Additional techniques for the total synthesis of PAF-acether.
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Optical Rotation↗
Biomedical subjects
C Broquet
Publications and source records attributed to C Broquet.
Synthesis and characterization of a radioiodinated, photoreactive and physiologically active analogue of platelet activating factor.
The multistep synthesis of a photoreactive, radioactive and aggregating analogue of platelet-activating factor (PAF)-acether is described. The photoreactive and radioactive moiety was added at the last step; the specific radioactivity was higher than 1000 Ci/mmol. The concentration of this new analogue which causes 50% of aggregation of platelets were of the same order of magnitude as for synthetic snPAF-acether, so as for two other analogues having a bulky group at the omega end of the fatty ether chain. The photoreactivity was proved by the covalent binding of the analogue to protein (BSA) after 10-min irradiation times at 300 nm. The binding was largely prevented by prior (not by later) addition of a high concentration of lyso phosphatidyl choline.
Acetylation↗
Effect of BN 52256 and other mediator antagonists on ouabain-induced cardiac arrhythmia in a model of anaphylaxis in guinea-pigs.
Different mediators released by anaphylaxis seem to be involved in different pathophysiological conditions, including cardiac arrhythmia. Histamine, 5-HT and platelet-activating factor (PAF) could participate in the enhanced arrhythmogenicity during anaphylaxis in guinea-pigs. The threshold dose of ouabain-induced arrhythmia is decreased in actively sensitized guinea-pigs by i.p. administration of ovalbumin. The purpose of the present paper was to investigate the effect of different mediator antagonists. Antagonists of PAF (WEB 2170), histamine (clemastine) and 5-HT (cyproheptadine) in doses of 5.0 mg/kg, 5.0 mg/kg and 0.5 mg/kg, respectively, can increase the threshold dose of ouabain-induced arrhythmias signalling an antiarrhythmic effect. A combination of WEB 2170 and clemastine, each of them in inactive doses (2.0 mg/kg and 1.0 mg/kg, respectively) showed a statistically significant antiarrhythmic effect. A combination of the same dose of WEB 2170 and cyproheptadine (0.1 mg/kg) under the same conditions induced an antiarrhythmic effect, too. BN 52256 is a new antiallergic drug synthesized on the basis of a novel concept of combining inhibitory activity against various inflammatory mediators in one molecule. BN 52256 in doses of 20-80 micrograms/kg exhibited a statistically significant antiarrhythmic effect. BN 52256 needed a 12.5-125 fold lower dose to induce the same antiarrhythmic effect compared to the antagonists of PAF, histamine or 5-HT investigated in this study. Depending on the pathophysiological conditions, different mediators seem to be involved in the occurrence of cardiac arrhythmia. A complex inhibition of these mediators could induce a more specific influence on such kinds of cardiac arrhythmias.
Anaphylaxis↗
Structure-activity relationships in platelet-activating factor (PAF). 5. Synthesis and in vitro antagonistic activities of ketophosphonates.
The synthesis of new ketophosphonate isosteres of biosynthetic precursors of ether glycerophospholipids resistant to phospholipase C is described following two routes depending on whether the alkoxy chain is introduced before or after the phosphonic moiety. The common intermediates are ketophosphonic acids: better yields were obtained by attaching the n-octadecyl chain to epichlorohydrin, opening and oxidation, blockage of the resulting ketone as the chlorohydrazone, followed by an Arbuzov reaction or by azoene formation and Michael addition. These ketophosphonates differing in chain length in position 3 exhibit potent agonistic activities on rabbit platelets which increase with the number of methylene groups between the phosphonate and the ammonium moieties.
Animals↗
Cytotoxic activity of synthetic aza alkyl lysophospholipids against drug sensitive and drug resistant human tumor cell lines.
The anti-tumor cytotoxic activity of four newly synthesized aza alkyl lysophospholipids (AALP), namely BN 52205, BN 52207, BN 52208 and BN 52211, was investigated. Using the 51Cr release assay, the four compounds were endowed with cytotoxic activity, in a concentration-dependent fashion, against various human tumor cell lines of different histological origin. Two different mechanisms appear to be involved in the AALP-mediated cytotoxicity. A rapid membrane damaging effect was observed in less than one hour's incubation of tumor cells with AALP and cytotoxicity was temperature-independent when AALP were used at greater than or equal to 200 micrograms/ml. A slower cytotoxic mechanism was observed after 18 hours incubation at 37 degrees C when AALP were used at concentrations of 30-100 micrograms/ml. The pattern and magnitube of the cytotoxic activity achieved with all the 4 AALP compounds tested were similar and the cytotoxicity mediated by combination of two compounds was additive. In addition to the cytotoxic effect, the AALP compounds also exerted a cytostatic anti-tumor effect, as assessed by inhibition of 3H TdR incorporation. Using a variety of human tumor cell lines as targets, the cytotoxic effect observed with the AALP was noted with tumor cells that were either sensitive or resistant to TNF-alpha and/or chemotherapeutic drugs such as mitomycin C, adriamycin and cis-platinum. The LD50 toxicity in mice was 100-125 mg/kg. The present findings demonstrate that AALP are cytotoxic to a variety of human tumor cell lines and do not appear to discriminate between drug/cytokine sensitive or resistant cells. Thus the present study suggests that some aza alkyl lysophospholipids may be considered as potential anticancer agents.
Drug Screening Assays, Antitumor↗
Action of platelet-activating factor (PAF) antagonists on the bronchopulmonary effects of PAF in the guinea-pig.
Intravenous injection of BN 52021 in anesthetized guinea-pigs, 5 min before challenge, inhibited in a dose-dependent fashion with an IC50 of 0.90 mg/kg the bronchoconstriction induced by PAF (60 ng/kg i.v.). However, BN 52021 did not prevent the leukopenia following PAF injection but significantly inhibited the thrombocytopenia induced by PAF. The dioxolan compound, BN 52111, dose-dependently reduced the bronchoconstriction (IC50 = 0.27 mg/kg) and at doses higher than 1 mg/kg partially antagonized the decrease in the number of circulating platelets and leukocytes induced by PAF. BN 52115 also markedly inhibited the bronchoconstriction (IC50 = 0.36 mg/kg) as well as the thrombocytopenia induced by PAF, but was without significant effect on the leukopenia. These results demonstrate that the two dioxolan compounds, BN 52111 and BN 52115, are more potent than BN 52021 in inhibiting the in vivo bronchopulmonary alterations induced by PAF. Since these alterations are related to the activation of platelets by the autacoid, these blood elements are probably the targets of BN 52111 and BN 52115. Injection of PAF (10 and 100 ng) via the pulmonary artery of ventilated and perfused guinea-pig lungs induced dose-dependent increases in pulmonary inflation pressure (PIP) and pulmonary perfusion pressure (PPP), associated with a dose-dependent release of thromboxane B2 (TxB2). Addition of BN 52021, BN 52111 or BN 52115 (0.1, 1 or 10 microM) to the perfusion medium, 15 min before challenge, dose-dependently inhibited the bronchopulmonary effects of PAF. Although BN 52111 was the more potent in inhibiting the PAF-induced increase in PIP, BN 52021 was the more active with respect to the PAF-evoked generation of TxB2, suggesting that the two phenomena are not directly related.
Animals↗