ABSTRACT
(+/-)-15-Fluoro-11,15-dideoxyprostaglandin E1 and its methyl and ethyl esters were synthesized. Dehydroxyfluorination reaction (+/-)-11-deoxyprostaglandin E1 esters with various reagents based on SF4 was studied. Along with the target 15-fluorides (mixtures of alpha- and beta-epimers), products of allylic shift and dehydration in a ratio dependent on the fluorination agent were shown to be formed. With a morpholinotrifluorosulfuran-tris(morpholine)sulfonium trimethyldifluorosilicate mixture, the maximal excess (70%) of one of the 15-fluoro epimers was achieved. Possible mechanisms of dehydroxyfluorination of (+/-)-11-deoxyprostaglandin E1 esters with dialkylaminoflluorosulfurans were proposed. Methyl esters of 15-alpha-fluoro- and 15-beta-fluoro-11,15-dideoxyprostaglandin E1 exhibited moderate antiaggregation activity in rabbit platelet tests.
Subject(s)
Alprostadil/analogs & derivatives , Platelet Aggregation Inhibitors/chemical synthesis , Alprostadil/chemical synthesis , Alprostadil/chemistry , Alprostadil/pharmacology , Animals , In Vitro Techniques , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Rabbits , StereoisomerismABSTRACT
We found that a number of new synthetic prostanoids caused a prominent reduction of human platelet aggregation in the in vitro experiments. Moreover, two of this agents, IOS 3933 and IOS 4732, gives storage stability. Hemoxygenase activity, metabolic homeostasis of bilirubin in brain and transport function of serum albumin in animals receiving cobalt chloride.
Subject(s)
Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Prostaglandins, Synthetic/pharmacology , Adenosine Diphosphate/pharmacology , Blood Donors , Dose-Response Relationship, Drug , Drug Storage , Humans , Powders , Solutions , Time FactorsABSTRACT
In the experiments on rabbits it was shown, that the administration of prostanoids IOS 3933 caused a reduction of ADP- and collagen induced platelet aggregation, platelet adhesion to collagen and elevation of t-PA level. This prostanoid prevented both a decrease in platelet count and reduction of AT III activity, but did not affect the protein C level during thromboplastin infusion.
Subject(s)
Blood Coagulation/drug effects , Prostaglandins, Synthetic/pharmacology , Animals , Blood Coagulation Tests/statistics & numerical data , Prostaglandins/pharmacology , Rabbits , Time FactorsABSTRACT
In order to study the physiological functions of 11-deoxyprostaglandin E1-alpha, a series of its amide derivatives with amino acids and some amines were synthesized using mixed anhydride technique. The myotropic properties of newly synthesized compounds were investigated.
Subject(s)
Alprostadil/analogs & derivatives , Amines/chemistry , Amino Acids/chemistry , Prostaglandins E, Synthetic/chemical synthesis , Alprostadil/chemical synthesis , Alprostadil/chemistry , Magnetic Resonance Spectroscopy , Prostaglandins E, Synthetic/chemistryABSTRACT
Four methods of the synthesis of model glycosides with 11-deoxyprostaglandin E1 and a connecting polymethylene chain as the aglycone are compared. Interaction of potassium salt of prostaglandin PG with omega-iodoalkylglycosides is the most promising approach.
Subject(s)
Alprostadil/analogs & derivatives , Glycosides/chemistry , Prostaglandins E/chemical synthesis , Alprostadil/chemical synthesis , Esters/chemical synthesis , Magnetic Resonance SpectroscopyABSTRACT
The effects of a synthetic prostaglandin E1 (PGE1) analog on colony-forming activity in agar cultures of peripheral blood and bone marrow was studied in 28 patients with chronic myeloid leukemia and 9 hematologically healthy subjects. Addition of PGE1 to normal bone marrow culture was followed by a significant drop in the number of colonies per dish in 8 out of the 9 subjects. In leukemic patients, the effect was bizarre. It proved to be in correlation with survival thus suggesting that the effect of PGE1 on colony-forming activity of granulocyte-macrophage precursors be used in predicting survival in patients with chronic myeloid leukemia.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Alprostadil/pharmacology , Blood Cells/drug effects , Bone Marrow/drug effects , Bone Marrow Cells , Colony-Forming Units Assay , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Prognosis , Tumor Cells, Cultured/drug effects , Tumor Stem Cell AssayABSTRACT
Total synthesis of a new prostaglandin analogue, 11-deoxy-4,4-dimethyl-4-sil-prostaglandin E1, is carried out through synthesis of a silicon-containing alpha-chain precursor and a 2-substituted cyclopentenone derivative followed by their cuprate-induced interaction.
