Natural Platelet-activating Factor Research Articles

Activities of platelet-activating factor (PAF) enzymes after daily consumption for two months of a yogurt enriched with natural origin PAF inhibitors

Background and Aims: Platelet-activating factor (PAF), a pro-inflammatory lipid mediator, plays a crucial role in the formation of the atherosclerotic plaque. Therefore, the inhibition of endothelium inflammation by nutraceuticals, such as PAF inhibitors, is a promising alternative for preventing cardiovascular diseases. The aim of the present study is to evaluate the impact of a new functional yogurt enriched with natural origin PAF inhibitors from olive oil by-products on PAF metabolism.

Progress in the Development of Platelet-Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases.

Platelet-activating factor (PAF) and its receptor (PAFr) have been implicated in a wide range of diseases and disorders that originate from the activation of inflammatory pathways. Although the exact structure of the binding site on the PAFr remains unknown, the PAFr is a well-established therapeutic target, and an array of structurally diverse PAFr antagonists have been identified. These include compounds that are structurally similar to the natural PAF ligand, synthetic heterocycles, complex polycyclic natural products, and various metal complexes. This review provides an update on more than 20 years of progress in this area. The development and synthesis of new PAFr antagonists, structure-activity relationship studies, the biological activity of these molecules, and their therapeutic potential are discussed.

Kadsurenone is a useful and promising treatment strategy for breast cancer bone metastases by blocking the PAF/PTAFR signaling pathway

Breast cancer (BC) is characterized by high incidences of bone metastases. Current treatment strategies for BC bone metastases primarily focused on breaking the ‘vicious osteolytic cycle’. Platelet-activating factor (PAF) is a potent phospholipid mediator, which has previously reported biological activities in BC progression and osteoclast differentiation by activating its receptor PAF receptor (PTAFR). However, the role of PAF in the mediation of BC bone metastases remains elusive. In the present study, it was revealed that the upregulation of PTAFR was associated with an increased incidence of bone metastases. It was also revealed that PAF significantly enhanced the processes of BC cell migration and BC mediated osteoclastogenesis. These results suggest that PAF serves a promotion role in BC bone metastases. It was further demonstrated that the natural PAF antagonist Kadsurenone may effectively attenuate each process by partially blocking the PAF/PTAFR signaling pathway. Therefore, targeting PAF/PTAFR by Kadsurenone may be a promising treatment strategy for BC bone metastases.

Ginkgolide B Suppresses TLR4-Mediated Inflammatory Response by Inhibiting the Phosphorylation of JAK2/STAT3 and p38 MAPK in High Glucose-Treated HUVECs.

Aim Ginkgolide B is a Ginkgo biloba leaf extract that has been identified as a natural platelet-activating factor receptor (PAFR) antagonist. We investigated the effect of ginkgolide B on high glucose-induced TLR4 activation in human umbilical vein endothelial cells (HUVECs). Methods Protein expression was analyzed by immunoblotting. Small-interfering RNA (siRNA) was used to knock down PAFR and TLR4 expression. Results Ginkgolide B suppressed the expression of TLR4 and MyD88 that was induced by high glucose. Ginkgolide B also reduced the levels of platelet endothelial cell adhesion molecule-1, interleukin-6, and monocyte chemotactic protein 1. Further, we examined the association between PAFR and TLR4 by coimmunoprecipitation. The result showed that high glucose treatment caused the binding of PAFR and TLR4, whereas ginkgolide B abolished this binding. The functional analysis indicated that PAFR siRNA treatment reduced TLR4 expression, and TLR4 siRNA treatment decreased PAFR expression in high glucose-treated HUVECs, further supporting the coimmunoprecipitation data. Ginkgolide B inhibited the phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and p38 mitogen-activated protein kinase (MAPK). Conclusion Ginkgolide B exerted protective effects by inhibiting the TLR4-mediated inflammatory response in high glucose-treated endothelial cells. The mechanism of action of ginkgolide B might be associated with inhibition of the JAK2/STAT3 and p38 MAPK phosphorylation.

Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats

Ginkgolide K, a natural platelet-activating factor receptor antagonist, was isolated from the leaves of Ginkgo biloba. However, little is known about its neuroprotective effect in ischemia-reperfusion (I/R)-induced cerebral injury. Hence, the present study was carried out to investigate the effect of ginkgolide K on neuroprotection and the potential mechanisms in the rat I/R model induced by middle cerebral artery occlusion (MCAO). The rats were pretreated with ginkgolide K 2, 4 and 8 mg/kg (i.v.) once a day for 5 days before MCAO. Neurological deficit score (NDS), brain water content, 2,3,5-triphenyltetrazolium chloride (TTC) staining and pathology of brain tissue, as well as indexes of oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS)] were measured at 24 h after ischemia. The results indicated that pretreatment with ginkgolide K significantly diminished the volume of infarction and brain water content, and improved NDS. Moreover, ginkgolide K markedly reversed the level of MDA, NO, NOS and SOD to their normal state in serum or cerebral ischemic section. In addition, hematoxylin and eosin staining showed the neuronal injury was significantly improved after being pretreated with ginkgolide K. These findings demonstrate that ginkgolide K exhibits neuroprotective properties through its antioxidative action in MCAO rats.

Efficacy and Safety of the Platelet-Activating Factor Receptor Antagonist BN???52021 (Ginkgolide??B) in Patients with Severe Sepsis

To evaluate the efficacy and safety of the natural platelet-activating factor receptor antagonist, BN 52021 (ginkgolide B) in the treatment of patients with severe sepsis related to Gram-negative and mixed bacterial infection. Prospective, randomised, double-blind, placebo-controlled, multicentre study carried out in 13 academic medical intensive care centres in Germany with up to 14 patients per centre. 88 patients with severe sepsis under standard medical and surgical care: nine patients with pure Gram-positive infection, 79 patients with Gram-negative or mixed bacterial infections (subgroup for which efficacy was to be established). Patients were randomised to receive either placebo or BN 52021 1.25 mg/kg bodyweight intravenously every 12h over a 4-day period in addition to their standard medical and surgical care. The primary efficacy variable was the 28-day all-cause mortality rate. The treatment groups were similar with respect to demographic data and prognostic factors influencing the outcome except for bodyweight and adequacy of antibiotic therapy. Analysis of patients with Gram-negative or mixed bacterial infection, for which efficacy was to be established, resulted in a 28-day all-cause mortality of 42.5% in the placebo group (n = 40; 17 deaths) versus 38.5% in the BN 52021 group (n = 39; 15 deaths). Among all randomised patients, the 28-day all-cause mortality rate was 40.9% in the placebo group (n = 44; 18 deaths) and 38.6% in the BN 52021 group (n = 44; 17 deaths). There were no differences in frequency and severity of adverse events between the two treatment groups. Four-day administration of BN 52021 failed to demonstrate a statistically significant reduction in mortality in patients with severe sepsis suspected or confirmed to be related to infections other than Gram-positive bacterial infection.

Inhibitory effects of xanthones on platelet activating factor receptor binding in vitro

Nine naturally occurring xanthones were investigated for their platelet activating factor (PAF) receptor binding inhibitory effects using rabbit platelets. 2-(3-methylbut-2-enyl)-1,3,5-trihydoxyxanthone, macluraxanthone, 1,3,5-trihydroxy-6,6′-dimethylpyrano(2′,3′:6,7)-4-(1,1-dimethylprop-2-enyl)xanthone, 6-deoxyjacareubin and 2-(3-methylbut-2-enyl)-1,3,5,6-terahydroxyxanthone showed strong inhibition with IC 50 values of 4.8, 11.0, 21.0, 29.0 and 44.0 μM, respectively. The prenyl group at C-2, the dimethylprop-2-enyl group at C-4 and the hydroxyl group at C-5 are all beneficial to the binding of xanthones to the PAF receptor. The results revealed that xanthones can represent a new class of natural PAF receptor antagonists.

