Design, synthesis, and activity of 5-cyano-2-thiacetyl aromatic pyrimidinone as DENV NS5 RdRp inhibitors / 药学学报

To screen novel anti-dengue virus (DENV) NS5 RdRp enzyme inhibitors, a series of 5-cyano-2-thiacetoaryl pyrimidinone compounds were designed and synthesized by molecular hybridization method with HCV NS5B RdRp inhibitor 3jc and ZIKV NS5 RdRp inhibitor 4w as lead compounds. The anti-DENV activity of these compounds was evaluated by MTT assay and plaque assay and five compounds showed anti-DENV activity. The most active compound 7a'k showed better anti-DENV activity than that of the positive control ribavirin (EC50 = 7.86 μmol·L-1 vs EC50 = 18.07 μmol·L-1), and the other four compounds showed almost the same anti-DENV activity as ribavirin. Finally, the prediction and simulation of the binding mode through molecular provided new ideas for the further development of this new DENV NS5 RdRp inhibitor.

Design, synthesis and biological activity of DB02 amino acid derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors / 药学学报

To improve the stability of amino acid ester derivatives of DB02, a series of 24 amide derivatives of DB02 amino acids as non-nucleoside HIV-1 reverse transcriptase inhibitor were designed and synthesized based on bioisosterism by replacing amino acid ester scaffold with more stable amide bond. The anti-HIV-1 activity of these compounds was evaluated by MTT assay and counting the number of syncytia. Most of the target compounds showed a potential anti-HIV-1 activity, among which compounds 2d, 2i, 2l, 2s, and 2w had better antiviral effect than lead compound DB02, with a therapeutic index > 1 000.00. Finally, the structure-activity relationship of these compounds was discussed, which provided new ideas for the further development of DB02 derivatives.

Problems in medicinal materials research of new traditional Chinese medicine / 中国中药杂志

Medicinal materials research and development of new drug of traditional Chinese medicine (TCM) research is the premise and foundation of new drug research and development, it throughout the whole process of new drug research. Medicinal materials research is one of the main content of the pharmaceutical research of new drug of TCM, and it is also the focus of the new medicine pharmaceutical evaluation content. This article through the analysis of the present problems existing in the development of TCM research of new drug of TCM, from medicine research concept, quality stability, quality standard, etc are expounded, including medicine research idea value medicine study should focus on the important role and from the purpose for the top-level design of new drug research problem. Medicinal materials quality stability should pay attention to the original, medicinal part, origin, processing, storage, planting (breeding), and other aspects. Aspect of quality standard of medicinal materials should pay attention to establish the quality standards of conform to the characteristics of new drug of TCM. As the instruction of TCM new drug research and development and the scientific nature of the review, and provide the basis for medicinal material standards.

Problems in quality standard research of new traditional Chinese medicine compound / 中国中药杂志

The new traditional Chinese medicine compound is the main part of the research of new drug of traditional Chinese medicine (TCM), and the new Chinese herbal compound reflects the characteristics of TCM theory. The new traditional Chinese medicine compound quality standard research is one of the main content of pharmaceutical research, and is also the focus of the new medicine pharmaceutical evaluation content. Although in recent years the research level of new traditional Chinese medicine compound has been greatly improved, but the author during the review found still some common problems existing in new traditional Chinese medicine compound quality standard research data, this paper analyzed the current quality standards for new traditional Chinese medicine compound and the problems existing in the research data, respectively from measurement of the content of index selection, determine the scope of the content, and the quality standard design concept, the paper expounds developers need to concern. The quality of new traditional Chinese medicine compound quality standard is not only itself can be solved, but quality standards is to ensure the key and important content of product quality, improving the quality of products cannot do without quality standards. With the development of science and technology, on the basis of quality by design under the guidance of the concept, new traditional Chinese medicine compound quality standard system will be more scientific, systematic and perfect.

