Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity.

BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 µM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 µM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

Advances in the treatment of hepatogenous diabetes: A review.

Hepatogenous diabetes (HD) is a glycogen metabolism disorder that arises as a consequence of chronic liver disease. The condition is frequently detected in patients diagnosed with cirrhosis, which is a result of advanced liver disease. The prognosis for patients with HD is generally poor, and they are at a heightened risk for serious complications such as gastrointestinal bleeding, primary peritonitis, and hepatic encephalopathy. Hepatogenous diabetes progression is often associated with cirrhosis progression, which leads to the development of liver cancer and increased patient mortality. Despite the prevalence and severity of HD, no systematic treatment strategy for clinical management of the condition has been proposed by any research or institutions to date. This paper conducts an extensive review of recent advancements in HD treatment in the quest for an effective treatment approach that may improve the overall prognosis of HD.

Insight on Structural Modification, Cytotoxic or Anti-Proliferative Activity, Structure-Activity Relationship of Berberine Derivatives.

Berberine (BBR) is a quaternary ammonium alkaloid isolated from the Traditional Chinese Medicine Coptis chinensis. It possesses a plethora of pharmacological activities because its unique structure properties make it readily interact with macromolecules through π-π stacking and electrostatic interaction. Its anti-tumor effects are receiving more and more attention in recent years. Cytotoxicity and anti-proliferation are the important anti-tumor modes of BBR, which have been studied by many research groups. This study aims to review the structural modifications of BBR and its cytotoxic derivatives. Also, to study the corresponding structure-activity relationship. BBR showed potential activities toward tumor cells, however, its modest activity and poor physicochemical properties hindered its application in clinical. Structural modification is a common and effective approach to improve BBR's cytotoxic or anti-proliferative activities. The structural modifications of BBR, the cytotoxic or anti-proliferative activities of its derivatives, and the corresponding structure-activity relationship (SAR) were summarized in the review. The concluded SAR of BBR derivatives with their cytotoxic or anti-proliferative activities will provide great prospects for the future anti-tumor drug design with BBR as the lead compound.

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review.

Berberine (BBR) is a plant derived quaternary benzylisoquinoline alkaloid, which has been widely used in traditional medicines for a long term. It possesses broad pharmacological effects and is widely applied in clinical. In recent years, the anti-tumor effects of BBR have attracted more and more attention of the researchers. The canonical right-handed double-stranded helical deoxyribonucleic acid (B-DNA) and its polymorphs occur under various environmental conditions and are involved in a plethora of genetic instability-related diseases especially tumor. BBR showed differential binding effects towards various polymorphic DNA structures. But its poor lipophilicity and fast metabolism limited its clinical utility. Structural modification of BBR is an effective approach to improve its DNA binding activity and bioavailability in vivo. A large number of studies dedicated to improving the binding affinities of BBR towards different DNA structures have been carried out and achieved tremendous advancements. In this article, the main achievements of BBR derivatives in polymorphic DNA structures binding researches in recent 20 years were reviewed. The structural modification strategy of BBR, the DNA binding effects of its derivatives, and the structure activity relationship (SAR) analysis have also been discussed.

Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds.

Cyclin-dependent kinase 1 (CDK1) plays an indispensable role in the whole cell cycle. It has become a new target for cancer therapy. According to the binding mode of a pan-CDK inhibitor, flavopiridol with CDK1, and our previous work, a new series of flavone derivatives were discovered. Among them, compound 2a showed the best CDK1 inhibitory and anti-proliferative potencies in the in vitro activity investigation. The IC50 of 2a against CDK1 was 36.42 ± 1.12 µM vs. 11.49 µM ± 0.56 of flavopiridol. In the anti-proliferation activity assays, 2a exhibited better activity toward RAW264.7 than MCF-7 cells. The results indicated that flavone derivatives, besides inhibiting the growth of tumor cells, can also antagonize inflammatory response. Molecular docking results showed that conformation of 2a can form hydrogen bonds and various hydrophobic interactions with the key amino acid residues of CDK1. It can be used as a promising lead compound for CDK1 inhibitor development.

Dual-target inhibitors based on PARP1: new trend in the development of anticancer research.

