Antiproliferative and antibacterial activity of some glutarimide derivatives

Antiproliferative and antibacterial activities of nine glutarimide derivatives (1–9) were reported. Cytotoxicity of compounds was tested toward three human cancer cell lines, HeLa, K562 and MDA-MB-453 by MTT assay. Compound 7 (2-benzyl-2-azaspiro[5.11]heptadecane-1,3,7-trione), containing 12-membered ketone ring, was found to be the most potent toward all tested cell lines (IC₅₀?=?9–27?μM). Preliminary screening of antibacterial activity by a disk diffusion method showed that Gram-positive bacteria were more susceptible to the tested compounds than Gram-negative bacteria. Minimum inhibitory concentration (MIC) determined by a broth microdilution method confirmed that compounds 1, 2, 4, 6–8 and 9 inhibited the growth of all tested Gram-positive and some of the Gram-negative bacteria. The best antibacterial potential was achieved with compound 9 (ethyl 4-(1-benzyl-2,6-dioxopiperidin-3-yl)butanoate) against Bacillus cereus (MIC 0.625?mg/mL; 1.97?×?10^?3?mol/L). Distinction between more and less active/inactive compounds was assessed from the pharmacophoric patterns obtained by molecular interaction fields.     

Synthesis and Antiviral Activity Evaluation of 2′,5′,5′-Trifluoro-Apiosyl Nucleoside Phosphonic Acid Analogs

Racemic synthesis of novel 2′,5′,5′-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity.     

Contrast agents for magnetic resonance angiographic applications: 1H and 17O NMR relaxometric investigations on two gadolinium(III) DTPA-like chelates endowed with high binding affinity to human serum albumin

N,N′,N″,N‴ -pentaacetic acid) bearing different substituents for binding to human serum albumin (HSA) are compared. In spite of the structural differences of the recognition synthon and of the residual electric charge, the two chelates display an analogous binding affinity for the serum protein. Upon formation of the adducts with HSA, the exchange rates of the coordinated water appear slowed down by an amount corresponding to ca. 50% of the rates found for the free complexes. The relaxivity of [Gd(BOM)₃DTPA (H₂O)]^2 − is significantly higher than that of MS-325 either in the free complex or in the macromolecular adduct. Finally, the effect of pH on the stability of the HSA adducts and on the values of their relaxivities has been investigated. Received: 11 June 1999 / Accepted: 15 September 1999     

High-performance liquid chromatographic method for sensitive determination of the alkylating agent CB1954 in human plasma

A high-performance liquid chromatography (HPLC) method is described for the measurement of the weak alkylating agent CB1954 in human plasma. CB1954 can be used as an innocuous prodrug designed for activation by bacterial nitroreductases in strategies of gene-directed enzyme–prodrug therapy, and becomes activated to a potent bifunctional alkylating agent. The HPLC method involves precipitation and solvent extraction and uses Mitomycin C (MMC) as an internal standard, with a retention time for MMC of 5.85±0.015 min, and for CB1954 of 10.72±0.063 min. The limit of detection for CB1954 is 2.9 ng/ml, and this compares favourably with systems involving direct analysis of plasma (limit of detection 600 ng/ml, approximately). The method is now being used for pharmacokinetic measurements in plasma samples from cancer patients entering phase I clinical trials of CB1954. Results using serial plasma samples from one patient are presented. The patient was treated intravenously with CB1954 (6 mg/m²), and plasma clearance of the drug showed biphasic kinetics with α half-life 14.6 min, and β half-life 170.5 min.     

蛋白质的错误折叠与疾病

蛋白质是生物体内一切功能的执行者.人体内的任何功能,从催化化学反应到抵御外来侵略都是蛋白质作用的结果.蛋白质折叠是生命活动的最基本过程,近年发现蛋白质的错误折叠可以导致一些疾病.蛋白质的错误折叠与疾病的关系已成为分子生物学新的研究前沿.介绍了细胞内保证蛋白质正常功能的“质量控制”系统,重点讨论了翻译后的质量控制、与蛋白质错误折叠有关的一些疾病和治疗这一类疾病的原则方法.     

