Excessive NF-κB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-κB signaling have significant therapeutic potential especially in treating inflammatory diseases and cancers. In this study, we performed a cell-based high-throughput screening to discover novel agents capable of inhibiting NF-κB signaling. On the basis of two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-κB activation, leading to successful discovery of the most potent compound Z9j with over 170-fold enhancement of inhibitory activity. Preliminary mechanistic studies revealed that Z9j inhibited NF-κB signaling via suppression of Src/Syk, PI3K/Akt, and IKK/IκB pathways. This novel compound also demonstrated antiinflammatory and anticancer activities, warranting its further development as a potential multifunctional agent to treat inflammatory diseases and cancers.

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This article describes a stimuli-responsive cross-linked network based on a poly(phthalaldehyde) (PPA) self-immolating polymer backbone which, upon removal of polymer end-caps, becomes degradable under ambient conditions. Self-immolating polymers (SIPs) are of particular interest due to their ability to undergo controlled depolymerization resulting in the elimination of the polymer structure and potential recovery and reuse of the original monomers. Linear copolymers of phthalaldehyde and unsymmetrical allylated-phthalaldehyde monomers are obtained via anionic polymerization with appreciable incorporation of the allyl-functional monomeric units. This approach enables crosslinking of the otherwise linear polymers via thiol-ene reactions with the allyl functional phthalaldehyde polymers. The polymer network thus formed unzips along the phthalaldehyde backbone to yield monomers and low molecular weight fragments in response to chemical (F − , H + ) or physical (light, sonication) stimuli that remove the stabilizing functional endcaps on the phthalaldehyde polymers. Rheology is used to demonstrate gelation within 5 s of light exposure of the allylated-phthalaldehyde polymers reacted with pentaerythritol tetrakis(3-mercaptopropionate) and photoinitiator (3 wt%). Triggerable degelation makes this material well suited for photolithography and additive manufacturing as well as other applications that necessitate polymer network degradation or elimination. Further, a method is described for determining the degelation temperature of a self-immolative cross-linked network.

Self‐immolative polymers are a class of polymers that undergo linear depolymerization of the main chain, often triggered by a single initial degradation event. Chain‐unzipping immolation processes followed by low‐ceiling‐temperature polymers yield regenerated monomers, demonstrating the remarkable potential of these polymers in the development of reversible and recyclable materials. In this work, we describe the synthesis of an amino‐acid‐derived poly(thioester) self‐immolative polymer with pendent functional groups allowing for selective decoration of the polymer backbone with solubilizing and reactive functional groups for subsequent post‐polymerization modification. Crosslinking norbornene‐functionalized, water‐soluble derivatives of these polymers via the thiol‐ene photoclick reaction yielded mechanically robust hydrogels within 15 s of light exposure. These networks were capable of immolation in response to deprotonation of an end‐capping thiol, unzipping along the poly(thioester) backbone to yield constituent monomers and larger molecular weight crosslinker fragments. Finally, degelation rates were controlled with pH and temperature in aqueous buffers. At physiological pH and temperature, complete degradation of approximately 20 wt% hydrogels was observed after 16 h, and raising the buffer pH to 10 resulted in network dissolution within 5 h. © 2022 Society of Industrial Chemistry.