Platelet-Activating Factor Antagonists

Platelet-activating factor (PAF) is a potent lipid-derived mediator of inflammation that is considered to have a potential role in the pathogenesis of asthma. PAF is produced by many cells associated with asthmatic inflammation and has the ability to evoke some of the clinical hallmarks of asthma, such as bronchoconstriction, mucus production and airway hyperresponsiveness (AHR). In addition, PAF has profound chemoattractant properties for eosinophils and neutrophils and it promotes an increase in microvascular permeability and oedema formation within the airways. Nevertheless, the definitive role of PAF in asthma remains elusive. PAF is formed as a result of the action of phospholipase A(2) and acetyltransferase on membrane phospholipids and it is degraded by a PAF-specific acetylhydrolase. The biological effects of PAF are mediated by the activation of specific receptors expressed on effector cell surfaces, although intracellular signalling and paracrine actions have been described. In addition, at least part of the pulmonary effects of PAF could be related to the secondary release of leukotrienes. In the clinical setting, different ways of modifying the activity of PAF have been explored, in particular the inhibitory actions of PAF receptor antagonists. Both natural and synthetic PAF receptor antagonists have shown conflicting results. Although second generation PAF antagonists (apafant, UK-74505, SR-27417A) appear to have a good protective effect against the systemic and pulmonary actions of inhaled PAF, the protective effects of these compounds on allergen-induced responses and AHR are more modest. In the treatment of asthma, PAF receptor antagonists have failed to produce a significant impact in either acute asthma attacks or the maintenance therapy of chronic forms. Other pharmacological interventions of proven efficacy in asthma, such as salbutamol or 5-lipoxygenase antagonists, have shown some anti-PAF effects. Whether the overall negative results with PAF receptor antagonists indicate that extracellular PAF is not a relevant mediator of airway inflammation or that the compounds explored are not capable of blocking the paracrine actions of PAF remains speculative. A PAF synthase inhibitor could be valuable in the elucidation of the role of PAF and it might be a promising and useful complementary therapeutic tool in the future.

Platelet activating factor (PAF) antagonists on cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC).

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) and its receptor are known to play important roles in modulating neuronal plasticity and inflammatory responses, particularly during neuronal injury. PAF receptors are widespread in different brain regions and are present on the cell surface as well as in intracellular membrane compartments. Astrocytes are immune active cells and are responsive to cytokines, which stimulate signaling cascades leading to transcriptional activation of genes and protein synthesis. Our recent studies indicate the ability of cytokines, e.g., tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta) and interferon-gamma (IFNgamma), to induce the inducible nitric oxide (iNOS) and secretory phospholipase A2 (sPLA2) genes in immortalized astrocytes (DITNC) (Li et al., J. Interferon and Cytokine Res. 19: 121-127. 1999). The main objective for this study is to examine the effects of PAF antagonists on cytokine induction of iNOS and sPLA2 in these cells. Results show that BN50730, a synthetic PAF antagonist, but not BN52021, a natural PAF antagonist (ginkolide B) can dose-dependently inhibit cytokine induction of NO production and sPLA2 release. Inhibition of NO production by BN50730 corroborated well with the decrease in iNOS protein and mRNA levels as well as binding of NF-kappaB STAT- 1 to DNA, suggesting that BN50730 action is upstream of the transcriptional process. These results are in agreement with the role of intracellular PAF in regulating the cytokine signaling cascade in astrocytes and further suggest the possible use of BN50730 as a therapeutic agent for suppressing the inflammatory pathways elicited by cytokines.

