Novel N-substituted-2-cyanopyrrolidines as potent inhibitors of dipeptidyl peptidase IV in the treatment of non-insulin-dependent diabetes mellitus

This is the second patent application from Novartis describing N-substituted-2-cyanopyrrolidines as inhibitors of dipeptidyl peptidase IV (DPP-IV). DPP-IV is a serine protease which cleaves Xaa-Pro- or Xaa-Ala- amino terminal sequences from biologically active peptides, transforming them into inactive or even antagonistic species. Among them is glucagon-like peptide 1 (GLP-1), a major stimulator of pancreatic insulin secretion with additional properties in lowering the blood glucose level, which is normally secreted in response to food ingestion. By inhibiting DPP-IV the endogenous GLP-1 is preserved for longer periods, the inhibitors being useful in the treatment of the non-insulin-dependent diabetes mellitus (NIDDM), obesity, arthritis, osteoporosis and other diseases generated or enhanced by impaired glucose tolerance. The compounds claimed in this application are novel N-substituted 2-cyanopyrrolidines bearing adamantyl moieties as biocompatible lipophylic groups; their low nanomolar level of DPP-IV inhibition, as well as their in vivo therapeutic profile, are improved as compared with the results obtained in previous studies.     

Artemisinin derivatives: a patent review (2006 – present)

Introduction: The isolation of artemisinin from an ancient Chinese remedy in the early 1970s heralded the beginning of a new era in antimalarial drug therapy culminating in artemisinin-based combination therapies currently being the mainstay of malaria treatment worldwide. Ongoing research on this compound and its derivatives has revealed its potential use in treating other infectious and noninfectious diseases.

Areas covered: This review provides a summary of patents published globally from January 2006 to June 2012 covering promising artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas.

Expert opinion: The diversity of semi-synthetic artemisinin derivatives has been limited to the same design strategy of modifying the artemisinin molecule at the same positions due to inherent synthetic challenges. To address this, future endeavors should include: the use of biotransformation strategies to modify other positions in the sesquiterpene ring while retaining the endoperoxide bridge; the design and synthesis of synthetic ozonides based on the pharmacophoric endoperoxide motif and drug repositioning approaches to artemisinin-based combination therapy. A better understanding of the mechanism of action of artemisinin derivatives and their biomolecular targets may provide an invaluable tool for the development of derivatives with a wider array of activity and greater clinical utility than currently appreciated.     

Caffeoyl phenols and alkamides of cultivated Echinacea purpurea and Echinacea atrorubens var. paradoxa

Echinacea purpurea (L.) Moench was recently introduced into Taiwan. In the present study, the biomass, the contents of caffeoyl phenols, and the content of dodeca-2E,4E,8Z,10E-tetraenoic acid isobutylamide plus dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (alkamides 8 and 9 respectively,) of locally selected line CLS-P2 and two introduced cultivars Magnus and White Swan of E. purpurea and an introduced E. atrorubens var. paradoxa were compared. The results indicated that both biomass and phytoactive constituents varied considerably among the introduced cultivars and selected line. Line CLS-P2 grew better and produced more aerial and ground parts than introduced cultivars Magnus and White Swan. It also produced more caffeoyl phenols, particularly cichoric acid and caftaric acid in its leaves than Magnus and White Swan. All the E. purpurea cultivars and line produced same amounts of alkamides 8 and 9 in their flower heads and leaves. But White Swan produced more alkamides 8 and 9 in its roots than CLS-P2 and Magnus. Line CLS-P2 was less homogenous in genetic background as compared to the introduced cultivars. E. atrorubens var. paradoxa also grew well in Taiwan, but it produced less aerial and ground dry mass than E. purpurea. E. atrorubens var. paradoxa produced more echinacoside in its flower heads, leaves, and root parts, while E. purpurea plants had more cichoric acid and caftaric acid in their flower heads and leaves. E. atrorubens var. paradoxa also produced more alkamides 8 and 9 in flower heads and leaves, while E. purpurea produced more alkamides 8 and 9 in roots.     

