Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

A practical flow synthesis of 1,2,3-triazoles.

A robust and versatile protocol for synthesis of 1-monosubstituted and 1,4-disubstituted 1H-1,2,3-triazoles was established under continuous flow conditions using copper-on-charcoal as a heterogeneous catalyst. This methodology allowed for the synthesis of a diverse set of substituted 1,2,3-triazoles with good functional group tolerance and high yields. 2-Ynoic acids were also used as small-chain alkyne donors in a decarboxylation/cycloaddition cascade, allowing gaseous reagents to be bypassed, delivering desired triazoles in high yields. The developed methodology was used to synthesize an antiepileptic agent, rufinamide, which was obtained in 96% isolated yield.

Visible-Light Photoactive, Highly Efficient Triplet Sensitizers Based on Iodinated Aza-BODIPYs: Synthesis, Photophysics and Redox Properties.

A series of novel iodinated NO2 -substituted aza-BODIPYs have been synthesized and characterized. Highly desirable photophysical and photochemical properties were induced in NO2 -substituted aza-BODIPYs by iodination of the pyrrole rings. In particular, high values of singlet oxygen quantum yields (ΦΔ ) ranging from 0.79 to 0.85 were measured. The photooxygenation process proceeds via a Type II mechanism under the experimental conditions applied. The compounds studied exhibited an absorption band within the so-called "therapeutic window", with λmax located between 645 nm to 672 nm. They were non-fluorescent at room temperature with excited singlet-state lifetimes within the picosecond range as measured by femtosecond transient absorption. Nanosecond laser flash photolysis experiments revealed T1 →Tn absorption spanning from ca. 400 nm to ca. 500 nm and allowed determination of the triplet-state lifetimes. The estimated triplet lifetimes (τT ) in deaerated acetonitrile ranged between 2.74 µs and 3.50 µs. As estimated by CV/DPV measurements, all iodinated aza-BODIPYs studied exhibited one irreversible oxidation and two quasi-reversible reductions processes. Estimation of the EHOMO gave the value of -6.06 to -6.26 eV while the ELUMO was found to be located at ca. -4.6 eV. Thermogravimetric (TGA) analysis revealed that iodinated aza-BODIPYs were stable up to approximately 300 °C. All compounds studied exhibit high photostability in toluene solution.