Synthesis of some guanylhydrazones and imidazolinylhydrazones as thromboxane-synthase and platelet aggregation inhibitors.

The imidazolinylhydrazones of (3-pyridinyloxy)-acetaldehyde and of 6-[3-(2-formyl-pyridinyl)oxy]hexanoic acid were synthesized as cyclic analogues of the corresponding guanylhydrazones which were found to be selective inhibitors of human thromboxane-synthase. The benzene isosters were also prepared in order to define the importance of the ring nitrogen for the activity. Moreover, the guanyl- and imidazolinyl-hydrazones of two 6-[(3-pyridinyl)oxy]hexanoic acids showing in the 2 position an alkyl chain with an alpha, beta-unsaturated ketonic function were prepared. Imidazolinylhydrazones 7 and 18 are selective inhibitors of thromboxane-synthase, while the two guanylhydrazones 14 and 15 which do not affect prostanoid biosynthesis seemed to be antagonists at the thromboxane receptor.     

Characterization of the cloned guinea pig leukotriene B4 receptor: comparison to its human orthologue

A cDNA clone coding for the guinea pig leukotriene B₄ (BLT) receptor has been isolated from a lung cDNA library. The guinea pig BLT receptor has an open reading frame corresponding to 348 amino acids and shares 73% and 70% identity with human and mouse BLT receptors, respectively. Scatchard analysis of membranes prepared from guinea pig and human BLT receptor-transfected human embryonic kidney (HEK) 293 EBNA (Epstein–Bar Virus Nuclear Antigen) cells showed that both receptors displayed high affinity for leukotriene B₄ (K_d value of 0.4 nM) and were expressed at high levels (B_max values ranging from 9 to 12 pmol/mg protein). The rank order of potency for leukotrienes and related analogs in competition for [³H]leukotriene B₄ specific binding at the recombinant guinea pig BLT receptor is leukotriene B₄>20-OH-leukotriene B₄>12(R)-HETE ((5Z,8Z,10E,12(R)14Z)-12-hydroxyeicosatetraen-1-oic acid)>12(S)-HETE ((5Z,8Z,10E,12(S)14Z)-12-Hydroxyeicosatetraen-1-oic acid)>20-COOH-leukotriene B₄>U75302 (6-(6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridinyl)-1,5-hexanediol)leukotriene C₄=leukotriene D₄=leukotriene E₄. For the human receptor the rank order of 12(S)-HETE, 20-COOH-leukotriene B₄ and U75302 was reversed. Xenopus melanophore and HEK aequorin-based reporter gene assays were used to demonstrate that the guinea pig and human BLT receptors can couple to both the cAMP inhibitory and intracellular Ca²⁺ mobilization signaling pathways. However, in the case of the aequorin-expressing HEK cells (designated AEQ17-293) transfected with either the guinea pig or human BLT receptor, expression of G_α16 was required to achieve a robust Ca²⁺ driven response. Leukotriene B₄ was a potent agonist in functional assays of both the guinea pig and human BLT receptors. U-75302 a leukotriene B₄ analogue which possesses both agonistic and antagonistic properties behaved as a full agonist of the guinea pig and human BLT receptors in AEQ17-293 cells and not as an antagonist. The recombinant guinea pig BLT receptor will permit the comparison of the intrinsic potencies of leukotriene B₄ receptor antagonists used in guinea pig in vivo models of allergic and inflammatory disorders.     

The peroxisome proliferator-activated receptor α activator, Wy14,643, is anti-inflammatory in vivo

The peroxisome proliferator-activated receptor system is exciting much interest as a novel point of therapeutic intervention in inflammation. Here, the effect of a peroxisome proliferatoractivated receptor α agonist, [4-chloro-6-(2,3-xylidine)-pyrimidinylthio]acetic acid (Wy14,643), was examined in arachidonic acid-induced murine ear inflammation. 3-[1-(4-Chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK886, a 5-lipoxygenase inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) were used as reference compounds. Wy14,643 dose dependently inhibited ear swelling and polymorphonuclear leukocyte influx, as did MK886, associated with reduced tissue leukotriene B₄ but not prostaglandin E₂ levels. Unlike MK886, Wy14,643 did not inhibit ex vivo leukotriene B₄ production. However, Wy14,643, but not MK886, induced peroxisomal enzyme activity. Indomethacin was less effective, though tissue prostaglandin E₂ but not leukotriene B₄ levels were reduced. Again, unlike indomethacin, Wy14,643 did not reduce ex vivo prostaglandin E₂ production. However, indomethacin did increase peroxisomal enzyme activity but to a lesser extent than Wy14,643. This study demonstrates that peroxisome proliferator-activated receptor α activation can inhibit arachidonic acid-induced inflammation in part by enhancing degradation of leukotriene B₄.     

