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The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity towards other S-adenosyl-L-methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC50 value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.

Xiebai San (XBS) is a traditional Chinese medicine (TCM) prescription that has been widely used to treat pediatric pneumonia since the Song dynasty. To reveal its underlying working mechanism, a network pharmacology approach was used to predict the active ingredients and potential targets of XBS in treating pediatric pneumonia. As a result, 120 active ingredients of XBS and 128 potential targets were screened out. Among them, quercetin, kaempferol, naringenin, licochalcone A and isorhamnetin showed to be the most potential ingredients, while AKT1, MAPK3, VEGFA, TP53, JUN, PTGS2, CASP3, MAPK8 and NF-κB p65 showed to be the most potential targets. IL-17 signaling pathway, TNF signaling pathway and PI3K-Akt signaling pathway, which are involved in anti-inflammation processes, immune responses and apoptosis, showed to be the most probable pathways regulated by XBS. UPLC-Q/Orbitrap HRMS analysis was then performed to explore the main components of XBS, and liquiritin, quercetin, kaempferol, licochalcone A and glycyrrhetinic acid were identified. Molecular docking analysis of the compounds to inflammation-associated targets revealed good binding abilities of quercetin, kaempferol, licochalcone A and liquiritin to NF-κB p65 and of quercetin and kaempferol to Akt1 or Caspase-3. Moreover, molecular dynamics (MD) simulation for binding of quercetin or kaempferol to NF-κB p65 revealed dynamic properties of high stability, high flexibility and lowbinding free energy. In the experiment with macrophages, XBS markedly suppressed the (Lipopolysaccharides) LPS-induced expression of NF-κB p65 and the production of pro-inflammatory cytokines IL-6 and IL-1β, supporting XBS to achieve an anti-inflammatory effect through regulating NF-κB p65. XBS also down-regulated the expression of p-Akt (Ser473)/Akt, Bax and Caspase-3 and up-regulated the expression of Bcl-2, indicating that regulating Akt1 and Caspase-3 to achieve anti-apoptotic effect is also the mechanism of XBS for treating pediatric pneumonia. Our study helped to reveal the pharmacodynamics material basis as well as the mechanism of XBS in treating pediatric pneumonia.