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PubMed2000

A novel in vitro effect of the mucosal protective agent sofalcone--inhibition of chemotactic motility in Helicobacter pylori.

BACKGROUND: Motility of Helicobacter pylori is essential for colonization. H. pylori has been shown to exhibit chemotactic activity toward urea and sodium and bicarbonate ions, which are secreted from the gastric epithelia. The importance of urease activity for chemotactic motility of H. pylori in a viscous environment has also been shown. Consequently, application of drugs inhibiting chemotactic motility has been proposed as a strategy for H. pylori eradication. This inhibitory effect can be evaluated through assay of chemotaxis and swarming. MATERIALS AND METHODS: H. pylori CPY3401 and ATCC43504 were grown on brucella agar plates/broth supplemented with 3% horse serum under microaerobic conditions (N2, 85%; O2, 5%; CO2, 10%). For motility assay, H. pylori cells grown on brucella-serum agar were stabbed into motility agar containing 0.35% refined agar in brucella-serum broth and the swarming zone was measured. For the chemotaxis assay, cells were suspended in 10 mM potassium phosphate buffer, pH 7.0, with 3% polyvinyl-pyrrolidone and assayed as described previously. Bacterial swimming in the fluid environment was observed under dark-field microscopy. RESULTS: Numbers of bacteria attracted toward 1 microM flurofamide were reduced with increasing concentrations of sofalcone (0.2-222 microM). In addition, the size of the swarming zone was reduced in motility agar containing 22 and 222 microM sofalcone. On the other hand, 22 microM sofalcone did not inhibit bacterial growth on day 3. Bacterial swimming speed in brucella broth was slower in the presence of 22 and 222 microM sofalcone than in its absence. CONCLUSION: Sofalcone was found to inhibit chemotactic motility of H. pylori. This drug may be useful for inhibiting the bacterium's ability to colonize the human stomach.

Anti-Ulcer Agents↗
PubMed2001

In vivo confocal Raman microspectroscopy of the skin: noninvasive determination of molecular concentration profiles.

Confocal Raman spectroscopy is introduced as a noninvasive in vivo optical method to measure molecular concentration profiles in the skin. It is shown how it can be applied to determine the water concentration in the stratum corneum as a function of distance to the skin surface, with a depth resolution of 5 microm. The resulting in vivo concentration profiles are in qualitative and quantitative agreement with published data, obtained by in vitro X-ray microanalysis of skin samples. Semi-quantitative concentration profiles were determined for the major constituents of natural moisturizing factor (serine, glycine, pyrrolidone-5-carboxylic acid, arginine, ornithine, citrulline, alanine, histidine, urocanic acid) and for the sweat constituents lactate and urea. A detailed description is given of the signal analysis methodology that enables the extraction of this information from the skin Raman spectra. No other noninvasive in vivo method exists that enables an analysis of skin molecular composition as a function of distance to the skin surface with similar detail and spatial resolution. Therefore, it may be expected that in vivo confocal Raman spectroscopy will find many applications in basic and applied dermatologic research.

Adult↗
PubMed2001

Activation of nuclear factor-kappa B by podocytes in the autologous phase of passive Heymann nephritis.

BACKGROUND: The present study examined whether activation of nuclear factor-kappa B (NF-kappa B) occurs within podocytes in passive Heymann nephritis (PHN) and contributes to the pathogenesis of proteinuria. METHODS: Electrophoretic mobility shift assays (EMSAs) were used to detect NF-kappa B activation, and supershift assays were used to determine the subunits involved. Localization of the activated NF-kappa B subunit p50 was performed by immunohistochemistry. Expression of the NF-kappa B-dependent genes interleukin-1 beta (IL-1 beta) and matrix metalloproteinase-9 (MMP-9) were determined by reverse transcription-polymerase chain reaction and, for IL-1 beta, immunohistochemistry. To inhibit activation of NF-kappa B in vivo, pyrrolidone dithiocarbamate (PDTC) was administered for 10 days following induction of PHN. RESULTS: Glomerular nuclear extracts from rats with PHN showed increased NF-kappa B binding activity in comparison to normal rats. The major Rel/NF-kappa B proteins in these activated complexes were p65 and p50. Immunohistochemistry showed that nuclear translocation of p50 occurred predominantly within podocytes. IL-1 beta mRNA was increased in the PHN rats, and increased IL-1 beta protein was localized predominantly to podocytes by immunohistochemistry. To investigate whether activation of NF-kappa B is involved in the pathogenesis of proteinuria, PDTC was administered to rats with PHN. Electrophoretic mobility shift assays of glomerular nuclear extracts showed a significant reduction in NF-kappa B binding activity in the PDTC-treated rats with a striking reduction in MMP-9 mRNA. Compared with control rats, there was a significant reduction in albuminuria at days 15 (P < 0.001) and 20 (P < 0.001) when PHN was induced with a suboptimal dose of anti-Fx1A antiserum. There was no detectable difference in the systemic immune response to sheep Ig in the treated rats. CONCLUSIONS: These data show that NF-kappa B is activated within podocytes in PHN and suggest that it contributes to autologous phase proteinuria. The critical genes regulated by NF-kappa B in the podocyte have not yet been determined, but may include MMP-9.

