Synthesis and in vitro antitumor activity of ring C and D-substituted phenanthrolin-7-one derivatives, analogues of the marine pyridoacridine alkaloids ascididemin and meridine.

A series of cycle C and D-substituted phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin have been synthesized on the basis of Diels-Alder reactions involving quinoline-5,8-dione and 2- (or un)-substituted-N,N-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.

Synthesis and in vitro antitumor activity of an isomer of the marine pyridoacridine alkaloid ascididemin and related compounds.

The isomer (9H-quino[4,3,2-de][1,7]phenanthroline-9-one) (2) of the marine alkaloid ascididemin (9H-quino[4,3,2-de][1,10]phenanthroline-9-one) (1) has been synthesized in six steps from 1,4-dimethoxyacridine (10) with an overall yield of 12%. Different related compounds were prepared and tested in vitro at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate and bladder cancers). Almost all the compounds present cytotoxic activity of micromolar order.

Synthesis and in vitro antitumor activity of phenanthrolin-7-one derivatives, analogues of the marine pyridoacridine alkaloids ascididemin and meridine: structure-activity relationship.

A series of substituted pyrido[4,3,2-de][1,7] or [1,10]-phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin, have been synthesized on the basis of Diels-Alder reactions involving different quinoline-5,8-diones and N,N-aldehyde-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.

Toxicity of chemicals to microalgae in river and in standard waters.

The influence of the composition of natural waters on the toxicity of chemicals to microalgae was studied on samples representative of western European rivers. Effects of zinc, pentachlorophenol (PCP), 4-nonylphenol (4-NP), phosalone, and 2,4,5-trichloroaniline (TCA) on algal growth were tested in river waters without adding any nutrients or cosolvents, and in the International Standards Organization (ISO) medium for comparison. The mean values of effective concentrations reducing the algal growth by 50% (EC50s) after 72 h based on measured concentrations did not differ significantly in natural waters and in standard medium for 4-NP (0.5 mg/L) and phosalone (0.8-0.9 mg/L). These values were two or three times higher in rivers than in ISO medium for PCP (0.25 vs 0.1 mg/L), TCA (1.69 vs 0.73 mg/L), and zinc (0.20 vs 0.056 mg/L). Although the mean values were of the same order of magnitude, the distribution of the EC50 values ranged over 1.5 and 2 log concentrations in surface waters. Therefore, in view of a refined hazard assessment of a chemical on a local scale, it would be advisable to use the actual river water of the concerned aquatic environment in testing. Correlations between toxicity data and the physicochemical characteristics of the waters identified classic parameters such as water hardness or conductivity as factors that significantly influenced the toxicity of the ionizable compounds PCP and zinc. On the other hand, organic materials or suspended solids, but only at high levels, affected the toxicity of 4-NP, an organic chemical with high adsorption potential. No correlation could be drawn for phosalone and TCA.

Soil transformation of prosulfuron.

The transformation of prosulfuron [1-(4-methoxy-6-methyltriazine-2-yl)-3-[2-(3,3,3-trifluropropyl)phenylsulfonyl]urea] in three soils at different pH values (sterilized and unsterilized) was studied, and it was shown that the rate of transformation was high in acidic soil. From the results obtained in sterile soils, it is shown that the mechanism of dissipation was mainly chemical in acidic soils. A new metabolite, 2-(3,3,3-trifluoropropyl)phenylsulfonic acid, was identified.

Dimethylphthalate hydrolysis by specific microbial esterase.

TWO BACTERIAL STRAINS: Arthrobacter sp. and Sphingomonas paucimobilis were isolated from soil by enrichment cultures using dimethylphthalate (DMP) or monomethylphthalate (MMP) as sole carbon source, respectively. DMP was rapidly transformed by an Arthrobacter sp. culture with formation of MMP and phthalic acid (PA) which is further degraded. This strain was unable to hydrolyse MMP. A mechanism of degradation of DMP was proposed with two ways: DMP-->PA and DMP-->MMP. The S. paucimobilis strain hydrolyses only MMP and a coculture of the two strains allowed a complete degradation of DMP.

Marine pyridoacridine alkaloids and synthetic analogues as antitumor agents.

Pyrido[4,3,2-mn]acridines are of major interest as metabolites in sponges and ascidians. During the last few years, numerous additional compounds of this family were isolated, some of them being polycyclic structures already reported with different substituents (shermilamine or kuanoniamine-derivatives), others, such as neoamphimedine, arnoamines and styelsamines having original structures. The synthesis of these compounds and analogues have been performed in order to allow their biological evaluation. In most of the cases, the cytotoxicity of analogues was improved compared to the natural product, specially in ascididemin or meridine series. The pyridoacridines have not a sole mode of action, but it seems that the reductive DNA cleavage mediated by reactive oxygen species is a potential general mode of action.

Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine ascididemin: structure-activity relationship.

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.

Synthesis and cytotoxic evaluation of analogues of the marine pyridoacridine amphimedine.

4-Substituted-7H-pyrido-[4,3,2-de][1,8] or [1,9]-phenanthroline-7-ones and 9-methyl-1,4-diazanaphtacene-3,10-dione, analogues of the marine pyridoacridine amphimedine were synthesised from isoquinoline-5,8-dione. The first compounds were obtained starting from a Diels-Alder reaction whereas the synthesis of the last compound was initiated by a reaction of condensation with 2-aminoacetophenone. The different tetra- and pentacyclic compounds were evaluated for in vitro cytotoxic activities against six distinct human cancer cell lines. All the compounds exhibit cytotoxic activity with IC(50) values (i.e., the drug concentration inhibiting the mean growth value of the six cell lines by 50%)<10(-7)M for two of them.

Spore diffusate isolated from some strains of Aspergillus fumigatus inhibits phagocytosis by murine alveolar macrophages.

Aspergillus fumigatus is a ubiquitous fungus that grows in decaying organic matter. It can cause disease in both immunodeficient and immunocompetent patients by using virulence factors to escape the host defenses. Some of these factors, such as a diffusate, released from the spores of A. fumigatus, have previously been described. This diffusate was demonstrated to inhibit oxidative burst and phagocytosis of coated red blood cells. The present study has shown that this substance can inhibit the phagocytosis of A. fumigatus spores by murine alveolar macrophages (MALU) and evaluated the action of this substance. We quantified phagocytosis by MALU cells with and without diffusate and evaluated the inhibition of phagocytosis by testing diffusates from different strains. We conclude that the spore diffusate of some strains of A. fumigatus can reversibly decrease the ability of alveolar macrophages to ingest A. fumigatus spores.