Effect of emulsification on the skin permeation and UV protection of catechin

Abstract

An anti-aging effect may be obtained by skin application of tea catechins (Camellia sinensis) since they have high ultraviolet (UV)-protection activity. In this study, the skin permeation of catechin (C), epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg) was determined and compared, and the effect of emulsification on the skin permeation of C was measured. The UV-protective effect of C was also determined. The in vitro skin permeability of each catechin derivative was determined using side-by-side diffusion of cells. The UV-protective effect of C was determined by applying different concentrations of C to the solution or emulsion on a three-dimensional cultured human skin model or normal human epidermal keratinocytes with UV-irradiation. ECg and EGCg with gallate groups showed lower skin permeability than C, EC and EGC without gallate groups, suggesting that the skin permeability of catechin derivatives may be dependent on the existence of a gallate group. Interestingly, the skin permeation of C was increased by an o/w emulsification. In addition, the C emulsion showed a significantly higher UV-protective effect by C than that with its aqueous solution. These results suggest that the o/w emulsion of catechin derivatives is probably useful as a cosmetic formulation with anti-aging efficacy.     

2-(4-Hydroxyphenyl)-5-(3-Hydroxypropenyl)-7-Methoxybenzofuran,a Novel Ailanthoidol Derivative,Exerts Anti-Inflammatory Effect through Downregulation of Mitogen-Activated Protein Kinase in Lipopolysaccharide-Treated RAW 264.7 Cells

We reported that ailanthoidol, a neolignan from Zanthoxylum ailanthoides and Salvia miltiorrhiza Bunge, inhibited inflammatory reactions by macrophages and protected mice from endotoxin shock. We examined the anti-inflammatory activity of six synthetic ailanthoidol derivatives (compounds 1-6). Among them, compound 4, 2-(4-hydroxyphenyl)-5-(3-hydroxypropenyl)-7-methoxybenzofuran, had the lowest IC₅₀ value concerning nitric oxide (NO) release from lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Compound 4 suppressed the generation of prostaglandin (PG) E₂ and the expression of inducible NO synthase and cyclooxygenase (COX)-2 induced by LPS, and inhibited the release of LPS-induced pro-inflammatory cytokines from RAW264.7 cells. The underlying mechanism of compound 4 on anti-inflammatory action was correlated with the down-regulation of mitogen-activated protein kinase and activator protein-1 activation. Compound 4 is potentially an effective functional chemical candidate for the prevention of inflammatory diseases.     

氨基吡唑衍生物的合成

目的 优化氨基吡唑类衍生物的合成工艺.方法 以丙二氰为起始原料,首先在碱性条件下聚合为二聚物,然后与85％的水合肼关环得3-氨基-4-氰基-5-氰甲基-2-吡唑,最终在不同的酸碱条件下水解,得到不同的氨基吡唑甲酸类衍生物.结果 考察了3步反应工艺对产品收率的影响,结果表明,较佳的反应条件为：聚合反应中,室温条件下,以氢氧化钠为碱试剂、乙醇为溶剂,二聚物的收率为86.1％;关吡唑环反应中,n（二聚物）：n（肼）=1∶3.5,产物收率为86.2％;碱性条件下水解反应,95 ～ 100℃条件下,10 mol/L氢氧化钠溶液中反应10 h,5-氨基-1-吡唑-3-乙酸收率为79.8％;酸性条件下水解反应,85℃条件下,浓硫酸∶乙酸（体积比）=1∶1,反应24 h,3-氨基-4-氰基吡唑-5-甲酸收率为69.7％.结论 本工艺路线环境友好,原料易得,便于操作.同时,所得产物经1HNMR及MS确证.     

噁唑烷酮醚类化合物的合成及其Ⅹa因子抑制活性

以利伐沙班结构为基础,根据其与Ⅹa因子相互作用的特点对其进行结构改造,设计并合成了一系列未见报道的GFDA2唑烷酮醚类化合物(7a~7m)。所合成化合物结构均经IR,¹H NMR和MS确证,并测定了目标衍生物Ⅹa因子抑制活性。实验数据表明,所合成化合物均表现出了一定的Ⅹa因子抑制活性,但活性低于利伐沙班。     