Albuminuria↗
PubMed2001

Pharmacokinetics of levetiracetam and its enantiomer (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide in dogs.

PURPOSE: The new antiepileptic drug, levetiracetam (LEV, ucb LO59), is a chiral molecule with one asymmetric carbon atom whose anticonvulsant activity is highly enantioselective. The purpose of this study was to evaluate and compare the pharmacokinetics (PK) of LEV [(S)-alpha-ethyl-2-oxo-pyrrolidine acetamide] and its enantiomer (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide (REV) after i.v. administration to dogs. This is the first time that the pharmacokinetics of both enantiomers has been evaluated. METHODS: Optically pure LEV and REV were synthesized, and 20 mg/kg of individual enantiomers was administered intravenously to six dogs. Plasma and urine samples were collected until 24 h, and the concentrations of LEV and REV were determined by an enantioselective assay. The levels of 2-pyrrolidone-N-butyric acid, an acid metabolite of LEV and REV, were determined by high-performance liquid chromatography (HPLC). The data were used for PK analysis of LEV and REV. RESULTS: LEV and REV had similar mean +/- SD values for clearance; 1.5 +/- 0.3 ml/min/kg and volume of distribution; 0.5 +/- 0.1 L/kg. The half-life (t1/2) and mean residence time (MRT) of REV (t1/2, 4.3 +/- 0.8 h, and MRT, 6.0 +/- 1.1 h) were, however, significantly longer than those of LEV (t1/2, 3.6 +/- 0.8 h, and MRT, 5.0 +/- 1.2 h). The renal clearance and fraction excreted unchanged for LEV and REV were significantly different. CONCLUSIONS: In addition to the enantioselective pharmacodynamics, alpha-ethyl-2-oxo-pyrrolidine acetamide has enantioselective PK. The enantioselectivity was observed in renal clearance. Because REV has more favorable PK in dogs than LEV, the higher antiepileptic potency of LEV is more likely due to intrinsic pharmacodynamic activity rather than to enantioselective PK.

Animals↗
PubMed2003

Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity.

PURPOSE: The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model. METHODS: All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining. RESULTS: No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA. CONCLUSIONS: Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.

Animals↗
PubMed1985

[Lipoproteins and malaria. II. Immunoregulatory role of immunoglobulin-lipoprotein complexes in mice infected with Plasmodium chabaudi on antibody producing cells].

Injection of lipoproteins from Plasmodium chabaudi infected mice into mice previously immunized with either human serum transferrin, bovine serum albumin, polyvinyl-pyrrolidone or tetanus toxoid, was followed by a decrease in the levels of antibodies directed against these antigens, suggesting a blockade of antibody secreting cells (Goumard et al., 1982). However, lipoproteins in P. chabaudi infected mice are complexed with immunoglobulins during the second week of infection (Demonchy et al., 1982). In this study, the effects of lipoproteins and Ig-lipoprotein complexes (Ig-Lp) on antibody secreting cells was investigated in vitro. Spleen cells from mice immunized with tetanus toxoid were cultured in microplates and the antitetanus antibodies (anti-TT Ab) were measured in the culture supernatants using a radioimmunoassay (Goumard et al., 1984). Ig-Lp purified from day-11 or day-13 P. chabaudi infected mice inhibited the secretion of anti-TT Ab when introduced into microcultures. On the contrary, lipoproteins purified from either day-5, day-7, day-21 or day-28 infected mice as well as lipoproteins from uninfected mice did not inhibit anti-TT Ab secreting cells. Ig-Lp formed in vitro with lipoproteins purified from day-7 infected mice (Lp J-7) and day-20 infected mice sera, inhibited anti-TT Ab secreting cells. IgG purified from day-20 sera and incubated with Lp J-7, inhibited anti-TT Ab secreting cells but no inhibitory effect was observed with the F(ab')2 fragments of these Ig. Pre-incubation of anti-TT Ab secreting cells with Fc fragments of mouse IgG blocked the inhibitory effect of Ig-Lp purified from infected mouse sera or formed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Effects of oxygen, CO2/pH and medium on the in vitro development of individually cultured porcine one- and two-cell embryos.