Effect of BN 50727 on pathological findings and tissue platelet activating factor levels during ileal ischemia in newborn piglets

The role of platelet activating factor (PAF), a potent ulcerogen mediator in the digestive tract, is thought to be important in the genesis of necrotizing enterocolitis. The aim of this study was to evaluate the role of PAF in the perpetuation and aggravation of gastrointestinal damage resulting from limited ischemia in the 2-day-old piglet using a natural PAF antagonist (BN 50727). Animals were separated into six groups: U 4, controls; S, sham operated animals undergoing laparotomy; I 4 and I 9, ligation of the mesenteric vessels in the last ileal loop; IT 4 and IT 9, same procedure together with treatment with BN 50727 (50 mg/kg), orally before and after surgery and intraperitoneally during surgery. Animals were killed at day 4 in groups U 4, S, I 4 and IT 4 and at day 9 in groups I 9 and IT 9, with histological studies and mediator measurements taken. Macroscopic and histological lesions of intestinal wall in groups I 4, I 9, IT 4 and IT 9 were similar to those of human neonatal necrotizing enterocolitis and did not vary according to the absence or the presence of BN 50727 treatment ( P = .7, I 4 v IT 4 and P = .9, I 9 v IT 9). Peritoneal bands were significantly reduced in treated groups IT 4 and IT 9 as compared with untreated ones I 4 and I 9 ( P = .003). Mucosal PAF levels in the terminal ileum were higher in group I 4 than in groups U 4 or I 9. In the upper loop, mucosal PAF levels were comparable in all groups. An increase in stool PAF levels was observed only in group I 9 (26.4 ng/g v 4.7 ng/g, I 9 v U 4 + S, P < .05), whereas values comparable to those observed in controls were detected in other groups (I 4, 7.2 ng/g; IT 4, 4.5 ng/g; IT 9, 6.8ng/g). Tumor necrosis factor alpha (TNF α) measurements did not exhibit any difference between groups. Using a PAF antagonist, the role of PAF in the aggravation of intestinal damage after ischemia was not remarkable because treatment did not induce any modifications of parietal intestinal lesions. PAF antagonists appeared to reduce significantly the local peritoneal consequences of local inflammation.

Platelet activating factor produced in vitro by Kaposi's sarcoma cells induces and sustains in vivo angiogenesis.

Imbalance in the network of soluble mediators may play a pivotal role in the pathogenesis of Kaposi's sarcoma (KS). In this study, we demonstrated that KS cells grown in vitro produced and in part released platelet activating factor (PAF), a powerful lipid mediator of inflammation and cell-to-cell communication. IL-1, TNF, and thrombin enhanced the synthesis of PAF. PAF receptor mRNA and specific, high affinity binding site for PAF were present in KS cells. Nanomolar concentration of PAF stimulated the chemotaxis and chemokinesis of KS cells, endothelial cells, and vascular smooth muscle cells. The migration response to PAF was inhibited by WEB 2170, a hetrazepinoic PAF receptor antagonist. Because neoangiogenesis is essential for the growth and progression of KS and since PAF can activate vascular endothelial cells, we examined the potential role of PAF as an instrumental mediator of angiogenesis associated with KS. Conditioned medium (CM) from KS cells (KS-CM) or KS cells themselves induced angiogenesis and macrophage recruitment in a murine model in which Matrigel was injected subcutaneously. These effects were inhibited by treating mice with WEB 2170. Synthetic PAF or natural PAF extracted from plasma of patients with classical KS also induced angiogenesis, which in turn was inhibited by WEB 2170. The action of PAF was amplified by expression of other angiogenic factors and chemokines: these included basic and acidic fibroblast growth factor, placental growth factor, vascular endothelial growth factor and its specific receptor flk-1, hepatocyte growth factor, KC, and macrophage inflammatory protein-2. Treatment with WEB 2170 abolished the expression of the transcripts of these molecules within Matrigel containing KS-CM. These results indicate that PAF may cooperate with other angiogenic molecules and chemokines in inducing vascular development in KS.