Effect of Polypodium leucotomos on acute, chronic and reactivated trinitrobenzene sulphonic acid colitis in rats

The effects were examined of a Polypodium leucotomos extract on trinitrobenzene sulphonic acid (TNBS) induced rat colitis. Pretreatment with the extract had a dose-dependent acute anti-inflammatory effect which was maximal at 100 mg/kg/day. This was characterized by preservation of glutathione levels at low doses (25-50 mg/kg) and inhibition of leukotriene B₄ synthesis at high doses (50-100 mg/kg). Treatment was also active in chronic colitis, induced by TNBS, as was evident by enhanced colonic fluid absorption and reducing myeloperoxidase levels, while glutathione levels and leukotriene B₄ synthesis were unaffected by treatment. Finally, treated animals were partially protected against colitis reactivation, showing lower myeloperoxidase and leukotriene B₄ synthesis than controls and normal fluid absorption, but no change in glutathione. In conclusion, Polypodium leucotomos is useful to control experimental colitis (acute, chronic and reactivated) but no common mechanism of action could be delineated, since neither an antioxidative mechanism nor inhibition of leukotriene B₄ synthesis can account for the overall effect.     

Synthesis and biological activity of potent,low molecular weight renin inhibitors*

A series of renin inhibitors containing the dipeptide transition state mimics (2R, 4S, 5S)-5-amino-4-hydroxy-2-methyl-6-cyclohexyl hexanoic acid (Cha-Ψ[CH(OH)CH₂]Ala) and (2R, 45, 5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexyl hexanoic acid (Cha-Ψ[CH(OH)CH₂]Val) were prepared. A structure-activity study, using pseudopeptide (Boc-Phe-His-Leu-Ψ[CH(OH)CH₂]Val-Ile-His-OH) as our lead structure, led to a new series of inhibitors, which correspond to tripeptides and contain no natural amino acids. For example, R, S-Bpma-Ape-Cha-Ψ[CH(OH)CH₂]Ala-NH₂ (IC₅₀= 1.26 nM against human plasma renin at pH 6.0; molecular weight = 564) has only two thirds of the molecular weight but twice the potency of our original lead. This new class of low molecular weight renin inhibitor displays excellent specificity toward human renin versus the related aspartic proteinase pepsin and angiotensin-1-converting enzyme. Examples are given of selected inhibitors showing encouraging evidence for intestinal absorption after intracolonic and oral administration in male Sprague-Dawley rats.     

Simultaneous blockade of 5-HT<Subscript>1A/B</Subscript> receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT<Subscript>1A/B</Subscript> receptor antagonist/5-HT transport inhibitor SB-649915-B

Rationale The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy. Objectives We report the in vivo characterization of the novel 5-HT_1A/1B autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B. Materials and methods Ex vivo binding was used to ascertain 5-HT_1A receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT_1A and 5-HT_1B receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B. Results SB-649915-B (1–10 mg/kg p.o.) produced a dose-related inhibition of 5-HT_1A receptor radioligand binding and inhibited ex vivo [³H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1–10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT_1A and 5-HT_1B receptors, respectively. SB-649915-B (0.1–3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs. Conclusions Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.     

Opposite Effects of Nicotinic Acid and Pyridoxine on Systemic Prostacyclin,Thromboxane and Leukotriene Production in Man

Abstract: The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300 mg orally twice daily for seven days) on the excretion of urinary 2,3‐dinor‐6‐ketoprostaglandin F_1α, 11‐dehydrothromboxane B₂ and leukotriene E₄, the markers of systemic prostacyclin, thromboxane A₂ and cysteinyl leukotriene production, respectively, were investigated in healthy male volunteers (n=6–8). Nicotinic acid increased 11‐dehydrothromboxane B₂ and leukotriene E₄ excretions to 2.6‐ and 2.0 times the initial values (P<0.05), respectively. In the volunteers treated with pyridoxine, 11‐dehydrothromboxane B₂ and leukotriene E₄ excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values, respectively, but the excretion of 2,3‐dinor‐6‐ketoprostaglandin F_1α was increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyridoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.     

The significance of the relative effects of loop diuretics and anti-brain edema agents on the Na+, K+, Cl− cotransport system and the Cl−/NaCO 3 − anion exchanger