The gas atmosphere and medium composition are critical factors in the in vitro development of one- and two-cell embryos of several species. The present study evaluated the effect of different O2/CO2 concentrations (2/5, 2/10, 5/2.5, 5/5, 5/10, 10/10 and 21/5) on pig one- and two-cell embryo development. The embryos were individually cultured, for 6 days at 39 degrees C in a medium rich in bicarbonate and glutamine and containing pyruvate and lactate but lacking glucose. When the CO2 levels increased from 2.5% to 10%, the pH of the medium decreased from 8.2 to 7.5 and the development of the embryos was affected, but this depended mainly on the O2 levels. Pig embryo development was inhibited by 2 and 21% O2 levels. The optimum level for pig embryo development was 5% O2 and 5% CO2, whatever the criteria used to evaluate embryo development. At these optimal levels, the mean number of cells per embryo was 26 +/- 1.7 (ls mean +/- SE), and 50% of the one- and two-cell embryos developed to blastocysts. The substitution of 0.5% bovine serum albumin (BSA) in the medium by 0.3% polyvinyl-pyrrolidone (PVP) significantly decreased the one- and two-cell embryo development. When the calcium and chloride contents of the medium with PVP were reduced, however, the embryo development was similar to that observed in the medium containing BSA. Pig embryo development in vitro was found to be optimal under an atmosphere of 5% O2 and 5% CO2 and PVP could replace BSA as the high molecular weight supplement.

Animals↗
PubMed2006

[Study of the toxicity of povidone-lodine for fibroblast-like cells (BALB-3T3) and primary human chondrocytes].

Povidone-iodine (polyvinyl-pyrrolidone-iodine complex, PVP-iodine, CAS 25655-41-8) is a commonly used antiseptic because of its broad spectrum of antimicrobial effect and its comparatively low allergic risk. It is also used for open joint lavage. Animal and organ culture studies provide controversial results about the risk of cartilage damage due to povidone-iodine. There is a paucity of in vitro study data concerning the effect of povidone-iodine on chondrocyte cultures are still missing. The aim of this study was therefore to investigate the effect of different concentrations and exposition times of povidone-iodine on cell growth and differentiation of human chondrocytes. Using of a vitality test (MTT) and a proliferation assay (BrdU) in the fibroblast-like cell line BALB3T3, suitable concentrations and incubation times were identified to investigate the influence of povidone-iodine on proteoglycan synthesis and DNA synthesis of primary human chondrocytes. Concentrations of up to 1% povidone-iodine had no significant effect on proteoglycan and DNA synthesis of chondrocytes after incubation for 30 min. An incubation time of 24 h did not inhibit DNA- and proteoglycan synthesis, until a concentration of 0.2% povidone-iodine was used. DNA synthesis rate was impaired after 10 min incubation with 0.2% and fully inhibited with 1% povidone iodine. BALB3T3 reacted more sensitively than chondrocytes. Vitality and proliferation rate were fully inhibited at a concentration of 0.5% after the same exposition time. However, cells recovered 24 h after 30 min incubation with 0.5% povidone-iodine. After incubation with 5% povidone iodine cells did not recover. From the results it can be concluded that low concentrations of povidone-iodine (< 1%) and short incubation times (< 30 min) have no damaging influence on chondrocytes. Previous studies have reported the antimicrobial effectiveness of low concentrations of povidone-iodine on the reduction of tissue damage by microorganisms. Data from previus studies and the current findings from this investigation support the clinical use of povidone-iodine at low concentrations and short incubation times for antiseptic treatment of cartilage tissues.

