Antitumour and antimalarial activity of artemisinin–acridine hybrids

Artemisinin–acridine hybrids were prepared and evaluated for their in vitro activity against tumour cell lines and a chloroquine sensitive strain of Plasmodium falciparum. They showed a 2–4-fold increase in activity against HL60, MDA-MB-231 and MCF-7 cells in comparison with dihydroartemisinin (DHA) and moderate antimalarial activity. Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle.     

Synthesis,characterization and antimalarial activity of quinoline–pyrimidine hybrids

The aim of this study was to synthesize a series of quinoline–pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC₅₀: 0.157 vs 0.417 μM, ～threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.     

Synthesis,antimalarial activity and cytotoxicity of 4-aminoquinoline–triazine conjugates

A series of 4-aminoquinoline–triazine conjugates with different substitution pattern have been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive and resistant strains of Plasmodium falciparum. Compounds 16, 19, 28 and 35 exhibited promising antimalarial activity against both strains of P. falciparum. Cytotoxicity of these compounds was tested against three cell lines. Several compounds did not show any cytotoxicity up to a high concentration (48 μM), others exhibited mild toxicities but selective index for antimalarial activity was high for most of these conjugates.     

A new α-galactosidase from symbiotic Flavobacterium sp. TN17 reveals four residues essential for α-galactosidase activity of gastrointestinal bacteria

The α-galactosidase gene, galA17, was cloned from Flavobacterium sp. TN17, a symbiotic bacterium isolated from the gut of Batocera horsfieldi larvae. The 2,205-bp full-length gene encodes a 734-residue polypeptide (GalA17) containing a putative 28-residue signal peptide and a catalytic domain belonging to glycosyl hydrolase family 36 (GH 36). The deduced amino acid sequence of galA17 was most similar to a putative α-galactosidase from Pedobacter sp. BAL39 (EDM38577; 66.6% identity) and a characterized α-galactosidase from Carnobacterium piscicola BA (AAL27305; 30.1%). Phylogenetic analysis revealed that GalA17 was similar to GH 36 α-galactosidases from symbiotic bacteria sharing two putative catalytic motifs, KWD and SDXXDXXXR, in which D480, S548, D549, and R556 were essential for α-galactosidase activity based on site-directed mutagenesis. Purified recombinant GalA17 showed apparent optimal activity at pH 5.5 and 45°C; exhibited strong resistance to digestion by trypsin, α-chymotrypsin, collagenase, and proteinase K; and efficiently hydrolyzed several synthetic and natural substrates (p-nitrophenyl-α-d-galactopyranoside, stachyose, melibiose, raffinose, soybean meal, locust bean gum, and guar gum).     

Identification of new antimalarial leads by use of virtual screening against cytochrome bc₁

Cytochrome bc(1) is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new drugs. We screened in silico the ZINC and MOE databases, using ligand- and structure-based approaches, to identify new leads for development. The most active compound presented an IC(50) value against cultured P. falciparum of 2 μM and a docking pose consistent with its activity.     

Aeschynanthus hildebrandii Hemsl. ex Hook. f. (Gesneriaceae)—A new record for China

Aeschynanthus hildebrandii Hemsl. ex Hook. f. is reported as a new record for China.     

Α-galactosylceramide analogs with weak agonist activity for human iNKT cells define new candidate anti-inflammatory agents

CD1d-restricted natural killer T cells with invariant T cell receptor α chains (iNKT cells) are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of α-galactosylceramide (αGalCer), the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-γ (IFNγ), and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-γ secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans.     

How does the brain control its own activity? A new function for the basal ganglia

It has long been a problem in neuroscience to known how the brain controls its own activity, how it is able to control the level of CNS excitability and how it is able to select and act on some information as opposed to some other information. In this paper I propose a new theory in which the basal ganglia play a role in selecting information ("selective attention") and in controlling the general level of excitability of the CNS ("state control"), the two processes being to some extent interdependent. The basal ganglia achieve these functions by actions on the thalamic-frontal cortical axis and on the brainstem mesencephalic reticular formation.     

A new synthesis of 4′-resveratrol esters and evaluation of the potential for anti-depressant activity

The 4′-ester analog of the disease preventative resveratrol 1 (RV), 4′-acetyl-RV 2 along with 4′-pivaloate 13 and benzoate 14 RV were synthesized. The previously developed palladium catalyzed decarbonylative Heck coupling was used to assemble the stilbene core together with 3,5-dibenzyl protected phenol intermediates that allowed for efficient coupling and deprotection using boron trifluoride etherate. Studies with Long-Evans rats were performed to establish safety, toxicity, and behavioral parameters. In addition, the Porsalt forced-swim test was used to demonstrate anti-depressant activity.     