Role of free radicale in the development of pneumocyte proliferation

Nutrients rich in omega-3 fatty acids (fish oil and flaxseed) have the potential to abrogate inflammatory and atherosclerotic mechanisms known to be involved in the pathogenesis of vascular damage of systemic lupus erythematosus nephritis. Fish oil dietary supplementation decreases proteinuria and preserves renal morphology in the NZB/NZW, BXSB, and MRL/lpr mouse models of lupus nephritis and decreases mortality in the NZB/NZW and BXSB models. The anti-inflammatory and anti-atherosclerotic potential, coupled with the animal experimental data, encouraged us to carry out a dosing study of low (6 g) and higher (18 g) doses of fish oil (MaxEPA) therapy in human lupus nephritis. At the lower dose, the fish oil inhibited inflammatory mechanisms; at the higher dose, it aHered both the inflammatory and atherosclerotic mechanisms. This led to a double-blind cross-over study of fish oil therapy in 26 patients with lupus nephritis followed for 2 years 10 weeks. The fish oil dietary supplementation had no significant effect on proteinuria, isotope glomerular filtration rate, disease activity index, or steroid consumption. However, it did have a significant effect on lipid levels. The cross-over design suffered carryover effects (even with a 10-week wash-out period) and placebo effects of the olive oil, which created a risk of type II error. Our interest in omega-3 fatty acids led us to assess the effects of dietary supplementation with flaxseed. Not only is the flaxseed a major source of alpha-linolenic acid but it is also the richest natural source of lignan, a natural plateletactivating factor receptor antagonist. The 15% flaxseed dietary supplementation in the MRL/lpr mouse model resulted in a significant preservation in glomerular fiHration rate, a delay in proteinuria, and abrogation of lymphoproliferation. In addition, unlike MaxEPA, the flaxseed dietary supplementation resuHed in a significant 60% reduction in mortality. We concluded that, at present, fish oil is not indicated as a form of treatment in patients with lupus nephritis, but flaxseed dietary supplementation warrants further study.

Continous intravenous infusion in rabbit teratology studies

Nutrients rich in omega-3 fatty acids (fish oil and flaxseed) have the potential to abrogate inflammatory and atherosclerotic mechanisms known to be involved in the pathogenesis of vascular damage of systemic lupus erythematosus nephritis. Fish oil dietary supplementation decreases proteinuria and preserves renal morphology in the NZB/NZW, BXSB, and MRL/lpr mouse models of lupus nephritis and decreases mortality in the NZB/NZW and BXSB models. The anti-inflammatory and anti-atherosclerotic potential, coupled with the animal experimental data, encouraged us to carry out a dosing study of low (6 g) and higher (18 g) doses of fish oil (MaxEPA) therapy in human lupus nephritis. At the lower dose, the fish oil inhibited inflammatory mechanisms; at the higher dose, it aHered both the inflammatory and atherosclerotic mechanisms. This led to a double-blind cross-over study of fish oil therapy in 26 patients with lupus nephritis followed for 2 years 10 weeks. The fish oil dietary supplementation had no significant effect on proteinuria, isotope glomerular filtration rate, disease activity index, or steroid consumption. However, it did have a significant effect on lipid levels. The cross-over design suffered carryover effects (even with a 10-week wash-out period) and placebo effects of the olive oil, which created a risk of type II error. Our interest in omega-3 fatty acids led us to assess the effects of dietary supplementation with flaxseed. Not only is the flaxseed a major source of alpha-linolenic acid but it is also the richest natural source of lignan, a natural plateletactivating factor receptor antagonist. The 15% flaxseed dietary supplementation in the MRL/lpr mouse model resulted in a significant preservation in glomerular fiHration rate, a delay in proteinuria, and abrogation of lymphoproliferation. In addition, unlike MaxEPA, the flaxseed dietary supplementation resuHed in a significant 60% reduction in mortality. We concluded that, at present, fish oil is not indicated as a form of treatment in patients with lupus nephritis, but flaxseed dietary supplementation warrants further study.