3T3 Cells↗
PubMed2001

Macroencapsulation of rat islets without alteration of insulin secretion kinetics.

Transplantation of encapsulated islets may restore endogenous insulin secretion in type 1 diabetics with no need of lifetime immunosuppression of the recipient. A biomaterial should be developed which combined immunoisolation with rapid and efficient diffusion of glucose and insulin. Rat islets were macroencapsulated in capillaries (molecular cut off 50 kD) of differently modified polysulphone. Macroencapsulated islets were perifused to study the kinetics of glucose induced insulin secretion into the perifusion medium. Blending polysulphone (PSU) with poly vinyl pyrrolidone or sodium dodecyl sulphate was not suited for islet macroencapsulation since glucose induced insulin release was absent after encapsulation. Hydroxy methylation (CH2OH) of PSU improved the secretory behaviour of macroencapsulated islets depending on the degree of substitution (DS). At 0.8 DS glucose induced insulin secretion was delayed and inefficient. At maximal degrees of PSU-substitution (1.8) the kinetics of insulin release and the efficiency of insulin release were very similar to that observed of free floating islets. In conclusion, highly substituted hydroxy methylated polysulphone allows a rapid and efficient insulin release after macroencapsulation and is suited for the further development of a bioartificial pancreas.

Animals↗
PubMed1984

[Prevention of postoperative adhesions--animal experiment study].

Standardised lesions were placed on both uterine horns and on the abdominal wall of seventy-five female rabbits. The animals were divided into five groups consisting of 15 animals each. Before closure of the peritoneum the following drugs were applied in the peritoneal cavity: Group I received NaCl (control), Group II received 10 ml poly-(1-vinyl-1-pyrrolidone)-iodine complex (Betaisodona), Group III received 100 000 I. U. streptokinase and 25 000 I. U. streptodornase (Varidase), Group IV received 100 000 KIE approtinine (AntagosanA) and Group V received triamcinolone acetonide (Volon A-Haftsalbe). Two weeks after surgery the animals were relaparotomised and the situs was inspected. Quality and extent of the adhesions were assessed and documented. The results obtained in group II did not differ from controls, while the remaining groups showed significantly fewer adhesions. The best results were obtained in animals receiving Volon A-Haftsalbe (Group V) where 86% fewer adhesions were observed.

Abdomen↗
PubMed1994

[Corneal ulcer in chronic graft-versus-host disease: treatment with collagen shields].

BACKGROUND: After bone marrow transplantation various ocular diseases have been described. Ocular involvement is very common in patients with chronic Graft-versus-Host Disease (GvHD). These patients show clinical and histological evidence of a dry-eye condition in 60-100 per cent. A severe complication is the development of a corneal ulcer with possible corneal perforation. Two patients with a severe dry-eye condition and development of corneal stroma ulceration are described. The corneal ulcers healed after treatment with collagen-shield. HISTORY AND SIGNS: In a 13-year-old boy an allogeneic bone marrow transplantation was performed in April 1989 because of Fanconi's anemia. In November 1989 a severe dry-eye condition occurred due to GvHD with skin, liver, and gastrointestinal tract manifestation. In April 1991 he presented with corneal stroma ulceration of the right eye. In a 24-year-old patient an allogeneic bone marrow transplantation was performed because of chronic myeloid leukemia in August 1989. In December 1989 he developed dry-eye condition due to GvHD with skin, mucosa and liver involvement. In December 1991 a corneal ulcer of the left eye occurred. THERAPY AND OUTCOME: Repeated conjunctival and corneal smears were negative. Local antibiotic and antiviral treatment showed no effect. Corneal ulcers deteriorated progressively with corneal thinning. Both patients were therefore treated with daily collagen-shields and hourly polyvinyl-pyrrolidon eye-drops resulting in healing of the corneal ulcer within 3 and 2 weeks respectively. CONCLUSION: Treatment of corneal stromal ulceration in dry eye condition caused by chronic GvHD is difficult. In noninfectious ulcers daily application of collagen-shields and hourly artificial tears may prevent severe ocular complications like corneal perforation.