Subject(s)
Alprostadil/analogs & derivatives , Prostaglandins E, Synthetic/chemical synthesis , Alprostadil/chemical synthesis , Chemical Phenomena , Chemistry , HydrolysisABSTRACT
The effect of none prostaglandin-like cyclopentanone derivatives on the prostaglandin H synthase activity was studied. Seven substances proved to be inhibitors of the enzyme, some of the being similar to the well-known nonsteroid antiinflammatory drugs with respect to their inhibitory activity.
Subject(s)
Cyclooxygenase Inhibitors , Prostaglandins, Synthetic/pharmacology , Animals , Chromatography, DEAE-Cellulose , Kinetics , Microsomes/enzymology , SheepABSTRACT
Administration of isoproterenol results in a marked increase (by 4.85 times) of the blood serum concentration of free fatty acids. In the heart there was found a four-fold increase of the concentration of long-chain acylcarnitine against the background of a reduction of free carnitine content. A preliminary administration of doprostone in a dose of 50 micrograms/kg intraperitoneally for 10 days completely prevents isoproterenol-induced increase of the serum concentration of free fatty acids and the heart concentration of long-chain acylcarnitine. Doprostone contributes also to preservation of the myocardium content of free carnitine under conditions of adrenergic influences. Correction of fatty acid metabolism under the influence of doprostone indicates the possibility of the heart protection against lesions caused by fatty acids and their detergent metabolites (long-chain acyl-CoA and acylcarnitine) during adrenergic and ischemic influences.
Subject(s)
Fatty Acids/metabolism , Heart/drug effects , Myocardium/metabolism , Acetylcarnitine/metabolism , Alprostadil/pharmacology , Animals , Carnitine/metabolism , Catecholamines/physiology , Heart/physiology , Isoproterenol/pharmacology , Male , RatsABSTRACT
Synthesis of a number of model triglycerides and lysoglycerides bearing the acyl moieties of 11-deoxyprostaglandin E1, and palmitic acid residues has been carried out.
Subject(s)
Prostaglandins/chemical synthesis , Triglycerides/chemical synthesis , Acylation , Chemical Phenomena , ChemistryABSTRACT
The effect of a native synthetic prostaglandin E1 on the blood supply and basic parameters of hemodynamics in acute myocardial ischemia induced by coronary artery occlusion was studied. It was found that the preparation in doses of 5 and 10 mg/kg increases the general and collateral coronary circulation by redistributing it into the endocardium of myocardial ischemic lesion. PGE1 increased the systolic discharge and the minute volume of the heart, enhanced the contractile myocardium activity. With an increase of the preparation dose its positive effect was not enhanced.
Subject(s)
Alprostadil/therapeutic use , Coronary Circulation/drug effects , Coronary Disease/drug therapy , Hemodynamics/drug effects , Prostaglandins E, Synthetic/therapeutic use , Acute Disease , Animals , Cats , Collateral Circulation/drug effects , Coronary Disease/diagnostic imaging , Coronary Disease/physiopathology , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Male , Phosphorus Radioisotopes , Radionuclide ImagingABSTRACT
(+/-) 15 alpha-OH-11-deoxyprostaglandin E1 was found to possess a pronounced antisecretory activity at stimulation of gastric secretion in cats with pentagastrin. In rats the compound exerted the protective effect of cells of the gastric mucosa, especially on indomethacin and stress models of ulcerogenesis. The cytoprotective effect of the compound seemed to be related to its action on secretion of mucus as well as to its stimulation of zinc accumulation in cells that stabilized cell membranes and suppressed the secretory activity of mast cells.
Subject(s)
Alprostadil/analogs & derivatives , Anti-Ulcer Agents/therapeutic use , Gastric Mucosa/drug effects , Prostaglandins E, Synthetic/therapeutic use , Alprostadil/therapeutic use , Animals , Cats , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gastric Mucosa/metabolism , Indomethacin , Male , Pentagastrin/pharmacology , Rats , Reserpine , Stomach Ulcer/drug therapy , Stomach Ulcer/etiology , Stress, Physiological/complicationsABSTRACT
Several novel prostaglandins containing an amide group in the alpha-chain have been prepared by the mixed carbonic anhydride method from 3 alpha-tetrahydrofuranyloxy-5-hydroxyimino-2 beta-(3 alpha- tetrahydrofuranyloxy-trans-1-octenyl)-cyclopentane-1 alpha-acetic acid and omega-amino acids with a linear chain of varying length (CH2-group number from 1 to 7). The physico-chemical properties of the title compounds were studied.
