Xiong-Li Liu,Shuang Chen,Xi-Rui Wang,Wei-Na Wang,Ke-Lan Xu,Pan Hu,Ying Zhou,Bo-Wen Pan,Qi-Lin Wang
Here, we demonstrate that the first example of harmaline scaffolds serving as acceptor/acceptor-based N-C-C synthons-triggered the ring opening and skeletal reconstruction of 3-vinyl benzofuranones for the construction of a library of skeletally-diverse polycyclic harmaline scaffolds. These products were smoothly afforded in up to 77% yield, >20:1 dr under catalyst-free conditions, and expanded the chemical space of biologically significant harmaline derivative species. All synthetic compounds showed cytotoxic activity against tumor cells, especially the compound 3at, which exhibited selective cytotoxicity against A549 cells and lower cytotoxicity against normal cells MRC-5 and HK-2. In further mechanism research, 3at inhibited A549 cell proliferation through the G1 phase arrest, induced A549 cell apoptosis through internal and external apoptosis pathways, and suppressed the migration and invasion abilities of A549 cells. These data indicated that compound 3at is the most effective compound in the series and can serve as a promising precursor for drug development.
Following the introduction of osteo-immunomodulation as a new and important strategy to enhance material osseointegration, designing an appropriate immune response after biomaterial implantation has become a significant challenge for efficient bone repair. In this study, a nanosilicate-reinforced sodium alginate (SA) hydrogel was fabricated by introducing montmorillonite (MMT) nanoparticles. Meanwhile, an immunogenically bioactive agent, harmine (HM), was loaded and released to induce macrophage differentiation into the M2 type. The fabricated SA/MMT/HM (SMH) hydrogel exhibited improved mechanical stiffness and stability, which also efficiently promoted macrophage anti-inflammatory M2 phenotype polarization and enhanced the secretion of pro-tissue healing cytokines for inducing a favorable immunomodulatory microenvironment for the osteogenic differentiation of bone marrow stromal cells (BMSCs). Furthermore, a rat air-pouch model and the critical-size bone defect model were used and the results showed that SMH hydrogel increased the proportion of M2 macrophages and markedly reduced local inflammation, while enhancing desirable new bone formation. Transcriptomic analysis revealed that the SMH hydrogel accelerated the M1-to-M2 transition of macrophages by inhibiting relevant inflammatory signaling pathways and activating the PI3K-AKT1 signaling pathway. Taken together, this high-intensity immunomodulatory hydrogel may be a promising biomaterial for bone regeneration and provide a valuable base and positive enlightenment for massive bone defect repair.
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