Oral bis(trl-nbutyftin) oxide influcnco on matemal behaviour in mice

Nutrients rich in omega-3 fatty acids (fish oil and flaxseed) have the potential to abrogate inflammatory and atherosclerotic mechanisms known to be involved in the pathogenesis of vascular damage of systemic lupus erythematosus nephritis. Fish oil dietary supplementation decreases proteinuria and preserves renal morphology in the NZB/NZW, BXSB, and MRL/lpr mouse models of lupus nephritis and decreases mortality in the NZB/NZW and BXSB models. The anti-inflammatory and anti-atherosclerotic potential, coupled with the animal experimental data, encouraged us to carry out a dosing study of low (6 g) and higher (18 g) doses of fish oil (MaxEPA) therapy in human lupus nephritis. At the lower dose, the fish oil inhibited inflammatory mechanisms; at the higher dose, it aHered both the inflammatory and atherosclerotic mechanisms. This led to a double-blind cross-over study of fish oil therapy in 26 patients with lupus nephritis followed for 2 years 10 weeks. The fish oil dietary supplementation had no significant effect on proteinuria, isotope glomerular filtration rate, disease activity index, or steroid consumption. However, it did have a significant effect on lipid levels. The cross-over design suffered carryover effects (even with a 10-week wash-out period) and placebo effects of the olive oil, which created a risk of type II error. Our interest in omega-3 fatty acids led us to assess the effects of dietary supplementation with flaxseed. Not only is the flaxseed a major source of alpha-linolenic acid but it is also the richest natural source of lignan, a natural plateletactivating factor receptor antagonist. The 15% flaxseed dietary supplementation in the MRL/lpr mouse model resulted in a significant preservation in glomerular fiHration rate, a delay in proteinuria, and abrogation of lymphoproliferation. In addition, unlike MaxEPA, the flaxseed dietary supplementation resuHed in a significant 60% reduction in mortality. We concluded that, at present, fish oil is not indicated as a form of treatment in patients with lupus nephritis, but flaxseed dietary supplementation warrants further study.

Omega-3 Fatty Acid Supplementation in Clinical and Experimental Lupus Nephritis

Nutrients rich in omega-3 fatty acids (fish oil and flaxseed) have the potential to abrogate inflammatory and atherosclerotic mechanisms known to be involved in the pathogenesis of vascular damage of systemic lupus erythematosus nephritis. Fish oil dietary supplementation decreases proteinuria and preserves renal morphology in the NZB/NZW, BXSB, and MRL/lpr mouse models of lupus nephritis and decreases mortality in the NZB/NZW and BXSB models. The anti-inflammatory and anti-atherosclerotic potential, coupled with the animal experimental data, encouraged us to carry out a dosing study of low (6 g) and higher (18 g) doses of fish oil (MaxEPA) therapy in human lupus nephritis. At the lower dose, the fish oil inhibited inflammatory mechanisms; at the higher dose, it aHered both the inflammatory and atherosclerotic mechanisms. This led to a double-blind cross-over study of fish oil therapy in 26 patients with lupus nephritis followed for 2 years 10 weeks. The fish oil dietary supplementation had no significant effect on proteinuria, isotope glomerular filtration rate, disease activity index, or steroid consumption. However, it did have a significant effect on lipid levels. The cross-over design suffered carryover effects (even with a 10-week wash-out period) and placebo effects of the olive oil, which created a risk of type II error. Our interest in omega-3 fatty acids led us to assess the effects of dietary supplementation with flaxseed. Not only is the flaxseed a major source of alpha-linolenic acid but it is also the richest natural source of lignan, a natural plateletactivating factor receptor antagonist. The 15% flaxseed dietary supplementation in the MRL/lpr mouse model resulted in a significant preservation in glomerular fiHration rate, a delay in proteinuria, and abrogation of lymphoproliferation. In addition, unlike MaxEPA, the flaxseed dietary supplementation resuHed in a significant 60% reduction in mortality. We concluded that, at present, fish oil is not indicated as a form of treatment in patients with lupus nephritis, but flaxseed dietary supplementation warrants further study.

