Aazdine Lamouri

Surface modification of polymers by reduction of diazonium salts: polymethylmethacrylate as an example

This paper describes the grafting of diazonium salts on polymethylmethacrylate (PMMA), a polymer of wide use. Diazonium salts have been grafted by reduction with hypophosphorous acid, or by thermal decomposition. The nanometer thick films have been characterized by IR, XPS and water contact angle and the thickness of the film estimated. With long chain perfluoroalkyl substitutents on the aryldiazonium group a water contact angle of 108° can be obtained on the smooth polymer, highlighting a hydrophobic surface. This process could be useful for modifying the PMMA surface when used as a glass substitute or as a substrate for microfluidic devices.

PAF receptor and “cache-oreilles” effect. Simple PAF antagonists

Nine simple and structurally flexible PAF antagonists were synthesized and their inhibitory effects on PAF induced platelet aggregation were measured. Compounds with PAF antagonistic activity exhibited a negative electrostatic potential generated by two trimethoxyphenyl groups (isocontour at −10 Kcal/mole) at various distances between the negative clouds. The optimal distance between the atoms generating the “cache-oreilles” system for exhibiting potent PAF antagonistic activity is estimated to be 11–13 Å. In the flexible molecules studied, the dispersion of the electronic distribution is not necessarily favorable for anti-PAF activity. The data support the simple bipolarized model for the PAF receptor that has been proposed by the authors.

PAF-receptor. III. Conformational and electronic properties of PAF-like agonists and antagonists

In order to compare electronic and conformational properties of PAF-agonists and PAF-antagonists, 14 analogues structurally related to PAF were studied. A common conformation of the glycerol backbone was present in all agonists and all constrained or flexible antagonists. The distinction between agonists and antagonists appears to be casted on position-2 where the folded conformation of the substituent for agonists should be the most probable. In position-3 the gauche conformation can be adopted by all the analysed compounds. The electrostatic potential well at -30 kcal/mol stretches to the carbonyl group in position-2 in the folded conformation of the agonists. On the contrary, in constrained antagonists, a second negative zone appears around the carbamate group. Given the modelling results, the triethylammonium PAF analogue considered in literature as a weak agonist, was resynthesized and proved to be more potent than previously reported. These experimental results confirm our hypothesis in terms of a common conformation of agonist and antagonist PAF-like molecules.

Preventive effects of two PAF-antagonists, PMS 536 and PMS 549, on cyclosporin-induced LLC-PK1 oxidative injury.

The present study was undertaken to evaluate the effects of platelet activating factor (PAF) antagonists, PMS 536 and PMS 549, on LLC-PK1 toxicity induced by Cyclosporin A (CsA). The LLC-PK1 cell line was used as an in vitro model. CsA cytotoxicity was determined in relation with ATP content. Alkaline phosphatase and N-acetyl-beta-glucosaminidase activities, which are directly correlated with tubular cell damage, were used as markers for renal injury. CsA alone provoked in the LLC-PK1 cell line a marked decrease in cell viability (55%) and membrane integrity (56%), and a significant increase in AP and NAG activities and in oxidized glutathione level. The ATP decrease and the ADP increase, resulting in a decline of the ATP/ADP ratio, is indicative of an anoxic energy charge. Co-treatment with CsA plus PMS 536 or PMS 549 resulted in a minor decrease in cell viability and in significant membrane integrity recovery. Moreover, the ATP depletion and the increase in ATP metabolites, hypoxanthine and uric acid induced by CsA were strongly prevented by PAF antagonists. In contrast, GSSG level remained high as in CsA-treated cells, but GSH level was in the range of controls. Our results suggest that both PAF antagonists attenuate CsA oxidative injury and prevent energy metabolism disturbances probably by maintaining cell integrity. The lipophilicity of both molecules may be responsible for membrane stabilization and may confer the protective effects observed in energy metabolism. The results obtained with PMS 536 and PMS 549 are indicative of interactions between PAF and CsA in renal injury and suggest the therapeutic potential of these PAF-antagonists against CsA-induced nephrotoxicity.

Design and modeling of new platelet-activating factor antagonists. 2. Synthesis and biological activity of 1,4-bis-(3′,4′,5′-trimethoxybenzoyl)-2-alkyl and 2-alkyloxymethylpiperazines☆

In the continuation of our investigations on the structure of platelet-activating factor (PAF)-receptor, 25 additional 2-substituted 1,4-bis-(poly- and mono methoxybenzoyl)-piperazines were synthesized and their in vitro biological activities measured. Substituent at position 2 is representative of the classical balance lipophilicity/hydrophilicity, i.e. alkyl, phenylalkyl, alkoxy and polyalkoxy groups. A potent PAF-induced platelet aggregation inhibitory activity measured in PRP medium is obtained with 5c, IC50 = 6 x 10(-8) M, which displaces the [3H]PAF from platelet membrane with an EC50 = 6 x 10(-8) M, and compound 4 presents an EC50 of 3 x 10(-8) M. Examination of structure-activity relationships shows that molecules bearing a hydrophilic or slightly hydrophobic appendix in position-2 are still potent; their IC50 being included between 10(-6) and 10(-7) M. After quantitative analysis, it seems that in PRP medium, the role of serum albumin must be taken into account instead of a pure hydrophobic interaction of the appendix Z into the receptor. The role of the methoxy groups in producing a potent antagonistic activity is demonstrated by syntheses of several 2-octylpiperazine analogs. These specific features will be quantitatively analysed in the following related publication (part 3).