芒果苷酯化衍生物的合成及其降血糖活性（英文）

目的：合成3个具有新化学结构的芒果苷酯化衍生物,并评价其降血糖活性。方法：芒果苷分别直接与乙酸酐、丙酸酐和丁酸酐反应,制备酯化衍生物;用链脲霉素（STZ）诱导的高血糖小鼠模型评价所得芒果苷酯化衍生物的降血糖活性;检查胰岛切片,观察胰岛细胞的形态变化。结果：3个芒果苷酯化衍生物为：7,2＇,3＇,4＇,6＇-penta-acetyl-mangiferin（PAM）、3,6,7,2＇,3＇,4＇,6＇-hepta-propionyl-mangiferin（HPM）和3,6,7,2＇,3＇,4＇-hexa-butyryl-mangiferin（HBM）,其结构用MS,1H,13CNMR和2D-NMR确证。这3个芒果苷酯化衍生物的结构为第一次报道。PAM高、中剂量组（0.5,0.25mmol·kg1）,HPM高、中剂量组（0.5,0.25mmol·kg1）和HBM高、中、低剂量组（0.5,0.25,0.125mmol·kg1）表现出较高的降血糖活性（P〈0.01）;芒果苷高、中剂量组（1,0.5mmol·kg1）、PAM低剂量组（0.125mmol·kg1）和HPM低剂量组（0.125mmol·kg1）有一定的降血糖活性（P〈0.05）;芒果苷低剂量组（0.25mmol·kg1）虽有降血糖的作用趋势,但统计学意义不显著。在切片检查中,PAM、HPM和HBM均能使STZ所致的胰岛细胞损伤得到很好地恢复,变得形态正常;芒果苷组的胰岛细胞也得到一定程度地恢复,但没有前三者的好。结论：芒果苷酯化衍生物比芒果苷本身具有更好的脂溶性和降血糖活性,并表现出一定的结构-效应关系和脂溶性-效应关系：酯化基团越长,衍生物的脂溶性越大,其降血糖活性也越高（无酯化→乙酯化→丙酯化→丁酯化）。脂溶性增加是芒果苷酯化衍生物降糖活性提高的根本原因。酯化衍生是提高芒果苷生物活性的一个重要途径;研究结果提示芒果苷酯化衍生物是一群具有开发成降血糖药物潜力的新结构化合物。     

Repeated-dose toxicological studies of Tithonia diversifolia (Hemsl.) A. gray and identification of the toxic compounds

Ethnopharmacological relevance

Tithonia diversifolia (Hemsl.) A. Gray has been commonly used in folk medicine to treat abscesses, microbiological infections, snake bites, malaria and diabetes. Both anti-inflammatory and anti-malarial properties have been identified using appropriate assays, but the effective doses have demonstrated toxic effects for the experimental animals. Most of the pharmacological activities have been attributed to sesquiterpene lactones (STLs) and some chlorogenic acid derivatives (CAs) in the leaves of this species. This work aimed to evaluate the repeated-dose toxicity of an aqueous extract (AE) from Tithonia diversifolia leaves and to compare the results with an extract rich in STLs (LRE) and a polar extract (PE) without STLs but rich in CAs. The purpose of this work was to provide insights into the identity of the compounds responsible for the toxic effects of Tithonia diversifolia.

Materials and methods

The major classes of compounds were confirmed in each extract by IR spectra and HPLC-UV-DAD profiling using previously isolated or standard compounds. The toxicity of each extract was evaluated in a repeated-dose toxicity study in Wistar rats for 90 days.

Results

The AE is composed of both STLs and CAs, the LRE is rich in STLs, and the PE is rich in CAs. The AE caused alterations in haematological parameters but few alterations in biochemical parameters and was relatively safe at doses lower than 100 mg/kg. However, the PE and LRE demonstrated several adverse effects by damaging the liver and kidneys, respectively.

Conclusion

STLs and CAs can be toxic in prolonged use at higher doses in extracts prepared from Tithonia diversifolia by affecting the kidneys and liver.     

同步放化疗治疗19例不能手术切除的局部晚期肝外胆管癌患者

目的：评估同步放化疗对不能手术切除的局部晚期肝外胆管癌患者的临床疗效及不良反应。方法：选取2007年2月至2012年2月绍兴市人民医院肿瘤放疗科收治的38例不能手术切除的局部晚期肝外胆管癌患者,随机分成序贯放化疗组（19例）与同步放化疗组（19例）,均采用调强适形放疗,其中同步放化疗组接受吉西他滨联合奥沙利铂化疗。治疗结束后观察比较两组患者的疗效、不良反应,并进行生存分析。结果：序贯放化疗组和同步放化疗组有效率分别为42.1%（8/19）和63.2%（12/19）,疾病控制率分别为78.9%（15/19）和84.2%（16/19）,中位疾病无进展生存时间分别为8.3和10.4个月,中位总生存时间分别为14.2和15.6个月,其中中位疾病无进展生存时间两组间差异有统计学意义（P=0.037）。两组患者放化疗不良反应均可控,其发生率差异均无统计学意义（均P＞0.05）。结论：对于不能手术且体力状况评分≤2分的局部晚期肝外胆管癌患者,序贯放化疗与同步放化疗均能有效延长疾病无进展生存时间和总生存时间,且耐受性良好,其中同步放化疗效果可能更佳。