Complexation of desferricoprogen with trivalent Fe, Al, Ga, In and divalent Fe, Ni, Cu, Zn metal ions: effects of the linking chain structure on the metal binding ability of hydroxamate based siderophores

Complexes of the natural siderophore, desferricoprogen (DFC), with several trivalent and divalent metal ions in aqueous solution were studied by pH-potentiometry, UV-Vis spectrophotometry and cyclic voltammetry. DFC was found to be an effective metal binding ligand, which, in addition to Fe(III), forms complexes of high stability with Ga(III), Al(III), In(III), Cu(II), Ni(II) and Zn(II). Fe(II), however, is oxidized by DFC under anaerobic conditions and Fe(III) complexes are formed. By comparing the results with those of desferrioxamine B (DFB), it can be concluded that the conjugated beta-double bond slightly increases the stability of the hydroxamate chelates, consequently increases the stability of mono-chelated complexes of DFC. Any steric effect by the connecting chains arises only in the bis- and tris-chelated complexes. With metal ions possessing a relatively big ionic radius (Cu(II), Ni(II), Zn(II), In(III)) DFC, containing a bit longer chains than DFB, forms slightly more stable complexes. With smaller metal ions the trend is the opposite. Also a notable difference is that stable trinuclear complex, [Cu(3)L(2)], is formed with DFC but not with DFB. Possible bio-relevance of the Fe(II)/Fe(III) results is also discussed in the paper.     

Some factors affecting metal ion-monohydroxamate interactions in aqueous solution

The chelating properties exhibited by a series of monohydroxamic acids (propanohydroxamic acid (Pha), hexanohydroxamic acid (Hha), benzohydroxamic acid (Bha), N-methyl-acetohydroxamic acid (MAha), N-phenyl-acetohydroxamic acid (PhAha) and 2-hydroxypyridine-N-oxide (PYRha)) towards copper(II), nickel(II), zinc(II), calcium(II), magnesium(II) and aluminium(III) ions were studied by pH-metric, spectrophotometric and, in one case, by 27Al NMR methods. The results were compared with the corresponding data for metal ion-acetohydroxamate (Aha) and metal ion-desferrioxamine B (DFB) complexes. Changes of the substituents either on the carbon or on the nitrogen of the hydroxamate moiety caused a measurable effect on the chelate stability only in the case of aluminium(III) complexes. The aromatic derivative, PYRha, formed significantly more stable complexes than expected on the basis of the ligand basicity. The higher complex-forming ability of DFB compared to monohydroxamic acids diminishes in the case of the largest calcium(II) ion.     

Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors

A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.     

Pteridine–sulfonamide conjugates as dual inhibitors of carbonic anhydrases and dihydrofolate reductase with potential antitumor activity

Recent evidences suggest that cancer treatment based on combination of cytostatic and conventional chemostatic therapeutics, which are usually cytotoxic, can provide an improved curative option. On the sequence of our previous work on methotrexate (MTX) derivatives, we have developed and evaluated novel MTX analogues, containing a pteridine moiety conjugated with benzenesulfonamide derivatives, thus endowed with the potential capacity for dual inhibition of dihydrofolate reductase (DHFR) and carbonic anhydrases (CA). These enzymes are often overexpressed in tumors and are involved in two unrelated cellular pathways, important for tumor survival and progression. Their simultaneous inhibition may turn beneficial in terms of enhanced antitumor activity.Herein we report the design and synthesis of several diaminopteridine–benzenesulfonamide and -benzenesulfonate conjugates, differing in the nature and size of the spacer group between the two key moieties. The inhibition studies performed on a set of CAs and DHFR, revealed the activities in the low nanomolar and low micromolar ranges of concentration, respectively. Some inhibitors showed selectivity for the tumor-related CA (isozyme IX). Cell proliferation assays using two tumor cell lines (the non-small cell lung carcinoma, A549, and prostate carcinoma, PC-3) showed activities only in the millimolar range. Nevertheless, this fact points out the need of improving the cell intake properties of these new compounds, since the general inhibitory profiles revealed their potential as anticancer agents.     

