Portrayal of the Color Polymorphism in the 5-Acetyl-derivative of ROY

A novel derivative of the prominent ROY compound, 5-acetyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (AcROY), was synthesized in a two-steps procedure by the nucleophilic aromatic substitution reaction between 1-fluoro-2-nitrobenzene and 2-aminothiophene-3-carbonitrile, followed by Friedel–Crafts acylation...

Synthesis of Arylene Ether-Type Hyperbranched Poly(triphenylamine) for Lithium Battery Cathodes

We synthesized a new poly(triphenylamine), having a hyperbranched structure, and employed it in lithium-ion batteries as an organic cathode material. Two types of monomers were prepared with hydroxyl groups and nitro leaving groups, activated by a trifluoromethyl substituent, and then polymerized via the nucleophilic aromatic substitution reaction. The reactivity of the monomers differed depending on the number of hydroxyl groups and the A2B type monomer with one hydroxyl group successfully produced poly(triphenylamine). Based on thermal, optical, and electrochemical analyses, a composite poly(triphenylamine) electrode was made. The electrochemical performance investigations confirmed that the lithium-ion batteries, fabricated with the poly(triphenylamine)-based cathodes, had reasonable specific capacity values and stable cycling performance, suggesting the potential of this hyperbranched polymer in cathode materials for lithium-ion batteries.

Synthesis of α- and β-Carbolines by a Metalation/Negishi Cross-Coupling/SNAr Reaction Sequence

Carbolines are considered to be privileged scaffolds in medicinal chemistry. An efficient method for the synthesis of α- and β-carbolines from fluoropyridines and 2-haloanilines is reported. This streamlined procedure consists of a four-step directed ortho-lithiation, zincation, Negishi cross-coupling, and intramolecular nucleophilic aromatic substitution, providing access to a diverse set of functionalized carbolines. While the procedure is applicable to batch conditions, the generation of arylzinc intermediates in continuous flow has been demonstrated.

Structure-Property Relationships in Benzofurazan Derivatives: A Combined Experimental and DFT/TD-DFT Investigation

In this work we seek to understand and to quantify the reactivity of benzofurazan derivatives toward secondary cyclic amines, like pyrrolidine, piperidine and morpholine, acting as nucleophile groups in SNAr reactions. For this aim, physico-chemical and structural descriptors were determined experimentally and theoretically using the DFT/B3LYP/6-31+ g (d,p) methodology. Thus, different 4-X-7-nitrobenzofurazans (X = OCH3, OC6H5 and Cl) and products corresponding to the electrophilic aromatic substitution by pyrrolidine, piperidine and morpholine, were investigated. Particularly, the HOMO and LUMO energy levels of the studied compounds, determined by Cyclic Voltammetry (CV) and DFT calculations, were used to evaluate the electrophilicity index (ω). The latter was exploited, according to Parr’s approach, to develop a relationship which rationalizes the kinetic data previously reported for the reactions of the 4-X-7-nitrobenzofurazans with nucleophiles cited above. Moreover, the Parr’s electrophilicity index (ω) of these benzofurazans determined in this work were combined with their electrophilicity parameters (E), reported in preceding papers, was found to predict the unknown electrophilicity parameters E of 4-piperidino, 4-morpholino and 4-pyrrolidino-7-nitrobenzofurazan. In addition, the relationship between the Parr’s electrophilicity index (ω) and Hammett constants σ, has been used as a good model to predict the electronic effect of the nucleophile groups. Finally, we will subsequently compare the electrophilicity index (ω) and the electrophilicity parameters (E) of these series of 7-X-4-nitrobenzofurazans with the calculated dipole moment (μ) in order to elucidate general relationships between E, ω and μ.

Proteolysis Targeting Chimeras With Reduced Off-targets

Proteolysis Targeting Chimeras (PROTACs), a class of heterobifunctional molecules that recruit target proteins to E3 ligases, have gained traction for targeted protein degradation. However, pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other targets, such as zinc-finger (ZF) proteins, that hold key functions in normal development and disease progression. This off-target degradation of pomalidomide-based PROTACs raises concerns about their therapeutic applicability and long-term side effects. Therefore, there is a crucial need to develop rules for PROTAC design that minimize off-target degradation. In this study, we developed a high-throughput platform that interrogates the off-target degradation of ZF domains and discovered, using this platform, that PROTACs with the current design paradigm induce significant degradation of several ZF proteins. To identify new rules for PROTAC design, we generated a rationalized library of pomalidomide analogs with distinct exit vector modifications on the C4 and C5 positions of the phthalimide ring and profiled their propensities for ZF protein degradation. We found that modifications on the C5 position with nucleophilic aromatic substitution (SNAr) reduce off-target ZF degradation. We applied our newfound design principles on a previously developed ALK oncoprotein-targeting PROTAC and generated PROTACs with enhanced potency and minimal off-target degradation. We envision the reported off-target profiling platform and pomalidomide analogs will find utility in the design of specific PROTACs.