Adolescent↗
PubMed1977

Purification and properties of the pyrrolidonecarboxylate peptidase of Streptococcus faecium.

Pyrrolidonecarboxylate peptidase (EC 3.4.11.8) from Streptococcus faecium was purified by fractionation with streptomycin sulphate and ammonium sulphate, by chromatography on Sephadex G200 and DEAE-cellulose, and by preparative electrophoresis on Sephadex G25. The purified enzyme on acrylamide gel showed a strong protein band which contained enzyme activity and a very faint band which had no activity. The subunit molecular weight of the purified enzyme was estimated by acrylamide gel electrophoresis in sodium dodecyl sulphate to be 42,000 +/- 1,000. The enzyme showed optimum activity at pH 7.6 and was unstable in the absence of 2-mercaptoethanol. The sensitivity of the enzyme to alkylating agents (N-ethylmaleimide and iodoacetamide) suggested that free sulphydryl groups were essential for enzyme activity. The enzyme was rapidly inactivated above 45 degrees C. The values of the Michaelis constants (Km) obtained with various L-pyrrolidonecarboxylyl dipeptides were similar although there was a 10-fold range in the maximal rates of hydrolysis of these substrates. Inhibition studies showed that the substrate analogues 2-pyrrolidone and pyrrolidonecarboxylate are competitive inhibitors of the enzyme. The binding of substrates and inhibitors to the active site of the enzyme is discussed.

Aminopeptidases↗
PubMed1972

Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF) (LH-hypothalamus-LRF-gas chromatography-mass spectrometry-decapeptide-Edman degradation).

The primary structure of ovine hypothalamic hypophysiotropic luteinizing hormone-releasing factor, LRF, has been established as pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH(2) by hydrolysis of the peptide with chymotrypsin or pyrrolidone-carboxylylpeptidase and by analysis of the products by an Edman-dansylation sequencing technique, as well as by mass spectrometry of the derived phenylthiohydantoins. A decapeptide with the proposed primary structure, prepared by total synthesis, gave the same result on sequencing. The synthetic decapeptide possesses the same biological activities as the native ovine LRF. The amino-acid sequence of ovine LRF is identical to that already published for porcine LRF.

Amino Acid Sequence↗
PubMed1972

Amino acid sequence of human apoLp-Gln-II (apoA-II), an apolipoprotein isolated from the high-density lipoprotein complex.

An apolipoprotein, designated by its carboxyl-terminal residue as apoLp-Gln-II, has been isolated from the human high-density lipoprotein family, and its complete aminoacid sequence was determined. The apoprotein, one of the two major apoproteins of this family, is composed of two identical polypeptide chains, each containing 77 amino acids. The two polypeptide chains are connected by a single disulfide bridge at position 6 in the sequence. The minimum molecular weight of the intact apoprotein is 17,380. The amino-terminal residue of each chain is pyrrolidone carboxylic acid, and the carboxyl-terminal residue is glutamine.

Amino Acid Sequence↗
PubMed1973

Inhibition of 5-oxoprolinase by 2-imidazolidone-4-carboxylic acid.

L-2-Imidazolidone-4-carboxylic acid is an effective competitive inhibitor of the reaction catalyzed by 5-oxoprolinase, in which 5-oxo-L-proline (L-pyroglutamic acid, L-2-pyrrolidone-5-carboxylic acid, L-5-oxopyrrolidine-2-carboxylic acid) is converted to L-glutamate, with concomitant cleavage of ATP to ADP and orthophosphate. L-2-Imidazolidone-4-carboxylate decreased the rate of metabolism of 5-oxo-L-[(14)C]proline to (14)CO(2) by rat-kidney slices but had no effect on the metabolism of [(14)C]glutamate. Mice injected with L-2-imidazolidone-4-carboxylate exhibited greatly reduced ability to metabolize 5-oxo-L-proline, but metabolized glutamate at an essentially normal rate. The findings provide an approach to an animal model for the human condition 5-oxoprolinuria, in which there is apparently a deficiency of renal 5-oxoprolinase activity. The evidence indicates that 5-oxoproline is a normal metabolite.

