Development of 10-Hydroxycamptothecin-crizotinib conjugate based on the synergistic effect on lung cancer cells.

The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.

Anastatin Derivatives Alleviate Myocardial Ischemia-Reperfusion Injury via Antioxidative Properties.

(±)-Anastatins A and B are flavonoids isolated from Anastatica hierochuntica. In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their preliminary antioxidant activities were evaluated. In the present study, the protective effect of myocardial ischemia-reperfusion (I/R) and the systematic antioxidant capacity of 24 derivatives were further studied. Compound 13 was the most potent among all the compounds studied, which increased the survival of H9c2 cells to 80.82%. The antioxidant capability of compound 13 was evaluated in ferric reducing antioxidant power, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging, and 2,2-diphenyl-1-picrylhydrazyl assays. It was observed that compound 13 significantly reduced infarcted areas and improved histopathological and electrocardiogram changes in rats with myocardial I/R injury. Moreover, compound 13 decreased the leakage rates of serum lactate dehydrogenase, creatine kinase, and malonyldialdehyde from rat myocardial tissues and increased the level of glutathione and superoxide dismutase activities following myocardial I/R injury in rats. Taken together, we concluded that compound 13 had potent cardioprotective effects against myocardial I/R injury both in vitro and in vivo owing to its extensive antioxidant activities.

Synthesis of tetracyclic oxindoles and evaluation of their α-glucosidase inhibitory and glucose consumption-promoting activity.

A series of tetracyclic oxindole derivatives was synthesized by asymmetric 1, 3-dipole reaction in 2-4 steps in 57-86% overall yields. These compounds were evaluated for α-glucosidase inhibitory and glucose consumption-promoting activity in vitro. Compound 4l competitively and reversibly inhibited α-glucosidase (IC50 = 3.64 µM) with activity 14-fold higher than that of acarbose. Docking analysis substantiated these findings. In addition, compound 4l exhibited significant glucose consumption promoting activity at 1 µM.

Synthesis and Antiproliferatory Activities Evaluation of Multi-Substituted Isatin Derivatives.

A series of multi-substituted isatin derivatives were synthesized using the powerful Sandmeyer reaction. The structures of these derivatives were confirmed by 1H-NMR, 13C-NMR, and HR-MS. Inhibition of proliferation activities of these derivatives against human leukemia cells (K562), human hepatocellular carcinoma cells (HepG2) and human colon carcinoma cells (HT-29) were evaluated in vitro using the MTT assay. Among the series, compound 4l exhibited strong antiproliferatory activities against K562, HepG2 and HT-29 cells with IC50 values of 1.75, 3.20, and 4.17 µM, respectively. The morphological, growth inhibitory and apoptosic effects of compound 4l in K562 cells, wound healing effect in HepG2 cells, and tube formating effect in matrix gel of HUVEC cells were evaluated consequently. All results indicated that compound 4l could be used as a potential antitumor agent in further investigations.

Synthesis and mechanism of action of new purine derivatives against triple negative breast cancer.

Triple negative breast cancer (TNBC) is considered to be the most difficult subtype of breast cancer to treat because of its extremely prone to metastasis and the lack of targeted therapy drugs. New purine derivatives were synthesized and evaluated in a series of kinases and cell lines. The most active compounds 3g and 3j were selected based on their antiproliferative activities, then their pharmaceutical activity and mechanism in MDA-MB-231 cells were analyzed. The results in vitro indicated that compounds 3g and 3j can induce MDA-MB-231 cells apoptosis, and inhibit its migration and angiogenesis through influencing protein expression such as Bcl-2, Bax, Bcl-xl, P38, MMP2, MMP9, AKT and EGFR. In vivo results indicate that compounds 3g and 3j can inhibit tumor growth and metastasis and reduce the expression of Ki67 and CD31 protein in TNBC xenograft models. These findings not only broaden our understanding of the anti-TNBC effects and mechanisms of compounds 3g and 3j, but also provide new ideas and reference directions for the treatment of TNBC.

Design, synthesis and anti-NASH effect evaluation of novel GFT505 derivatives in vitro and in vivo.