Subject(s)
Cyclopentanes/chemical synthesis , Furans/chemical synthesis , Prostaglandins/chemical synthesis , Amides/chemical synthesis , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Cyclopentanes/analysis , Furans/analysis , Magnetic Resonance Spectroscopy , Prostaglandins/analysis , Spectrophotometry, InfraredABSTRACT
Hydroxyl-containing 11-deoxyprostaglandin E1 esters were synthesised by using the methods of mixed anhydrides and nucleophilic displacement.
Subject(s)
Alprostadil/analogs & derivatives , Alprostadil/chemical synthesis , Alprostadil/isolation & purification , Chemical Phenomena , Chemistry , Chromatography, Thin Layer , Esters/chemical synthesis , Esters/isolation & purification , Mass SpectrometryABSTRACT
The theoretical conformational analysis of PGE2 has been performed using semiempirical approach and fixed values of the bond length and valence angles. A set of low-energy conformations was obtained for the alpha-chain and the whole PGE2 molecule. Unlike the PGE1 molecule, PGE2 alpha-chain prefers semifolded conformations. The hairpin structures with the parallel orientation of alpha- and omega-chains are the lowest-energy conformations of PGE2 conformations of PGE1 and PGE2. Sterically similar explain the similar biological activity of the two molecules.
Subject(s)
Prostaglandins E , Dinoprostone , Models, Molecular , Models, Theoretical , Molecular ConformationABSTRACT
The review surveys current literature on microbiological synthesis and modification of prostaglandins. Three possible approaches to the use of microorganisms for prostaglandin production are considered including synthesis de novo, arachidonic acid transformation, and prostaglandin modifications. The most typical reactions of prostaglandin transformations by microorganisms are analysed: hydrolysis, hydroxylation, reduction and beta-oxidation.
Subject(s)
Bacteria/metabolism , Fungi/metabolism , Prostaglandins/biosynthesis , Biotransformation , Chemical Phenomena , Chemistry , Microbiological Techniques , Prostaglandins/metabolismABSTRACT
A comparative analysis of the effect of racemic PGF2 alpha--(+/-)PGF2 alpha, 15 alpha OH-II-deoxy-PGE1-(+/-)DPGE1, aceclidine, neostigmine methylsufate, galanthamini hydrobromidum, and pituitrine on the ileum motility was performed in rabbits with dynamic ileus induced by surgical trauma and peritonitis. In the model under study (+/-)PGF2 alpha was similar in its action to neostigmine methylsulfate and aceclidine, with (+/-)DPGE1 having a week effect.
Subject(s)
Alprostadil/analogs & derivatives , Gastrointestinal Motility/drug effects , Intestinal Obstruction/physiopathology , Intestine, Small/physiopathology , Prostaglandins F/pharmacology , Alprostadil/pharmacology , Animals , Dinoprost , Intestinal Obstruction/etiology , Male , Peritonitis/complications , Prostaglandins E, Synthetic/pharmacology , Prostaglandins F, Synthetic/pharmacology , Rabbits , StereoisomerismABSTRACT
The effects of prostaglandin F2 alpha and (+/-) 11-deoxyprostaglandin E1 (DPGE) on the levels of progesterone and estradiol in the blood plasma or serum of experimental animals were studied and compared. It was found for the first time that the synthetic analog of natural PGE1, DPGE, is capable to substantially reduce the progesterone level in the blood (rats and cows) and to induce the luteolysis of yellow bodies in the cow ovaries. It was demonstrated that DPGE promotes the resolution of both cyclic and persistent yellow bodies. The pattern of the drug action on rat blood steroid hormones depends on the time of pregnancy and is most pronounced in the last trimester of pregnancy.
Subject(s)
Alprostadil/analogs & derivatives , Corpus Luteum/drug effects , Estradiol/blood , Progesterone/blood , Prostaglandins E, Synthetic/pharmacology , Animals , Cattle , Estrus/drug effects , Female , Pregnancy , Rats , Rats, Inbred StrainsABSTRACT
Derivatives of 1,4-naphthoquinones increased the lipolytic activity of epididymal and perinephric fatty tissues. A compound AK-45 Na at a dose of 30 mg/kg elevated the positive effect of rheopolyglucine on lipid metabolism, contributing to mobilization as well as to consumption of lipids in hemorrhagic shock in rats and rabbits.