PARP1 is a hot target, and its inhibitors have been approved for cancer therapy. However, some undesirable properties restrict the application of PARP1 inhibitors, including drug resistance, side effects and low efficiency. For multifactorial diseases, dual-target drugs have exhibited excellent synergistic effects, such as reduced drug resistance, low side effects and high therapeutic efficacy, by simultaneously regulating the main pathogenic and compensatory signal pathways of diseases. In recent years, several dual-target inhibitors based on PARP1 have been reported and have demonstrated unique advantages. In this review we summarize the research progress in dual-target inhibitors based on PARP1 and discuss the related drug design strategies and structure-activity relationships. This work is expected to provide references for the development of PARP1 inhibitors.

Chemical Composition, Pharmacological, and Toxicological Effects of Betel Nut.

Betel nut, the fruit of Areca catechu L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and processed extensively in subtropical regions, such as South China and India. Betel nut almost appears as a "snack" in various occasions in most parts of China. Clinically, betel nut can play a certain pharmacology role and was used in malaria, ascariasis, arthritis, enterozoic abdominalgia, stagnation of food, diarrhea, edema, and beriberi. The nervous excitement of betel nut chewing has made it gradually become popular. However, chewing betel nut can induce oral submucosal fibrosis (OSF) and oral cancer (OC). At the same time, long-term chewing of betel nut also causes inhaled asthma, sperm reducing, betel quid dependence (BQD), and uterine and esophageal cancers. The main components of processed betel nut are the goal of this review. This study will mainly start from the pharmacological activity and toxicology study of betel nut in recent years, aiming to seek its advantages and disadvantages. In the meantime, this study will analyze and emphasize that betel nut and arecoline are the high-risk factors for oral cancer, which should arouse attention and vigilance of the public.

Design, synthesis, and primary activity assays of baicalein derivatives as cyclin-dependent kinase 1 inhibitors.

Malignant tumor is a disease with high mortality. Traditional treatment methods have many disadvantages, such as side-effects, drug resistance. Because cyclin-dependent kinase 1 (CDK1) plays an indispensable role in cell cycle regulation, it became an attractive target in rational anti-cancer drug discovery. Herein, we reported a series of baicalein derivatives, which remarkably repressed the proliferation of MCF-7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a displayed better inhibition rate than flavopiridol against MCF-7 proliferation at the concentration of 50 µg/ml, comparable to compound CGP74514A, while compound 3o possessed the best activity against CDK1/cyclin B kinase (IC50  = 1.26 µM). The inhibitory activities toward the kinase well correlated with anti-proliferative activities. Molecular docking results suggested that compound 3o can interact with the key amino acid residues, E81, L83, and D146, of CDK1 through hydrogen bond just like flavopiridol does. And it can also form an extra hydrogen bond with D146 by its introduced 7-acrylate group, which flavopiridol does not have. These findings proved that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer.

Inhibitors of Cyclin-Dependent Kinase 1/2 for Anticancer Treatment.

BACKGROUND: The cell cycle is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins, along with their endogenous inhibitors (CDKIs). CDKs act as central regulators in this process. Different CDKs play relevant roles in different phases. Among all CDKs, CDK1 is indispensible, which can drive all events that are required in the cell cycle in the absence of interphase CDKs (CDK2, CDK3, CDK4 and CDK6). So, CDK1 is an attractive target for anticancer drug development. METHODS: CDK1 and CDK2 have 89.19% similar residues and 74.32% identical residues, their structures especially the ATP-binding sites are of great similarity. So, it is difficult to inhibit CDK1 and CDK2 individually. In this review, recent advances about CDK1/2 inhibitors were summarized. The chemical structures of different classes of CDK1/2 inhibitors and their structure activity are presented. RESULTS: 19 kinds of CDK1/2 or CDK1 inhibitors with different scaffolds, including CDK2 allosteric inhibitors, were summarized. Some inhibitors are nature derived, for example, phenanthrene derivatives, nortopsentin derivatives, variolin B derivatives and meridians. CONCLUSION: Nature products, especially marine ones are potential resources for CDK1 inhibitors development. The findings of CDK2 allosteric inhibitors open an avenue to the discovery of novel selective CDK1 or other CDKs allosteric inhibitors.

Evaluation of Anti-Inflammatory Activities of a Triterpene ß-Elemonic Acid in Frankincense In Vivo and In Vitro.

