in the corresponding trifluoromethyl products with high yields (up to 99%). This strategy showed a great tolerance for various acyl fluorides containing aryloyl, (heteroaryl)oyl, or aliphatic acyl moieties, providing good to excellent yields of the trifluoromethyl products. Synthetic drug-like molecules were also transformed into the corresponding trifluoromethyl compounds under the same reaction conditions. A reaction mechanism is proposed.