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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 IC 50 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 IC 50 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.

Background: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC), is metabolized by cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients., Methods: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs) and adjacent normal hepatic microsomes (NHLMs) of HCC patients (n = 18). Commercial hepatic microsomes (CHLMs) were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting., Results: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax) of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold) than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs., Conclusions: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

Pogostemonis Herba (PH) is the dried aerial parts of Pogostemon cablin (Blanco) Benth, which is mainly distributed and used in Asian countries. PH is an aromatic damp-resolving drug in traditional Chinese medicine (TCM), which is usually used for the treatment of vomiting, chest tension, tiredness, abdominal pain, diarrhea, and headache. In this review, the summary of chemical constituents in the aerial parts, biological activities, history of uses, quality control methods, industrial applications, pharmacokinetics and network pharmacology are reported. By collating the chemical constituents of various parts of PH, a total of 174 components were identified, including 66 terpenes, 6 pyrones, 40 flavonoids, 21 phenylpropanoids, 9 steroids, 4 polysaccharides and 28 others. Pharmacological research has found that PH possesses multi-pharmacological activities, including regulating the gastrointestinal tract, inhibition of pathogenic microorganisms, and anti-inflammation, which provide more scientific interpretation for the clinical usage of PH. In addition, the shortcomings of the current research on PH and the recommendation of future studies on PH are analyzed. We hope this review can provide some insight for further research and applications of PH in future. [ABSTRACT FROM AUTHOR]

Selaginella doederleinii Hieron is a widely used as folk Chinese medicine for treatment of different cancers. Our previous investigations have confirmed that the total biflavonoids in ethyl acetate extract from S. doederleinii (SDEA) have favorable anticancer potentials. However, the in vivo process of its bioactive ingredients remains unknown. In this paper, a sensitive and reliable method was developed for simultaneous quantification of main five biflavonoids, including amentoflavone, robustaflavone, 2″,3″-dihydro-3′,3″-biapigenin, 3′,3″-binaringenin and delicaflavone in the ethyl acetate extract of S. doederleinii (SDEA extract) in rat plasma by high-performance liquid chromatography with electrospray ionization-mass spectrometry (HPLC-ESI–MS/MS). Chromatographic separation was performed using an Ultimate ® XB-C18 (100 × 2.1 mm, 3.5 μm) with gradient elution of water (0.5% acetic acid) and acetonitrile at 0.2 mL/min. All analytes with internal standard (chrysin) were detected using selective reaction monitoring (SRM) in negative ionization mode. The method showed a good linearity over a wide concentration range (r 2 > 0.99). The limits of quantification for the biflavonoids were less than 10 ng/mL. The developed method was applied to the comparatively pharmacokinetic study of the five biflavonoids after oral or intravenous administration of SDEA extract in rats. In addition, in silico assessments of permeability and solubility of these biflavonoids were also performed to understand their poor bioavailability. It is the first time to report the in vivo process profiles of the biflavonoids of SDEA extract in rats. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Selaginella doederleinii Hieron has been used as a folk medicine for the treatment of different cancers, especially for nasopharyngeal carcinoma, lung cancer and trophoblastic tumor in China. Previously, the ethyl acetate extract from S. doederleinii (SDEA extract) showed favorable anti-cancer potentials. However, the main chemical composition and anticancer mechanism of the SDEA extract were still not very clear. Until now, there are no reports available about the oral toxicity of the extract. Aim of study The present study was to further elucidate the chemical composition and anti-lung cancer mechanism of the SDEA extract, and evaluate the acute oral toxicity of the extract. Materials and methods The SDEA extract was separated and analysed by HPLC to disclose its main chemicals. The effects of the extract were then investigated in vitro on cell viability, apoptosis and cell cycle using fluorescence microscopy and flow cytometry, and the molecular mechanism against human lung cancer cells A549 was further studied by western blot assays. The in vivo anti-cancer effect of the extract was evaluated in A549 xenograft mice model by histochemical assay, and tumor growth, microvascular density (MVD) and Ki67 expression were also measured. In addition, acute oral toxicity test of the extract was executed in mice. Results SDEA extract mainly contained eight biflavonoids. The extract caused the loss of mitochondrial membrane potential and induced cell apoptosis by upregulating Bax, downregulating Bcl-2, activating caspase-9 and caspase-3 and blocked the cell cycle in S phase. The extract reduced expression of antigen Ki67, decreased MVD, and significantly inhibited the tumor growth. The extract did not show apparent oral acute toxicity in healthy mice. Conclusion The SDEA extract exerted anti-tumor effect through activating mitochondrial pathways and reducing Ki67 expression and MVD. Low oral acute toxicity suggested it a promising chemotherapy agent. [ABSTRACT FROM AUTHOR]