ABSTRACT
Precise length, shape, and linker attachment points are all integral components to designing efficacious proteolysis targeting chimeras (PROTACs). Due to the synthetic complexity of these heterobifunctional degraders and the difficulty of computational modeling to aid PROTAC design, the exploration of structure-activity relationships remains mostly empirical, which requires a significant investment of time and resources. To facilitate rapid hit finding, we developed capabilities for PROTAC parallel synthesis and purification by harnessing an array of preformed E3-ligand-linker intermediates. In the next iteration of this approach, we developed a rapid, nanomole-scale PROTAC synthesis methodology using amide coupling that enables direct screening of nonpurified reaction mixtures in cell-based degradation assays, as well as logD and EPSA measurements. This approach greatly expands and accelerates PROTAC SAR exploration (5 days instead of several weeks) as well as avoids laborious and solvent-demanding purification of the reaction mixtures, thus making it an economical and more sustainable methodology for PROTAC hit finding.
ABSTRACT
A new generation of saturated benzene mimetics, 2-oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2-oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta-disubstituted benzenes.
ABSTRACT
Two novel solid reagents-1-sulfonimidoyl- and 1-sulfamimidoyl-3-methylimidazolium derivatives-for the synthesis of sulfonimidamides and imidosulfuric diamides, respectively, were developed. It is shown that these reagents are very effective in substitution reactions with various N- and O-nucleophiles; therefore, they significantly extend the accessibility to the chemical space covered by organosulfur(VI) compounds with S=N bonds. In addition, previously unknown imidosulfuric diamides with free imino nitrogen groups were prepared, and their physical and chemical properties were characterized (including molecular geometry, pKa , Log P, microsomal stability, and reactivity towards typical electrophiles). Similar to other organosulfur(VI) derivatives with S=N bonds, these compounds can be considered as promising bioisosteres of amides, ureas, or sulfonamides.
