Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents

A total of 24 pirfenidone derivatives were designed, synthesized and evaluated for their inhibitory activity against the human lung fibroblast cell line MRC-5. These compounds showed the remarkable proliferation inhibition against MRC-5 compared to pirfenidone as the positive control. The possible mechanism of this kind of derivatives as antifibrotic agents was explored. The molecular docking and p38 binding affinity assays demonstrated that the antifibrotic potential of the pirfenidone derivatives was possibly through the inhibition of p38 MAPK signaling pathway. The data from this study suggested that p38 might be a potential therapeutic target for the new generation antifibrotics. All the pirfenidone derivatives are reported here for the first time.     

Design,synthesis and biological evaluation of novel 2,3-indolinedione derivatives against mantle cell lymphoma

2,3-Indolinedione derivatives have been identified as a novel class of promising agents for cancer treatment. In this study, eighteen 2,3-indolinedione derivatives were designed and synthesized, and their anticancer activities against mantle cell lymphoma (MCL) cells were evaluated. Most of them exhibited significant antiproliferative activity against the tested cell lines, and compound K5 was the most potent (MCL cellular IC₅₀ = 0.4–0.7 μM). Further, compound K5 could induce cell apoptosis and cell cycle arrest in G2/M phase. Additionally, the results of drug-likeness analysis demonstrated that these novel 2,3-indolinedione derivatives could have potential as novel treatment strategies for MCL.     

SYNTHESIS AND ANTITUMOR ACTIVITY OF 5-BROMO-1-MESYLURACIL

Large-scale preparation of 5-bromo-1-mesyluracil (BMsU) 4 has been optimized. BMsU was synthesized by condensation of silylated 5-bromouracil and MsCl in acetonitrile or by the reaction of 5-bromouracil with MsCl in pyridine. The same product was obtained by bromination of 1-mesyluracil. The purpose of this study was to elucidate the effects of BMsU on the biosynthetic activity of tumor cell enzymes involved in DNA, RNA and protein syntheses, and in de novo and salvage pyrimidine and purine syntheses. Investigations were performed in vitro on human cervix carcinoma cells (HeLa). BMsU displayed inhibitory effects on DNA and RNA syntheses in HeLa cells after 24 h of treatment. De nova biosynthesis of pyrimidine and purine was also affected. Antitumor activity of BMsU is closely associated with its inhibitory activity on the enzymes that play an important role in the metabolism of tumor cells. In vivo antitumor activity of BMsU was also investigated. The model used in investigations was a mouse anaplastic mammary carcinoma transplanted into the thigh of the right leg of CBA mice. Significant reduction in tumor growth time was achieved with BmsU administered at a dose of 50 mg/kg.     

Digoxin Derivatives with Enhanced Selectivity for the α2 Isoform of Na,K-ATPase: EFFECTS ON INTRAOCULAR PRESSURE IN RABBITS*

In the ciliary epithelium of the eye, the pigmented cells express the α1β1 isoform of Na,K-ATPase, whereas the non-pigmented cells express mainly the α2β3 isoform of Na,K-ATPase. In principle, a Na,K-ATPase inhibitor with selectivity for α2 could effectively reduce intraocular pressure with only minimal local and systemic toxicity. Such an inhibitor could be applied topically provided it was sufficiently permeable via the cornea. Previous experiments with recombinant human α1β1, α2β1, and α3β1 isoforms showed that the classical cardiac glycoside, digoxin, is partially α2-selective and also that the trisdigitoxose moiety is responsible for isoform selectivity. This led to a prediction that modification of the third digitoxose might increase α2 selectivity. A series of perhydro-1,4-oxazepine derivatives of digoxin have been synthesized by periodate oxidation and reductive amination using a variety of R-NH₂ substituents. Several derivatives show enhanced selectivity for α2 over α1, close to 8-fold in the best case. Effects of topically applied cardiac glycosides on intraocular pressure in rabbits have been assessed by their ability to either prevent or reverse acute intraocular pressure increases induced by 4-aminopyridine or a selective agonist of the A3 adenosine receptor. Two relatively α2-selective digoxin derivatives efficiently normalize the ocular hypertension, by comparison with digoxin, digoxigenin, or ouabain. This observation is consistent with a major role of α2 in aqueous humor production and suggests that, potentially, α2-selective digoxin derivatives could be of interest as novel drugs for control of intraocular pressure.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Environmental monitoring through functional biodiversity tools