Non-alcoholic fatty liver disease (NAFLD) is emerging as the largest burden of chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is a progressive form of NAFLD that can progress to cirrhosis and hepatocellular carcinoma. Unfortunately, current treatment options for NASH are very limited. Among the multiple pathways of NASH, peroxisome proliferators-activated receptors (PPARS) are recognized as an important and effective target. GFT 505 is a dual excitement agent for the treatment of PPAR-α/δ for the treatment of NASH. However, its activity and toxicity need to be further improved. Therefore, here we would like to report the design, synthesis and biological evaluation of 11 GFT 505 derivatives. The initial cytotoxicity through proliferation activity of HepG2 cells and in vitro anti-NASH activity evaluation demonstrated that under the same concentration, the compound 3d possess significantly lower cytotoxicity and better anti-NASH activity than that of GFT 505. Moreover, Molecular docking also shows that 3d and PPAR-α/δ can form a stable hydrogen bond and have the lowest binding energy. Therefore this novel molecule 3d was selected to go further in vivo investigation. Methionine-choline deficiency (MCD) induced C57BL/6J NASH model mice was used for the in vivo biological experiments and the compound 3d demostrated lower liver toxicity than that of GFT 505 in the body at the same dose, and it did more effectively improve hyperlipidemia, liver fat degeneration and liver inflammation as well as significantly enhance the content of the GSH which is inportant for the liver protection. This study suggested that the compound 3d is a very promising lead compound for the treatment of NASH.

Synthesis and immunogenicity of Brucella monovalent neoglycoconjugate.

Brucellosis is a highly infectious zoonotic disease caused by Brucella. It is necessary to control and eliminate brucellosis. The cell wall O-polysaccharides of pathogenic Brucella species are homopolymers of the rare sugar 4,6-dideoxy-4-formamido-α-d-mannopyranose. Herein, one neoglycoconjugate was successfully synthesized based on disaccharide [Rha4NFo(1 â†’ 2)Rha4NFo] as epitope. Disaccharide specific antibodies were detected by ELISA and the immune protective effect was further evaluated with PBS as control. The result showed that the synthetic neoglycoconjugate can produce moderate immune responses in mice and significantly decreased splenic Brucella M5 burden comparing with control group. The chemically defined antigen identified the A antigenic determinant and provided a structural basis for understanding the fine specificity of polyclonal antibodies that bind the A antigen. The neoglycoconjugate shows the potential in detection reagent or vaccine development for brucellosis.

Recent advances in the development of cyclin-dependent kinase 7 inhibitors.

Cyclin dependent kinase 7 (CDK7) plays a double role as it activates several other cyclin dependent kinases and participates to the initiation of transcription. This kinase is overexpressed in various types of tumors. Relatively few selective CDK7 inhibitors have been up to now disclosed. Most of these inhibitors belong to two chemical families: pyrazolopyrimidines and pyrazolotriazines on one side and pyrimidines on another side. They also differ by their molecular mechanism of action. Some are acting as competitive inhibitors and some others are covalent inhibitors. With these tools, the understanding of the potential therapeutic interest of CDK7 inhibitors in cancer is rapidly growing. They display antiproliferative activity against various types of tumors and leukemia and synergies have been identified. Two inhibitors are undergoing clinical testing. The most potent compounds inhibit a large number of cell-lines with IC50 < 200 nM.

Inhibitor of the human telomerase reverse trancriptase (hTERT) gene promoter induces cell apoptosis via a mitochondrial-dependent pathway.

Telomerase is aberrantly expressed in many cancers and plays an important role in the development of cellular immortality and oncogenesis, which makes it a potential cancer therapeutic target for drug discovery. Here, we constructed a firefly luciferase reporter driven by the human telomerase reverse trancriptase (hTERT) gene promoter to screen for inhibitory compounds. Compound 5c was discovered and shown to significantly inhibit the promoter activity of hTERT gene. Furthermore, five analogs of compound 5c were synthesized, and compound 8b was shown to be a more potent inhibitor of hTERT gene promoter activity and subsequent expression of hTERT mRNA and protein. The viability of HeLa cells was inhibited by a knockdown of hTERT gene expression, and the same effect was also observed by treating with compound 8b. Moreover, our results indicated that compound 8b induced apoptosis of HeLa cells, and activated caspase-9 and caspase-3 enzymes. Taken together, these results suggested that compound 8b down-regulates the expression of hTERT and induces mitochondrial-dependent apoptosis.

Total synthesis of 8-(6″-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents.

The naturally occurring flavone 8-(6″-umbelliferyl)apigenin, a hybrid structure of apigenin and coumarin, as well as seven of its analogues were synthesized for the first time by using iodination and Suzuki coupling reactions as key steps. The synthesis of 8-(6″-umbelliferyl)-apigenin was achieved in seven linear steps from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one and 7-hydroxyl coumarine with 31% overall yield. Effects of these compounds on glucose disposal were investigated in adipocytes. All of the flavonoid and coumarin hydrids were found to have better bioactivities than their corresponding flavonoid cores. The most potent compound 15 (10 µΜ) could promote glucose consumption by 57% which exhibited similar effect as the positive control metformin at 1 mM. Moreover, fluorescence microscopy showed that four 8-(6″-umbelliferyl)apigenin analogues 2, 15, 30 and 31 could promote the 2-NBDG uptake into 3T3-L1 cells, which consist with those observed in the regulation of glucose.