Amidohydrolases↗
PubMed1974

Formation of 5-oxoproline from glutathione in erythrocytes by the gamma-glutamyltranspeptidase-cyclotransferase pathway.

gamma-Glutamyltranspeptidase activity was demonstrated in the membrane fraction of rabbit erythrocytes. The activity observed (with glutathione and various amino-acid acceptors) was similar in magnitude to that of the gamma-glutamylcyclotransferase and gamma-glutamylcysteine synthetase activities found in the soluble fraction of the cell. No transpeptidase activity was observed with either gamma-glutamyl p-nitroanilide or oxidized glutathione in contrast to the rabbit-kidney enzyme for which these compounds and glutathione serve as substrates. Erythrocyte suspensions and hemolysates formed 5-oxoproline (pyroglutamate; pyrrolidone carboxylate); the rate of 5-oxoproline formation from glutathione by hemolysates was increased by addition of methionine. The findings indicate that 5-oxoproline is an end-product of glutathione metabolism in erythrocytes, and that 5-oxoproline passes out of the erythrocyte and is metabolized in other tissues. The observed rate of 5-oxoproline formation is consistent with the conclusion that the gamma-glutamyltranspeptidase-cyclotransferase pathway, together with the synthesis of glutathione from glycine, cysteine, and glutamate, account for a large fraction of the observed amino-acid turnover of erythrocyte glutathione.

Acyltransferases↗
PubMed1974

Accumulation of 5-oxoproline in mouse tissues after inhibition of 5-oxoprolinase and administration of amino acids: evidence for function of the gamma-glutamyl cycle.

5-Oxoprolinase catalyzes the conversion of 5-oxo-L-proline (L-pyroglutamate, L-2-pyrrolidone-5-carboxylate) to L-glutamate with concomitant stoichiometric cleavage of ATP to ADP and inorganic orthophosphate. In this reaction, a step in the gamma-glutamyl cycle, 5-oxoproline (formed by the action of gamma-glutamylcyclotransferase on gamma-glutamyl amino acids, which are in turn formed by transpeptidation of amino acids with glutathione), is made available for glutathione synthesis. When mice are injected with L-2-imidazolidone-4-carboxylate, a competitive inhibitor of 5-oxoprolinase, they accumulate 5-oxoproline in their tissues (kidney, liver, brain, and eye) and excrete it in the urine. Mice given the inhibitor together with one of several L-amino acids accumulate and excrete much more 5-oxoproline than when they are given the inhibitor alone. Such augmentation of 5-oxoproline accumulation offers evidence for the function of the gamma-glutamyl cycle in vivo and supports the view that 5-oxoproline is a quantitatively significant metabolite.

Amidohydrolases↗
PubMed1996

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

A convenient, high yield conversion of doxorubicin to 3'-deamino-3'-(2''-pyrroline-1''-yl)doxorubicin is described. This daunosamine-modified analog of doxorubicin is 500-1000 times more active in vitro than doxorubicin. The conversion is effected by using a 30-fold excess of 4-iodobutyraldehyde in anhydrous dimethylformamide. The yield is higher than 85%. A homolog of this compound, 3'-deamino-3'-(1'',3''-tetrahydropyridine-1''-yl)doxorubicin, was also synthesized by using 5-iodovaleraldehyde. In this homolog, the daunosamine nitrogen is incorporated into a six- instead of a five-membered ring. This analog was 30-50 times less active than its counterpart with a five-membered ring. A similar structure-activity relationship was found when 3'-deamino-3'-(3''-pyrrolidone-1''-yl)doxorubicin (containing a five-membered ring) and 3'-deamino-3'-(3''-piperidone-1''-yl)doxorubicin (with a six-membered ring) were tested in vitro, the former being 5 times more potent than the latter. To further elucidate structure-activity relationships, 3'-deamino-3'-(pyrrolidine-1''-yl)doxorubicin, 3'-deamino-3'-(isoindoline-2''-yl)doxorubicin, 3'-deamino-3'-(2''-methyl-2''-pyrroline-1''-yl)doxorubicin, and 3'-deamino-3'-(3''-pyrroline-1''-yl)doxorubicin were also synthesized and tested. All the analogs were prepared by using reactive halogen compounds for incorporating the daunosamine nitrogen of doxorubicin into a five- or six-membered ring. These highly active antineoplastic agents can be used for incorporation into targeted cytotoxic analogs of luteinizing hormone-releasing hormone intended for cancer therapy.

Aldehydes↗