The anti-HIV activity of three 2-alkylsulfanyl-6-benzyl-3, 4-dihydropyrimidin-4 (3H)-one derivatives acting as non-nucleoside reverse transcriptase inhibitor in vitro / 药学学报

It was recently shown that several new synthetic 2-alkylsulfanyl-6-benzyl-3, 4-dihydropyrimidin-4(3H)-one (S-DABO) derivatives demonstrated anti-HIV-1 activity. Three of the derivatives namely RZK-4, RZK-5 and RZK-6 were used in this study to explore their inhibitory effects on a variety of HIV strains. These compounds at a concentration of 200 microg mL(-1) almost completely inhibited the activity of recombinant HIV-1 reverse transcriptase. All of the three compounds reduced replication of HIV-1 laboratory-derived strains, low-passage clinical isolated strain, and the drug resistant strain. In particular RZK-6 showed potent activity against the HIV-1 drug resistant strain. In general, the antiviral activities are similar in magnitude to nevirapine (NVP), which is a non-nucleoside reverse transcriptase inhibitor approved by FDA. The therapeutic indexes of these compounds were remarkable, ranging from 3704 to 38462 indicating extremely low cytotoxicity. These results suggest that the three S-DABO derivatives in this study have good potential for further development in anti-HIV-1 therapy. It may be particularly useful to target at the non-nucleoside reverse transcriptase inhibitors resistant HIV-1 strain.

Arginine vasopressin stimulates proliferation of adult rat cardiac fibroblasts via protein kinase C-extracellular signal-regulated kinase 1/2 pathway / 生理学报

Arginine vasopressin (AVP), a neurohormone and hemodynamic factor implicated in the pathophysiology of hypertension and congestive heart failure, can also act as a growth-stimulating factor. Our previous work demonstrated that AVP is a mitogen for neonatal rat cardiac fibroblasts (CFs). In the present study, we extended our investigations to adult rat CFs to explore whether AVP could induce adult rat CF proliferation and, if so, to identify the mechanism involved. Adult rat CFs were isolated, cultured and subjected to AVP treatment. DNA synthesis and cell cycle distribution were analyzed by [(3)H]-thymidine incorporation and flow cytometry. Cellular extracellular signal-regulated kinase 1/2 (ERK1/2) activity was measured by in vitro kinase assay using myelin basic protein (MBP) as a substrate. Protein expressions of total- and phospho-ERK1/2, p27(Kip1), cyclins D1, A, E were assessed by Western blot. The results showed that AVP stimulated DNA synthesis in adult rat CFs, and the effect was abolished by a V1 receptor antagonist, d(CH(2))(5)[Tyr(2)(Me), Arg(8)]-vasopressin (0.1 μmol/L), but not by a V2 receptor antagonist, desglycinamide-[d(CH(2))(5), D-Ile(2), Ile(4), Arg8]-vasopressin (0.1 μmol/L). AVP induced an activation of ERK1/2, which could be mimicked by the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA, 30 nmol/L, 5 min), but abolished by depletion of PKC via chronic PMA incubation (2.5 μmol/L, 24 h). In addition, AVP down-regulated protein expression of p27(Kip1), increased protein expressions of cyclins D1, A and E, and induced cell cycle progression from G(0)/G(1) into S stage. Inhibition of ERK1/2 activation by PD98059 (30 μmol/L) abolished the effect of AVP on DNA synthesis, protein expressions of p27(Kip1), cyclins D1, A and E as well as cell cycle progression. These results suggest that AVP is also a growth factor for adult rat CFs. The mitogenic effect of AVP is mediated via V1 receptors and PKC-ERK1/2 pathway. Moreover, AVP modulates the expressions of cell cycle regulatory proteins p27(Kip1) and cyclins D1, A and E, which lie downstream of ERK1/2 activation, and induces cell cycle progression in adult rat CFs.

The Role of Transforming Growth Factor-?_1 in the Proliferation of Cardiac Fibroblasts Induced by Chymase / 中华高血压杂志

Objective To investigate the effect of chymase on the proliferation of rat cardiac fibroblasts (CFs) and the role of transforming growth factor-?1 (TGF-?_1).Methods Cultured CFs of neonatal SD rats were isolated by trypsinization.Cell number and DNA synthesis were evaluated by MTT assay (A_(490) value) and [~3H]-deoxythy- midine [~3H]-TdR incorporation.The mRNA expression of TGF-?_1 in CFs was determined by RT-PCR.Results Chymase increased CFs numbers and [~3H]-TdR incorporation in a dose-dependent manner.The A_(490) value of CFs stimulated by 15,30 and 60 ng/mL chymase was 0.263?0.033,0.348?0.031 and 0.387?0.026,respectively, which were all significantly higher than that of control (0.201?0.019,P