Designing active template molecules by combining computational de novo design and human chemist's expertise.

We used a new software tool for de novo design, the "Molecule Evoluator", to generate a number of small molecules. Explicit constraints were a relatively low molecular weight and otherwise limited functionality, for example, low numbers of hydrogen bond donors and acceptors, one or two aromatic rings, and a small number of rotatable bonds. In this way, we obtained a collection of scaffold- or templatelike molecules rather than fully "decorated" ones. We asked medicinal chemists to evaluate the suggested molecules for ease of synthesis and overall appeal, allowing them to make structural changes to the molecules for these reasons. On the basis of their recommendations, we synthesized eight molecules with an unprecedented (not patented) yet simple structure, which were subsequently tested in a screen of 83 drug targets, mostly G protein-coupled receptors. Four compounds showed affinity for biogenic amine targets (receptor, ion channel, and transport protein), reflecting the training of the medicinal chemists involved. Apparently the generation of leadlike solutions helped the medicinal chemists to select good starting points for future lead optimization, away from existing compound libraries.

Modelling of migration from multi-layers and functional barriers: estimation of parameters.

Functional barriers form parts of multi-layer packaging materials, which are deemed to protect the food from migration of a broad range of contaminants, e.g. those associated with reused packaging. Often, neither the presence nor the identity of the contaminants is known, so that safety assessment of the materials has to rely on predictive tools. Several complementary freeware described here allow one to model diffusion in multi-layer films. These tools require the input of parameters that are not easy to determine or predict. Previous work has focused on the prediction of diffusion coefficients at storage temperatures of packaging in contact with food. However, many other kinetic and thermodynamic parameters are needed to describe transport properties during the processing of a material at high temperature and during its shelf-life. All parameters needed for the calculations are discussed. In order to propose default values, the approach consists of (1) reviewing the available literature data, (2) running experiments on polypropylene, polyethylene and poly(ethylene vinyl alcohol) in typical conditions (separately diffusion during processing and migration) and (3) simulating numerical sets for typical situations. Several freeware are proposed to simulate migration from multi-layers and functional barriers using the default parameters.

Inhibition of nucleoside transport proteins by C8-alkylamine-substituted purines.

4-nitrobenzylthioinosine (NBTI, 1) is a well-known inhibitor for the nucleoside transport protein ENT1. Here we report on the synthesis and the biological evaluation of compounds that are less polar than NBTI. Compound screening in our laboratory indicated that introduction of an alkylamine substituent at the C(8)-position of N(6)-cyclopentyladenosine (CPA, 2) led to an increment in affinity for the transport protein. It was investigated whether this would also apply for NBTI derivatives. Two series of C(8)-alkylamine-substituted compounds were prepared, one in which the nitro group was absent (46-58) and another in which the ribose moiety was replaced by a benzyl group (72-75). Comparison of the biological data of these compounds with 6-benzylthioinosine (4, K(i) = 53 nM) and 9-benzyl-6-(4-nitrobenzylsulfanyl)purine (59, K(i) = 135 nM) confirmed the hypothesis. The K(i) values improved upon elongation of the alkylamine chain from methylamine to n-hexylamine with an optimum for n-pentylamine (50, K(i) = 2.3 nM). Substitution with 2-methylbutylamine (52), cyclopropylamine (53), cyclopentylamine (54, 72), and cyclohexylamine (55, 73) revealed that the presence of a bulky group enhanced the affinity. The presence of tertiary amines obtained by substitution with pyrrolidine, piperidine, and morpholine gave only poor results. For both series substitution with cyclopentylamine was most effective. Compound 54 (LUF5942) proved the most active, showing a comparable affinity (K(i) = 0.64 nM) to NBTI but a significantly lower polar surface area.

Inhibition of nucleoside transport by new analogues of 4-nitrobenzylthioinosine: replacement of the ribose moiety by substituted benzyl groups.

4-Nitrobenzylthioinosine (NBTI, 1) is a well-known inhibitor for the nucleoside transport protein ENT1. However, its highly polar nature is unfavorable for oral absorption and/or penetration into the CNS. In the search for compounds with lower polarity than NBTI we replaced its ribose moiety by substituted benzyl groups. Halogen, hydroxyl, (trifluoro)methyl(-oxy), nitro, and amine functionalities were among the substituents at the benzyl group. In general, substitution of the benzyl group resulted in a lower affinity for ENT1. Only 2-hydroxyl substitution showed a higher affinity. Most likely this is the result of hydrogen bonding. Substitution at the 2-position of the benzyl group with aryl groups was also addressed. Compared to parent compound carrying a 2-phenylbenzyl group, all synthesized analogues gave higher affinities. Introduction of fluoro, trifluoromethyl, methoxy, and hydroxyl groups at the phenyl group clearly showed that addition to the 4-position was preferable. Despite the highly different character of a ribose and a benzyl group, Ki values in the low nanomolar range were obtained for the benzyl-substituted derivatives. Compound 35, LUF5919, and compound 60, LUF5929, displayed the highest affinity (Ki = 39 nM for both compounds), having a polar surface area of 101 A2 and 85 A2, respectively.

The beta-glucuronyl-based prodrug strategy allows for its application on beta-glucuronyl-platinum conjugates.