The purpose of this research was to extract and separate the compounds from frankincense, and then evaluate their anti-inflammatory effects. The isolated compound was a representative tetracyclic triterpenes of glycine structure according to ¹H-NMR and 13C-NMR spectra, which is ß-elemonic acid (ß-EA). We determined the content of six different localities of frankincense; the average content of ß-EA was 41.96 mg/g. The toxic effects of ß-EA administration (400, 200, 100 mg/kg) for four weeks in Kunming (KM) mice were observed. Compared with the control group, the body weight of mice, the visceral coefficients and serum indicators in the ß-EA groups showed no systematic variations. The anti-inflammatory effects of ß-EA were evaluated in LPS-induced RAW264.7 cells, xylene-induced induced ear inflammation in mice, carrageenin-induced paw edema in mice, and cotton pellet induced granuloma formation in rats. ß-EA inhibited overproduction of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), soluble TNF receptor 1 (sTNF R1), Eotaxin-2, Interleukin 10 (IL-10) and granulocyte colony-stimulating factor (GCSF) in the RAW264.7 cells. Intragastric administration with ß-EA (300, 200, and 100 mg/kg in mice, and 210, 140, and 70 mg/kg in rats) all produced distinct anti-inflammatory effects in vivo in a dose-dependent manner. Following treatment with ß-EA (300 mg/kg, i.g.), the NO level in mice ears and PGE2 in mice paws both decreased (p < 0.01). In conclusion, our study indicates that ß-EA could be a potential anti-inflammatory agent for the treatment of inflammatory diseases.

9-O-benzoyl-substituted berberine exerts a triglyceride-lowering effect through AMPK signaling pathway in human hepatoma HepG2 cells.

Berberine is an isoquinoline alkaloid extracted from Rhizoma coptidis and shows anti-hyperlipidemia effect in vivo and in vitro. We previously found that berberine could decrease the intracellular triglyceride content in human hepatoma HepG2 cells through activation of AMP-activated protein kinase (AMPK), a major regulator of lipid metabolism. Herein, to find a more effective agent, several berberine analogues (A1-A13) were isolated and synthesized, and the triglyceride-lowering effects and potential mechanisms were investigated in HepG2 cells. Among these berberine analogues, 9-O-benzoyl-substituted berberine (A13) showed strong affinity to AMPK and significantly up-regulated the levels of phospho-Thr172 AMPK α subunit. Meanwhile, A13 reduced the cellular triglyceride levels. Furthermore, A13 could mediate the mRNA levels of downstream proteins involved in triglyceride synthesis and fatty acid oxidation of AMPK signaling pathway. These results suggested that A13 exerts a triglyceride-lowering effect via stimulation of AMPK pathway, which may be beneficial to regulate hyperlipidemia.

Identification of pro-inflammatory CD205+ macrophages in livers of hepatitis B virus transgenic mice and patients with chronic hepatitis B.

Hepatic macrophages play a central role in disease pathogenesis during hepatitis B virus (HBV) infection. Our previous study found that CD205+ macrophages in the liver of hepatitis B surface antigen transgenic (HBs-Tg) mice increased significantly compared with those in wild-type mice, and these increased CD205+ macrophages were involved in CpG-oligodeoxynucleotide-induced liver injury in HBs-Tg mice. Here, we analysed the phenotype and function of CD205+ macrophages derived from the liver of HBs-Tg mice and patients with chronic hepatitis B (CHB). We found that HBs-Tg mice-derived hepatic macrophages produced larger amounts of pro-inflammatory cytokines, including IL-6, IL-12, TNF-α, and of the anti-inflammatory cytokine IL-10 after stimulation with CpG-oligodeoxynucleotides or commensal bacteria DNA than B6 mice-derived hepatic macrophages. Furthermore, hepatic CD205+ macrophages from HBs-Tg mice showed an activated phenotype and expressed higher levels of inflammatory cytokine genes, chemokine genes, and phagocytosis-related genes than hepatic CD205- macrophages. In addition, CD205+ macrophages displayed an inflammatory phenotype and were increased in the liver of patients with CHB compared with those in healthy controls. Our data suggest that hepatic CD205+ macrophages are a unique pro-inflammatory subset observed during HBV infection. Thus, development of intervention targeting these cells is warranted for immunotherapy of HBV-induced liver diseases.

Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma.

Tumor-associated macrophages, crucial components of the microenvironment in hepatocellular carcinoma, hamper anti-cancer immune responses. The aim of the present study was to investigate the effect of sorafenib on the formation of the tumor microenvironment, especially the relationship between polarized macrophages and hepatocytes. Macrophage infiltration was reduced in patients with hepatocellular carcinoma who were treated with sorafenib. In vitro, sorafenib abolished polarized macrophage-induced epithelial mesenchymal transition (EMT) and migration of hepatocellular carcinoma cells but not normal hepatocytes. Moreover, sorafenib attenuated HGF secretion in polarized macrophages, and decreased plasma HGF in patients with hepatocellular carcinoma. Additionally, sorafenib abolished the polarized macrophage-induced activation of the HGF receptor Met in hepatocellular carcinoma cells. Our findings suggest that sorafenib inhibits polarized macrophage-induced EMT in hepatocellular carcinoma cells via the HGF-Met signaling pathway. These results contribute to our understanding of the immunological mechanisms that underlie the protective effects of sorafenib in hepatocellular carcinoma therapy.

Overexpression of Mortalin in hepatocellular carcinoma and its relationship with angiogenesis and epithelial to mesenchymal transition.

Mortalin is highly expressed in a variety of human tumors and associated with tumor metastasis. However, the relationship among the overexpression of Mortalin, epithelial to mesenchymal transition (EMT) and neovascularization is largely unknown. The aim of the present study was to investigate the expression of Mortalin in human HCC cell lines, clinical HCC specimens and its association with angiogenesis and EMT. The results of our study showed that the expression levels of Mortalin in cell lines with higher metastatic potential were significantly higher compared to those with lower metastatic potential. Compared with paracarcinomatous tissues and normal liver tissues, the expression of Mortalin was significantly increased in HCC tumor tissues. The expression of Mortalin was correlated with invasion and metastasis, Edmondson grade and TNM stage. A significant positive correlation was found between the expression of Mortalin and Vimentin, and tumors with high expression of Mortalin had a tendency to higher MVD compared to those with low expression of Mortalin. Using shRNA-mediated Mortalin knockdown, we found that decreased expression of Mortalin was accompanied by a reduction of Vimentin expression. Our findings demonstrated that the overexpression of Mortalin is correlated with the metastatic phenotype of HCC cells and can promote EMT, but cannot induce angiogenesis in HCC. The decreased expression of Mortalin is accompanied by an inhibition of EMT in the HCC cell lines.

STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib.

There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3(Hep-/-)) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib.

Traditional Chinese medicine and immune regulation.

Traditional Chinese medicines (TCMs) have a long history in Asian countries and are traditionally used to prevent and treat a variety of diseases. The rising interest in TCMs in recent years is reflected in both the increase in their market demand as well as scientific research. Previous studies show that TCMs perform dual roles on immunological regulation: immunological activation and immunological suppression. This review highlights studies focusing on the immunomodulatory effects of TCMs, describing their stimulatory effect on immune cells, immune organs, cytokine production, tumorigenesis, as well as their inhibitory function on inflammation, allergy, autoimmune disease, and graft rejection. Components of both innate and adaptive immunity may be modulated by specific TCMs. TCMs may also have antitumor effects and may play a role in regulating apoptosis. Immunomodulatory effects of TCMs may lead to new medications to treat allergic and autoimmune diseases. More high quality studies are needed to achieve scientific validity to these potential treatments. Evidence presented in this review reveals the role of TCMs in immune regulation and proposes a promising future for them in immunomodulatory therapies.

[Studies on chemical constituents in herb of Lamium maculatum var. kansuense (II)].

OBJECTIVE: To study the chemical constituents from Lamium maculatum var. kansuense. METHOD: The chemical constituents were isolated and repeatedly purified on silica gel column and the structures were elucidated by the NMR spectra and physico-chemical properties. RESULT: Six compounds were obtained and identified as polypodine B (I), 5-OH-8-epiloganin (II), shlanzhiside methyl ester (III), liriodendrin (IV), quercitroside (V), uridine (VI). CONCLUSION: Compound IV was found from genus Lamium for the first time and the rest of the compounds were found from Lamium maculatum var kansuense for the first time.