A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity**

Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4^CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4^CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4^CRBN neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4^CRBN molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.     

Kinetic study of Hg(II)-promoted substitution of cyanide from hexacyanoferrate(II) in an anionic surfactant medium by 2,2′-bipyridine

The kinetic investigation of Hg(II)-promoted reaction between [Fe(CN)₆]⁴⁻ and 2,2′-bipyridine (Bipy) has been performed in anionic sodium dodecyl sulfate (SDS) micellar medium by recording the surge in absorbance at 400 nm, corresponding to ultimate reaction product [Fe(CN)₄ Bipy]²⁻ using UV–visible spectrophotometer. Pseudo-first-order condition has been used to examine the progress of reaction as a function of temperature, [Fe(CN)₆⁴⁻], ionic strength, [SDS], pH, [Hg²⁺], and [Bipy] by changing one parameter at a time. The results exhibit that [Hg²⁺], [SDS], and pH are the decisive parameter showing maximum reaction rate at 1.5 × 10⁻⁴ mol dm⁻³, 6.0 × 10⁻³ mol dm⁻³, and 3.8, respectively. [Fe(CN)₆]⁴⁻ does not show any appreciable effect on the critical micellar concentration (CMC) of SDS as the polar head of SDS and [Fe(CN)₆]⁴⁻ both are negatively charged. Variable order kinetics was observed for [Fe(CN)₆]⁴⁻ and Bipy in their examined concentration range. The reverse response observed in the reaction rate with [KNO₃] shows a negative salt effect. The K⁺ provided by K₄[Fe(CN)₆] and KNO₃ decreases the repulsion between the negatively charged heads of the surfactant molecules thereby decreasing the CMC of SDS. The negative value for the entropy of activation also supports the interchange dissociative (I_d) mechanism recommended by us.     

Synthesis of Benzenesulfonamide Derivatives via Ring Opening of Aziridines in the Presence of Magnetically Retrievable Graphene Based (CoFe@rGO) Nanohybrid

Graphene based magnetic nanohybrids have engrossed considerable research curiosity because of their exceptional properties and diverse applications associated with green chemistry. In this regard, a practical, facile and regioselective preparation of 1,2-diamines from N-tosylaziridine/(S)-(+)-2-Benzyl-1-(p-tolylsulfonyl)aziridine and aryl amines in the presence of magnetically separable graphene based nanohybrid (CoFe@rGO) has been proposed under mild and solvent free conditions. The FT-IR, FE-SEM, XPS, XRD and TEM spectroscopic analysis confirmed the formation of the CoFe@rGO nanohybrids. For unsymmetrical aziridine, nucleophilic attack of aryl amines was observed to take place selectively at the more substituted carbon atom of aziridine ring. Environmentally benign, efficient, shorter reaction time, solvent-free conditions, low catalyst loading, excellent reaction yields and reusability of the catalyst for six consecutive runs without significant loss in its activity are the key advantages of this protocol.

Graphical Abstract