The use of platinum drugs in antitumour therapy is well established. An important drawback of these chemotherapeutics is the lack of selectivity for tumour cells, usually resulting in severe toxic side effects. A glucuronyl-platinum conjugate was designed and synthesised to test the compatibility of platinum compounds with beta-glucuronidase-based prodrug therapy. Instantaneous cleavage of the beta-glucuronic bond in the glucuronyl-platinum conjugate was observed upon addition of beta-glucuronidase resulting in Pt(II)(dach)(4-hydroxybenzylmalonate) and glucuronic acid.

Stereochemistry of intramolecular Diels-Alder furan (IMDAF) reactions of furyl-substituted chiral ethanolamides.

This paper describes the stereoselective outcome of the intramolecular Diels-Alder furan (IMDAF) reaction of substituted (2S,3S)-ethanolamides 9-13, which were synthesised from a furyl substituted cyanohydrin. The latter was obtained from 2-furaldehyde with high enantioselectivity by an oxynitrilase catalysed addition of hydrogen cyanide. The stereochemistry of the IMDAF products was shown to be dependent on the size of the ethanolamide substituents R. Small substituents (H, Me, CN) gave exclusively exo-cycloaddition, whereas more bulky ones (Ph, Et) gave both evo- and endo-addition, the larger phenyl substituent giving a high endo-exo-ratio.

Migration of additives from polymers into food simulants: numerical solution of a mathematical model taking into account food and polymer interactions.

The principle of a computing program describing precisely the migration of additives from a polymer into a food simulant is presented. As six parameters are used to fit the simulnnt sorption and additive extraction kinetics, the parameters have been determined by independent experiments. Owing to the complicated coupling between the liquid and additive diffusion processes, migration kinetics cannot be obtained by a mathematical resolution of kinetic equations, but they must be calculated by numerical analysis. The method is applied to a UV absorber in polypropylene migrating into glyceryl tripelargonate, a pure triglyceride, of which behaviour and average molecular weight are similar to official fatty food simulants. Properly designed experiments validate the model used to fit the migration kinetics. The possibility of erasing any parameters is also discussed.

Prediction of worst case migration: presentation of a rigorous methodology.

An improvement of the Piringer model, allowing the prediction of a worst case migration from packaging to food is presented here. The authors are proposing other constants for the calculation of the upperbound value of the diffusion coefficient, using experimental data determined by a film to film method. Considering the plasticizing effects of food simulants, a model involving the variation of the diffusion coefficient versus space and time must be used. Future fields of investigation are discussed: the relationship between diffusion coefficients and the volume of the migrant (instead of molar mass), and the variation of diffusion coefficient activation energy with temperature.

A model for non-invasive estimation of in vivo dialyzer performances and patient's conductivity during hemodialysis.

On-line monitoring of hemodialysis sessions requires a non-invasive estimation of the parameters concerning the patient's status and the dialyzer performances. We describe here a model based on a new method for non-invasive dialysance and patient conductivity measurements. In this technique the same probe measures alternately the conductivity at the dialysate inlet and outlet for two different dialysate conductivity values. From these data, an appropriate model allows to determine the patient's conductivity as well as the effective dialysance of ionised solutes, that is to say the dialysance corrected for recirculation. A strong correlation is evidenced between the effective dialysance measured by this method and the urea clearance measured by conventional methods (r = 0.98 for in vitro solutions; r = 0.82 in vivo situations).

[Treatment of upper metaphyso-epiphyseal fractures of the tibia by Ilizarov's method. Report of 4 cases]. / Traitement des fractures métaphyso-épiphysaires supérieures du tibia par la méthode d'Ilizarov. A propos de 4 observations.

The authors report four cases of comminuted metaphyso-epiphyseal fractures of the proximal end of the tibia treated by the Ilizarov method. Three of the cases were polytraumatisms, the fourth one had a severely contused skin. Due to this method early rehabilitation was made possible and treatment of associated lesions was made easy.

[Value of the scanner for diagnosing synovial cysts of the hip. Apropos of 2 cases. Review of the literature]. / Intérêt du scanner pour le diagnostic des kystes synoviaux de la hanche. A propos de deux cas. Revue de la littérature.

Two cases of synovial cysts of the hip have been observed by the authors. They were extending anteriorly and were developing from the psoas iliac muscle bursa. After a review of the literature it is concluded that this is a rare condition, and that CT scan made the diagnosis much easier. In one case the cyst complicated a rheumatoid arthritis, in the other the origin was not clear. The clinical features and differential diagnoses are recalled.

[Respiratory manifestations and intolerance to aspirin and non-steroidal anti-inflammatory agents]. / Manifestations respiratoires et intolérance à l'aspirine et aux anti-inflammatoires non stéroïdiens.

This pathology is not due to the drug but revealed or aggravated by it. The most commonly implicated drugs are the anti-inflammatory group, especially aspirin. However, the list of drugs liable to induce intolerance continues to grow. The clinical manifestations are mainly observed in middle age and may regress. Drug intolerance can be demonstrated by provocative tests; it can be limited by methods of drug tolerance. The most commonly pathogenic mechanisms are: -inflammatory mechanisms (role of kinin), -disturbance of the metabolism of arachidonic acid, prostaglandin blockage, stimulation of leukotrienes. This expanding pathogenic entity is independent though similar in many aspects to the immediate forms of allergy, so explaining its importance in the general field of pseudo-allergy.