Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation.

By introducing a reactive oxygen species (ROS) triggered leaving group (arylboronic acid) to the parent PROTACs, ROS-responsive Pre-PROTACs were designed and evaluated. Pre-PROTAC (7) efficiently degraded the target protein BRD3 according to ROS levels. Our research provides an effective approach to control PROTAC activation by the endogenous ROS-related microenvironment.

N-Methyl- N-phenylvinylsulfonamides for Cysteine-Selective Conjugation.

Use of N-methyl- N-phenylvinylsulfonamides to perform chemoselective modification of cysteine-containing peptides and proteins is reported. Probes linked to the drug were applicable to prepare antibody-drug conjugates (ADCs). The drug-antibody ratio for ADCs was controlled by rationally tuning the electron deficiency and linker hydrophilicity of the probes.

Divinylsulfonamides as Specific Linkers for Stapling Disulfide Bonds in Peptides.

A new class of N-phenyl-divinylsulfonamides which can be easily prepared have been successfully developed and utilized as efficient linkers in the field of disulfide bond modification. Functional divinylsulfonamides provide opportunities for the specific introduction of various functionalities, including affinity probes, fluorescent tags, and drugs, into peptides.

Selective lysine modification of native peptides via aza-Michael addition.

A series of vinylsulfonamides were synthesized and screened for site-selective modification of the ε-amino group of lysine-bearing free α-amine residues. N-Methyl-N-phenylethenesulfonamide has emerged as an applicable reagent and has been developed for efficient and highly selective modification of the lysine residue of native peptides in the presence of a free N-terminus via aza-Michael addition. We demonstrated that functional N-phenylvinylsulfonamide derivatives with a fluorescent moiety or drug could also be conjugated to the lysine residue of octreotide and insulin with high specificity, without modifying the N-terminus. Our method provides a promising strategy for site-selective lysine functionalization in native peptides with a free N-terminus.

Accessible Method for the Development of Novel Sterol Analogues with Dipeptide-like Side Chains That Act as Neuroinflammation Inhibitors.

A number of novel sterol derivatives with dipeptide-like side chains were synthesized using an Ugi four-component condensation method and assayed to test their anti-inflammatory effects in activated microglial cells. Compound 18b ((3S,10R,13S)-N-((R)-1-(tert-butylamino)-1-oxo-3-phenylpropan-2-yl)-3-hydroxy-N,10,13-trimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide) was identified as the most potent anti-inflammatory agent in the series of compounds analyzed. Compound 18b markedly inhibited the expression of proinflammatory factors, including inducible nitric oxide synthase, interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, and cyclooxygenase-2 in lipopolysaccharide-stimulated microglial cells. Further studies showed that compound 18b significantly suppressed the transcriptional activity of AP-1 and NF-κB in activated microglial cells, which was likely mediated by the inhibition of the p38 MAPK and JNK signal transduction pathways. In addition, compound 18b displayed neuroprotective effects in a microglial-conditioned medium/neuron coculture and an experimental focal ischemic mouse model.