Assessment of the potential of Nostoc strains from the Pasteur Culture Collection for the production of polysaccharides of applied interest

The exocellular polysaccharides released during thephotoautotrophic growth by 25 Nostoc strainsbelonging to the Pasteur Culture Collection (PCC) wereinvestigated with regard to their chemical andrheological properties in order to assess theirpotential for the production of polysaccharides ofindustrial interest.All the released polysaccharides (RPSs) were complexanionic heteropolymers, composed of a number ofmonosaccharides ranging from six to nine, alwaysincluding glucose and fucose, and most frequentlygalactose. Ribose, rarely reported to be present incyanobacterial RPSs, was found in seven polymers. TheRPSs were shown to possess an anionic charge due tothe presence of uronic acids and in most cases also ofpyruvil and sulphate groups. Moreover, a large numberof polymers showed the presence of significant amountsof constituents such as acetyl groups, peptidicmoieties and deoxysugars, that may contribute to thehydrophobicity of the macromolecules. The viscositydependence on the shear rate of aqueous solutions ofthe RPSs was, in three cases, comparable with that ofxanthan gum, and one RPS showed a very satisfactorystability of the viscosity over a wide range of pH,temperature and salinity values. The most promisingPCC Nostoc strains for the production of RPSsfor specific applications were thus singled out, basedon the characteristics of their polymers.     

溶栓剂研究的新进展

近年来对溶栓剂的研究取得了很好的成果 ,主要集中在单链尿激酶型纤溶酶原激活剂 (scu PA) ,组织型纤溶酶原激活剂 (t PA) ,葡萄球菌激酶 (SAK)等 ,对分子进行设计改造 ,保留它们高效的溶栓功能同时赋予新的功能。在对分子空间结构域和活性功能区分析的基础上 ,研制出更有效的、更安全的溶栓制剂具有广阔的发展前景。     

Reprobing into Rice Breeding for High Photosynthetic Efficiency

The leaf area index (LAI) development, which is related to the capacity of light interception, and the maximum leaf photosynthetic rate (Pmax), which related to the efficiency of light energy conversion, are two key photosynthetic traits to increase the utilization efficiency of solar energy. Using the Guangdong rice "Qiguizao', which belongs to low light adapt-able ecotype and characterized by quick developing LAI, and the US rice "Lemont', which belongs to high light adaptable ecotype and characterized by higher light saturation point of photosynthesis, as parents to make a hybrid (Le/Qi) by means of chemical hybridizing agent, the authors successfully solved the contradiction between LAI and Prix. The hybrid Le/Qi not only showed quick developing LAI, but also higher Pmax, less or no midday depression of photosynthesis and less or no photooxidation under high light induced conditions. The photosynthetic productivity and adaptability of Le/Qi were increased over 20 % and improved a lot according to the growth analysis under different light and temperature conditions in growth chambers and field trials in flatlands, hilly land or mountain area. This study indicated that utilization of high light adaptable US elite rice as parent to make a hybrid with Guangdong low light adaptable local elite rice by means of chemical hybridizing agent is an effective and quick breeding approach to improve the adaptability of Guangdong rice to high light and to increase the photosynthetic productivity in turn the economic income.     

Consumo crónico de edulcorantes en ratones y su efecto sobre el sistema inmunitario y la microbiota del intestino delgado

Introduction:

Sweeteners are additives used in different foods. They can be natural (sucrose and stevia) or artificial (sucralose). Currently, they are routinely consumed in multiple products and their effects on the mucosa of the small intestine and its microbiota are still controversial.

Objective:

To relate the consumption of sweeteners and their effect on the immune system and the microbiota of the small intestine in CD1 mice.

Materials and methods:

We used 54 three-week-old CD1 mice divided into three groups in the experiments: 1) A group of three weeks without treatment, 2) a group treated for six weeks, and 3) a group treated for 12 weeks using sucrose, sucralose, and stevia. We obtained CD19+ B lymphocytes, IgA+ antibodies, transforming growth factor-beta (TGF-b), and interleukins 12 and 17 (IL-12 and -17) from Peyer''s patches and lamina propria cells while DNA was obtained from intestinal solids to identify bacterial species.

Results:

After 12 weeks, sucrose and sucralose consumption caused a reduction in bacterial communities with an increase in CD19+, a decrease in IgA+ and TGF-b, and an increase in IL-12 and -17 in the Peyer''s patches while in the lamina propria there was an increase in all parameters. In contrast, stevia led to an improvement in bacterial diversity and percentage of CD19+ lymphocytes with minimal increase in IgA+, TGF-b, and IL-12, and a decrease in IL-17.

Conclusion:

Sucrose and sucralose caused negative alterations in bacterial diversity and immune parameters after 12 weeks; in contrast, stevia was beneficial for the intestinal mucosa.