An in vitro study of interactions between insulin-mimetic zinc(II) complexes and selected plasma components

The speciations of some potent insulin-mimetic zinc(II) complexes of bidentate ligands: maltol and 1,2-dimethyl-3-hydroxypyridinone with (O,O) and picolinic acid with (N,O) coordination modes, were studied via solution equilibrium investigations of the ternary complex formation in the presence of small relevant bioligands of the blood serum such as cysteine, histidine and citric acid. Results show that formation of the ternary complexes, especially with cysteine, is favoured at physiological pH range in almost all systems studied. Besides these low molecular mass binders, serum proteins among others albumin and transferrin can bind zinc(II) or its complexes. Accordingly, the distribution of zinc(II) between the small and high molecular mass fractions of the serum was also studied by ultrafiltration. Modelling calculations relating to the distribution of zinc(II), using the stability constants of the ternary complexes studied and those of the serum proteins reported in the literature, confirmed the ultrafiltration results, namely, the primary role of albumin in zinc(II) binding among the low and high molecular mass components of the serum.     

Purification and characterization of Dolichos lablab lectin

The mannose/glucose-binding Dolichos lablab lectin (designated DLL) has been purified from seeds of Dolichos lablab (hyacinth bean) to electrophoretic homogeneity by affinity chromatography on an ovalbumin- Sepharose 4B column. The purified lectin gave a single symmetric protein peak with an apparent molecular mass of 67 kDa on gel filtration chromatography, and five bands ranging from 10 kDa to 22 kDa upon SDS-PAGE. N-Terminal sequence analysis of these bands revealed subunit heterogeneity due to posttranslational proteolytic truncation at different sites mostly at the carboxyl terminus. The carbohydrate binding properties of the purified lectin were investigated by three different approaches: hemagglutination inhibition assay, quantitative precipitation inhibition assay, and ELISA. On the basis of these studies, it is concluded that the Dolichos lablab lectin has neither an extended carbohydrate combining site, nor a hydrophobic binding site adjacent to it. The carbohydrate combining site of DLL appears to most effectively accommodate a nonreducing terminal alpha-d-mannosyl unit, and to be complementary to the C-3, C-4, and C-6 equatorial hydroxyl groups of alpha-d-mannopyranosyl and alpha-d-glucopyranosyl residues. DLL strongly precipitates murine IgM but not IgG, and the recent finding that this lectin interacts specifically with NIH 3T3 fibroblasts transfected with the Flt3 tyrosine kinase receptor and preserves human cord blood stem cells and progenitors in a quiescent state for prolonged periods in culture, make this lectin a valuable tool in biomedical research.      

Pharmacophore-based discovery of 3,4-disubstituted pyrrolidines as a novel class of monoamine transporter inhibitors

3,4-Disubstituted pyrrolidines were discovered as a novel class of monoamine transporter inhibitors through 3-D database pharmacophore searching using a new pharmacophore model. The most potent analogue 12 has Ki values of 0.084 microM in [3H]mazindol binding, 0.20, 0.23, and 0.031 microM in inhibition of dopamine (DA), serotonin (SER), and norepinephrine (NE) reuptake, respectively. Functional antagonism testing in vitro showed that 11 and 12 are weak cocaine antagonists.     

不同胁迫预处理提高水稻幼苗抗寒性期间蛋白质的变化

水稻(Oryza sativa L.)幼苗经盐、热激和冷三种不同胁迫预处理均提高了幼苗的抗寒性。与未预处理苗相比,在处理后、低温伤害后和常温下恢复2d的三个时期,不同胁迫预处理苗的可溶性和热不稳定蛋白含量变化趋势甚为相似,但热稳定蛋白含量变化则各有异同。SDS-PAGE图谱分析显示,不同胁迫预处理提高水稻幼苗抗寒性时,其可溶性蛋白、热稳定和热不稳定蛋白组成变化亦各有异同。除诱导出共有的新多肽外,还各自诱导出特有的新多肽。结果表明,植物对不同胁迫的交叉适应存在一定的共同机理,但亦可看出植物对同一种环境胁迫似乎不是以同一的机理去适应。     

Investigating small molecules to inhibit germinal center kinase-like kinase (GLK/MAP4K3) upstream of PKCθ phosphorylation: Potential therapy to modulate T cell dependent immunity

Germinal center kinase-like kinase (GLK, also known as MAP4K3) has been hypothesized to have an effect on key cellular activities, including inflammatory responses. GLK is required for activation of protein kinase C-θ (PKCθ) in T cells. Controlling the activity of T helper cell responses could be valuable for the treatment of autoimmune diseases. This approach circumvents previous unsuccessful approaches to target PKCθ directly. The use of structure based drug design, aided by the first crystal structure of GLK, led to the discovery of several inhibitors that demonstrate potent inhibition of GLK biochemically and in relevant cell lines.