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1.
Chem Commun (Camb) ; 58(72): 10072-10075, 2022 Sep 08.
Article in English | MEDLINE | ID: mdl-35993284

ABSTRACT

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.


Subject(s)
Neoplasms , Proteolysis , Humans , Neoplasm Proteins , Reactive Oxygen Species , Tumor Microenvironment
2.
Org Lett ; 20(20): 6526-6529, 2018 10 19.
Article in English | MEDLINE | ID: mdl-30284842

ABSTRACT

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.

4.
Org Lett ; 19(18): 4972-4975, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28880566

ABSTRACT

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.


Subject(s)
Peptides/chemistry , Disulfides , Molecular Structure , Sulfonamides
5.
Org Biomol Chem ; 15(35): 7339-7345, 2017 Sep 13.
Article in English | MEDLINE | ID: mdl-28853470

ABSTRACT

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.


Subject(s)
Lysine/chemistry , Peptides/chemistry , Sulfonamides/chemical synthesis , Vinyl Compounds/chemical synthesis , Molecular Structure , Sulfonamides/chemistry , Vinyl Compounds/chemistry
6.
ACS Chem Neurosci ; 7(3): 305-15, 2016 Mar 16.
Article in English | MEDLINE | ID: mdl-26815166

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Microglia/metabolism , Neurons/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Blotting, Western , Cell Line , Coculture Techniques , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Ischemic Attack, Transient/pathology , Male , Mice , Mice, Inbred ICR , Microglia/drug effects , Neurons/metabolism , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Rats , Real-Time Polymerase Chain Reaction , Sterols
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