The foundational concept for our research, which is largely shared by statisticians and ecologists, is that biodiversity is one of the most important indicators for environmental assessment. Because this indicator decreases in relation to ecosystem stressors, its measurement is essential for predicting future biological impacts of environmental damages. Although many indices have been proposed, no universally accepted measure for biodiversity has yet been established. In this context, the use of diversity profiles allows the analyst to display a family of indices in a single graph. However, this approach presents two critical limitations: first, a community composition is not always interpretable; second, the diversity profiles could lead to ranking issues when the curves intersect each other. The aim of this paper is to resolve these limitations by introducing functional biodiversity tools. In particular, three functional measures are proposed: the derivatives, the radius of curvature and the curve length. The analysis of derivatives and of the radius of curvature addresses the first limitation and highlights the characteristics, the differences and the similarities among communities. Arc length addresses the second limitation, providing a scalar measure that leads to a unique communities ranking for a given pattern of richness even if profiles intersect. The proposed functional models are applied to a real data set involving lichen biodiversity in the province of Genoa, Italy. Our approach allowed us to analyze the characteristics of lichen communities and to identify the biodiversity ranking. The combined use of these tools provides a useful method for identifying areas of high environmental risk, with the potential to address the monitoring of environmental policies.     

Synthesis of andrographolide derivatives and their TNF-alpha and IL-6 expression inhibitory activities

The synthesis of a series of andrographolide derivatives was described and their inhibitory effects on TNF-α and IL-6 secretion in mouse macrophages were also evaluated. Most of the tested compounds showed inhibitory effects, and the compounds with the structure of 12-hydroxy-14-dehydroandrographolide showed better inhibitory activity than the compounds with the structure of isoandrographolide.     

Microbial 2,3-butanediol production: a state-of-the-art review

2,3-Butanediol is a promising bulk chemical due to its extensive industry applications. The state-of-the-art nature of microbial 2,3-butanediol production is reviewed in this paper. Various strategies for efficient and economical microbial 2,3-butanediol production, including strain improvement, substrate alternation, and process development, are reviewed and compared with regard to their pros and cons. This review also summarizes value added derivatives of biologically produced 2,3-butanediol and different strategies for downstream processing. The future prospects of microbial 2,3-butanediol production are discussed in light of the current progress, challenges, and trends in this field. Guidelines for future studies are also proposed.     

壳聚糖及其衍生物抗肿瘤作用研究进展

壳聚糖为天然多糖甲壳素脱除部分乙酰基的产物,是自然界存在的唯一碱性多糖,无毒,可生物降解,具有免疫功能和良好的生物相容性。近年发现,壳聚糖具有抗肿瘤作用,却因其难溶于水及中性溶剂而影响其应用,壳聚糖衍生物改善了壳聚糖的这个缺点,也具有更广泛的药理作用。本文对壳聚糖及其壳聚糖衍生物在抗肿瘤方面的研究情况做了综述。     

Modeling of human CCR5 as Target for HIV-I and Virtual Screening with Marine Therapeutic compounds

Marine derivatives are of great pharmaceutical interest as inhibitory compound and search of bioactive compounds from Marine organism which is relatively new to medicinal chemistry. Our main aim in the study is to screen possible inhibitors against CCR5 which acts as co-receptor M-tropic HIV-1, through virtual screening of 122 Marine derived compounds from various organisms known to have biological activity. Homology Model of CCR5 was constructed using MODELLER and the Model was energy minimized and validated using PROCHECK to obtain a stable structure, which was further used for virtual screening of Marine derived compounds through molecular Docking studies using GOLD. The Docked complexes were validated and Enumerated based on the GOLD Scoring function to pick out the best Marine inhibitor based on GOLD score. Thus from the entire 122 Marine compounds which were Docked, we got best 4 of them with optimal GOLD Score. (LAMIVUDINE: 45.0218, BATZELLINE-D: 44.3852.ACYCLOVIR: 43.1362 and THIIOACETAMIDE: 42.7412) Further the Complexes were analyzed through LIGPLOT for their interaction for the 4 best docked Marine compounds. Thus from the Complex scoring and binding ability its deciphered that these Marine compounds could be promising inhibitors for M-tropic HIV-1 using CCR5 as Drug target yet pharmacological studies have to confirm it.