Synthesis,characterization, antimicrobial activity and structure–activity relationships of new aryldisulfonamides

A series of aromatic disulfonamide (1-8) derivatives and 4-methylbenzenesulfonyl hydrazide (9) were synthesized and characterized. All compounds were evaluated in vitro for their antimicrobial activity against Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633, Bacillus magaterium RSKK 5117, Escherichia coli ATCC 11230, Salmonella enterititis ATCC 13076 by microdilution and disc diffusion methods. Antimicrobial activity of the aromatic disulfonamides decreased as the length of the carbon chain increased. An analysis of the structure- activity relationship (SAR) along with computational studies showed that the most active compound (9) possessed low lipophilicity (AlogP=0.59) and high solubility (logS = -1.33).     

Molecular epidemiology: new rules for new tools?

Molecular epidemiology combines biological markers and epidemiological observations in the study of the environmental and genetic determinants of cancer and other diseases. The potential advantages associated with biomarkers are manifold and include: (a) increased sensitivity and specificity to carcinogenic exposures; (b) more precise evaluation of the interplay between genetic and environmental determinants of cancer; (c) earlier detection of carcinogenic effects of exposure; (d) characterization of disease subtypes-etiologies patterns; (e) evaluation of primary prevention measures. These, in turn, may translate into better tools for etiologic research, individual risk assessment, and, ultimately, primary and secondary prevention. An area that has not received sufficient attention concerns the validation of these biomarkers as surrogate endpoints for cancer risk. Validation of a candidate biomarker's surrogacy is the demonstration that it possesses the properties required for its use as a substitute for a true endpoint. The principles underlying the validation process underwent remarkable developments and discussion in therapeutic research. However, the challenges posed by the application of these principles to epidemiological research, where the basic tool for this validation (i.e., the randomized study) is seldom possible, have not been thoroughly explored. The validation process of surrogacy must be applied rigorously to intermediate biomarkers of cancer risk before using them as risk predictors at the individual as well as at the population level.     

Ca-inhibited binding of melittin with parvalbumin. A new role for parvalbumins?

It was found that pike parvalbumins pI 4.2 and 5.0 bind amphiphilic peptide melittin extracted from bee venom in an extraordinary Ca-dependent manner: in apo-state the protein forms a tight equimolar complex with melittin (Ka = 10(6) M-1 at 18 degrees C); in Ca- (and Mg-) loaded state it does not take place. Heating of the protein up to temperatures above the denaturation temperature of apo-parvalbumin does not change the stoichiometry of the complex but increases its association constant by an order of magnitude (Ka = 1.2.10(7) M-1 at 44 degrees C). Isolated Ca-binding domain of parvalbumin, 38-108, retains the ability for Ca-inhibited binding of equimolar quantities of melittin. The possible function of parvalbumin in vivo is suggested: Ca-inhibited interactions with some intracellular components.     

A new approach for determination of Na,K-ATPase activity: application to intact pancreatic β-cells

It has been postulated that a decrease in Na,K-ATPase-mediated ion gradients may be a contributing mechanism to insulin secretion. However, the precise role of the Na,K-ATPase in pancreatic β-cell membrane depolarization and insulin secretion signalling have been difficult to evaluate, mostly because data reporting changes in enzymatic activity have been obtained in cell homogenates or membrane preparations, lacking intact intracellular signalling pathways. The aim of this work was to develop a method to characterize Na,K-ATPase activity in intact pancreatic β-cells that will allow the investigation of putative Na,K-ATPase activity regulation by glucose and its possible role in insulin secretion signalling. This work demonstrates for the first time that it is possible to determine Na,K-ATPase activity in intact pancreatic β-cells and that this is a suitable method for the study of the mechanisms involved in the Na,K-ATPase regulation and eventually its relevance for insulin secretion signalling.     

Do we need new antibiotics? The search for new targets and new compounds

Resistance to antibiotics and other antimicrobial compounds continues to increase. There are several possibilities for protection against pathogenic microorganisms, for instance, preparation of new vaccines against resistant bacterial strains, use of specific bacteriophages, and searching for new antibiotics. The antibiotic search includes: (1) looking for new antibiotics from nontraditional or less traditional sources, (2) sequencing microbial genomes with the aim of finding genes specifying biosynthesis of antibiotics, (3) analyzing DNA from the environment (metagenomics), (4) reexamining forgotten natural compounds and products of their transformations, and (5) investigating new antibiotic targets in pathogenic bacteria.     

Discovery and preliminary structure–activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds

Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC₅₀ 0.89 μM). Preliminary structure–activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC₅₀ 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics.     

Novel antimalarial drugs from plants?

In all countries where malaria is endemic, plants are used in traditional medicine for treatment of the disease. Examples are numerous - the plant product data base napralert (Box I) lists 152 genera which are allegedly used for the treatment of malaria. But with the urgent need to develop new, safe and effective drugs against malaria, it is vital that such claims be fully investigated. In this article, David Phillipson and Melanie O'Neill discuss the potential of plant products for new antimoloriols, drawing attention particularly to the quassinoids - a diverse group of terpenoids from the family Simoroubaceoe.