Phosphonolipids 4. A phosphonic acid analogue of platelet activating factor

A phosphonic acid analogue of platelet activating factor (PAF) bearing a backbone that is isosteric with and has stereochemistry corresponding to that of natural PAF has been synthesized. The synthesis uses a route maintaining stereochemical integrity.

Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents

Ginkgolides are unique twenty-carbon terpenes, occurring naturally only in the roots and leaves of Ginkgo biloba. The molecules incorporate a tert-butyl group and six 5-membered rings, and are specific and potent antagonists of platelet-activating factor (PAF), a potent inflammatory autacoid. Studies in animal models with the most potent ginkgolide, BN 52021, and other specific PAF antagonists have demonstrated that PAF plays an important role in pathologies such as asthma, shock, ischemia, anaphylaxis, graft rejection, renal disease, CNS disorders and numerous inflammatory conditions. Ginkgolides are now being developed as therapeutic agents and very promising results have been obtained in clinical trials on shock, organ preservation and thermal injury. In addition to ginkgolides, several other types of natural PAF antagonists have been identified from various medicinal plants. These compounds have not only helped to explain the pharmacological basis of several traditional medicines, but have also provided man with a valuable new class of therapeutic agents.

Asymmetric synthesis of (+)- and (-)-batyl alcohol, a key synthetic intermediate for platelet-activating factor, by using biocatalysts.

Asymmetric synthesis of platelet-activating factor (PAF) and its enantiomer by using biocatalysts was studied. Microbial reduction of the pro-chiral α-ketoester (3) afforded (+) -4 (> 99% ee), which could be converted to (+) -and (-) -batyl alcohol (12), a key synthetic intermediate for PAF. Compound (-) -4 (96% ee), with the requisite configuration for the synthesis of natural PAF, could also be obtained by enzyme-catalyzed enantioselective hydrolysis of (±) -15.

Platelet activating factor analogues: lack of correlation between their activities to produce hypotension and endothelium-mediated vasodilation.

Hypotensive activities of 11 synthetic derivatives of platelet activating factor (PAF) were examined and compared with their activities to produce endothelium-related relaxation of isolated rat thoracic aorta. The derivatives showed variety of hypotensive activities; some of the derivatives were more potent than natural PAF and some were virtually inactive compared to PAF. However, all of the compounds tested exhibited exactly the same activities to produce endothelium-related vasodilation. These results confirmed our previous view that the PAF-induced hypotension is not solely due to the endothelium-related vascular relaxation observed in vitro.

Synthetic studies on platelet-activating factor (PAF).

Chemical synthesis of platelet-activating factor (PAF, 1) and its enantiomer was studied. Several alkoxymethyl alkenyl ketones (5a-c, n=14 or 16) were synthesized from Wittig-Horner reagents (4, n=14 or 16) with cyclohexanecarboxaldehyde, octylaldehyde, and benzaldehyde, and subjected to asymmetric reduction with BINAL-H1) which is known to show high enantioselectivity in the reduction of enones. Optical purities of the reduction products (6) were determined from the 400 MHz proton nuclear magnetic resonance spectra after conversion of 6 to the esters (9) of optically active α-methoxy-α-trifluoromethyl-phenylacetic acid (MTPA). The MTPA ester of (+)-6b showed high optical purity (80%ee). Upon oxidative cleavage of the double bond with ozone followed by reduction with NaBH4, the acetate of (+)-6b afforded two known compounds (11 and 12), which have previously been transformed into natural PAF (1).