Photolysis and thermolysis of platinum(IV) 2,2'-bipyridine complexes lead to identical platinum(II)-DNA adducts.

Two Pt(IV) and two Pt(II) complexes containing a 2,2'-bipyridine ligand were treated with a short DNA oligonucleotide under light irradiation at 37°C or in the dark at 37 and 50°C. Photolysis and thermolysis of the Pt(IV) complexes led to spontaneous reduction of the Pt(IV) to the corresponding Pt(II) complexes and to binding of Pt(II) 2,2'-bipyridine complexes to N7 of guanine. When the reduction product was [Pt(bpy)Cl(2)], formation of bis-oligonucleotide adducts was observed, whereas [Pt(bpy)(MeNH(2))Cl](+) gave monoadducts, with chloride ligands substituted in both cases. Neither in the dark nor under light irradiation was the reductive elimination process of these Pt(IV) complexes accompanied by oxidative DNA damage. This work raises the question of the stability of photoactivatable Pt(IV) complexes toward moderate heating conditions.

Occurrence and ecological determinants of the contamination of floodplain wetlands with Klebsiella pneumoniae and pathogenic or antibiotic-resistant Escherichia coli.

The survival and multiplication of human pathogenic and antibiotic-resistant bacteria in ecosystems is of increasing concern but has been little explored. Wetlands can be contaminated by water fluxes from rivers and may present environmental conditions leading to bacterial survival and multiplication. To test this hypothesis, we sampled 16 wetlands located along three rivers of the Jura Massif, France. The bacterial contamination of the wetland and river waters was measured monthly over a one-year cycle together with the water physico-chemical characteristics. We assessed the abundance of three pathogenic species: Escherichia coli,Klebsiella pneumoniaeand Pseudomonas aeruginosa. The concentrations of E. coli producing extended-spectrum ß-lactamase (ESBL E. coli) or belonging to the phylogenetic group B2 (E. coli B2-more pathogenic) were also measured. We found that rivers carried total E. coli, ESBL E. coli, and K. pneumoniae to wetlands. ESBL E. coli poorly survived in wetlands, whereas total E. coli and K. pneumoniae possibly met favourable physico-chemical conditions for survival and multiplication in these habitats. K. pneumoniae peaked in summer in warm and shallow wetlands. Total E. coli and E. coli B2 potentially reached wetlands through sources other than rivers (hillslope groundwater or leaching from contaminated fields).

Relationships between key functional traits of the waterlily Nuphar lutea and wetland nutrient content.

Little attention has been paid to how aquatic habitat characteristics affect the traits of plant species. Nuphar lutea (L.) Sm. is a keystone species distributed across temperate regions of Europe, northwest Africa and western Asia. Its apparently low phenotypic variability compared to other aquatic plants led us to test whether the species exhibited significant phenotypic variability and whether trait values correlated to environmental parameters. The hypotheses were that (1) the environmental variation within our set of wetlands (both water and sediment characteristics) led to significant variation among four sets of traits related respectively to growth, reproduction, defence and storage and (2) that nutrient limitation (nitrogen and especially phosphorus) should affect plant traits towards a higher investment in storage and defence and a lower investment in growth and reproduction, thereby negatively affecting the success of N. lutea. To test these hypotheses, 11 populations of N. lutea were sampled in wetlands differing in physicochemical characteristics and spread along three rivers. A total of 15 traits, grouped into four sets (growth, reproduction, storage and defence), were measured during the growing season. Most N. lutea traits were related to the environmental characteristics of wetlands. The growth and reproduction traits were mostly positively related to habitat resource conditions, whereas the defence traits were positively correlated with both ammonium concentration and temperature, outlining possible anoxic stress (habitat adversity). Nitrogen or phosphorus limitation led to the variation of only a few traits: the rhizome starch content was higher in phosphorus-limited wetlands, while the rhizome length and volume, and the number of flowers were higher in nitrogen-limited wetlands.

Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine.

Trioxaquines, potential antimalarial agents, and heme-artemisinin adducts, resulting from the alkylation of heme by artemisinin, were evaluated as inhibitors of beta-hematin formation in 10 M acetate medium at pH 5.

Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes.

Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

Synthesis of new macrocyclic chiral manganese(III) Schiff bases as catalysts for asymmetric epoxidation.

We describe a general synthetic strategy for the preparation of a series of macrocyclic chiral manganese(III) salen complexes. The developed reaction pathway allows the modulation of the different key groups, namely, the chiral diimine, the bulky substituents in positions 3 and 3', and the linker used in the macrocyclization of the Schiff base. The different complexes presented here illustrate these readily available structural variations. The catalytic properties of the catalysts (5 mol %) were improved for the asymmetric epoxidation of 2,2'-dimethylchromene with NaOCl or H2O2 as oxygen atom donor. A large range of enantiomeric excesses was obtained (ee values from 30% to 96%), depending on the features and the stability of the complexes. The most efficient catalyst, in terms of stereoinduction (ee value = 96%), contains a diiminocyclohexyl moiety, ethyl groups in positions 3 and 3', and a short polyether junction arm.

Heme alkylation by artesunic acid and trioxaquine DU1301, two antimalarial trioxanes.

The sesquiterpene Artemisinin, an antimalarial drug that is effective against multidrug-resistant Plasmodium falciparum strains, contains a 1,2,4-trioxane, and the endoperoxide function plays a key role in its biological activity. However, its poor solubility means that hemisynthetic derivatives, such as artesunic acid, are preferred for drugs. The reductive activation of the peroxide function of artemisinin by iron(II)-heme produces heme derivatives that are alkylated at meso positions by a C-centered radical derived from artemisinin. We checked if the alkylating ability of trioxane-based drugs toward heme, which might be related to its parasiticidal activity, is a general feature by comparing the chemical reactivity toward heme of the clinically relevant derivative artesunic acid and DU1301, a drug of the trioxaquine family, that is active against P. falciparum. Both artesunic acid and trioxaquine DU1301 efficiently alkylated the heme macrocycle after activation of their peroxide function by the iron(II) of heme itself and thus gave rise to covalently coupled heme-drug products. This heme-drug adduct formation might be related to the high antimalarial activity of DU1301.

Synthesis and antimalarial activity of trioxaquine derivatives.

Trioxaquines are dual molecules that contain a trioxane motif linked to an aminoquinoline entity. Among the different compounds of this series, trioxaquine cis-15 (DU1302 c), prepared from alpha-terpinene, a cheap natural product, showed efficient antimalarial activity in vitro on both sensitive and resistant strains of Plasmodium falciparum (IC(50)=5-19 nM). A stereochemical description of this stable, nontoxic, and non-genotoxic antimalarial agent is detailed. Mice infected with P. vinckei were successfully treated with cis-15 in a four-day suppressive test. The doses required to decrease parasitemia by 50 % (ED(50)) were 5 and 18 mg kg(-1) d(-1) after intraperitoneal and oral administration, respectively. Parasitemia clearance was complete without recrudescence at an intraperitoneal dose of 20 mg kg(-1) d(-1).