Summary 3-Amino-5-sulfamoylbenzoic acids and several series of (aryloxy)alkanoic acids were evaluated for their inhibitory effects on two human erythrocyte ion transport systems — the Na⁺, K⁺ cotransport system and the DIDS-sensitive anion carrier.Several classic loop diuretics, including the (aryloxy)alkanoic acid-ethacrynic acid and several 3-amino-5-sulfamoylbenzoic acids, like bumetanide and furosemide, displayed relatively strong inhibitory activity versus the cotransport system with relatively weaker action versus the anion carrier. Furthermore, diuretic potency correlated with cotransport inhibitory potency.Another class of (aryloxy)alkanoic acids, namely the [(2,3-dihydro-1 H-inden-5-yl)oxy]acetic acids, such as indacrinone and MK-473, which exhibit less potent loop dacrinone and MK-473, which exhibit less potent loop diuretic activity, were less potent cotransport inhibitors and more effective inhibitors of the anion carrier.Still other (aryloxy)alkanoic acids, with little saliuretic activity, namely a sub-class of [(2,3-dihydro-1 H-inden-5-yl)oxy]alkanoic acids and a series of [(2,3,9,9a-tetrahydro-1 H-fluoren-7-yl)oxy]acetic acids displayed little or no inhibitory action on the cotransport system but enhanced inhibitory action on the anion carrier. Most interestingly, the relative anion carrier inhibitory potency correlated well with the relative inhibitory activity of each compound on bicarbonate-stimulated cell swelling in cat cerebrocortical slices.Abbreviations DIDS 4,4-diisothiocyanostilbene-2,2-disulfonate - SITS 4-acetamido-4-isothio-cyanostilbene-2,2-disulfonate - Tris tris(hydroxymethyl)aminomethane - MOPS 4-morpholinopropanesulphonic acid     

Patent Evaluation: Bicyclic Bisaryl Compounds as LTB4 Antagonists

Summary

Novelty: Novel LTB₄ antagonists are claimed; they are potentially useful for the treatment of inflammatory or hypersensitive conditions. The compounds described are (di)substituted aryl or heteroaryl substituted carboxylic acids.

Biology: IC₅₀ data for 150 compounds are tabulated for in vitro receptor binding studies and LTB₄-induced g.p. parenchyma contraction assays. Values given are in the range of 0.5–5000 nM. Details of other tests are provided but no data for the claimed compounds are reported.

Chemistry: There are twenty-one synthetic examples. The compound shown is 6[[4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridyl]oxy]hexanoic acid.

Structure:      

The effects of isoimperatorin isolated from <Emphasis Type="Italic">Agelicae dahuricae</Emphasis> on cyclooxygenase-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells

Isoimperatorin (4-[(3-Methyl-2-butenyl)oxy]-7H-furo[3,2-g][1]benzopyran-7-one) is a medicinal herbal product that is isolated from the dried roots of Angelicae dahuricae. Isoimperatorin inhibits the cyclooxygenase-2 (COX-2) and COX-1-dependent phases of prostaglandin D₂ (PGD₂) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner, with IC₅₀ values of 10.7 μM and 24 μM, respectively. However, this compound was not able to inhibit COX-1 and 2 protein expression in BMMC that were treated with concentrations of up to 50 μM, which indicates that isoimperatorin directly inhibits COX-2 activity. Furthermore, this compound consistently inhibited the production of leukotriene C₄ (LTC₄), as well as the degranulation reaction in BMMC, with an IC50 value of 5.7 μM and 9 μM, respectively, and these effects occurred in a dose dependent fashion. These results demonstrate that isoimperatorin has a dual cyclooxygenase-2 selective/5-lipoxygenase inhibitory activity, and therefore may provide the basis for novel anti-inflammatory drugs. Tae Chul Moon and Meihua Jin contributed equally to this work.     

Current status of leukotriene A4 hydrolase inhibitors

Background: Leukotriene A₄ hydrolase (LTA₄H) is a ubiquitously distributed 69-kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA₄H stereospecifically catalyzes the transformation of the unstable epoxide LTA₄ to the diol leukotriene B₄ (LTB₄), a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, T cells, dendritic cells, smooth muscle cells and keratinocytes. Inhibiting the formation of LTB₄ is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease, asthma and atherosclerosis. Objective: The focus of this review will be on patent applications/patents containing LTA₄H inhibitors that were published between 1996 and March 2008 from four different companies. The documents reviewed are presented in a tabular manner. Method: The first part of this review focuses on the primary literature supporting LTA₄H as a potential target. The second part covers the patent literature organized by applicant identified during the prescribed period. Conclusion: Activity towards identifying small molecule inhibitors of LTA4H has escalated in the last few years in line with important scientific and clinical developments involving the leukotriene pathway. One inhibitor from deCODE, DG-051, is reported to be in clinical trials for myocardial infarction and future reports of clinical efficacy will undoubtedly stimulate further work in the field by others.     

4-Sulfobenzyl ester – an anionic protecting group for peptide synthesis

The preparation of the 4-sulfobenzyl esters of 18 amino acid derivatives is described. This carboxyl protecting group was introduced according to Hubbuch et al. (1980). The caesium or dicyclohexylammonium salts of N-terminal protected amino acids were reacted with 4-(bromomethyl)benzenesulfonate (1). After N-terminal deblocking, the amino acid-4-sulfobenzyl esters were isolated as zwitterions. The protecting group was removable by catalytic hydrogenation and by saponification. The 4-sulfobenzyl esters could be easily converted to amides and hydrazides. They were stable to 2 M hydrogen bromide in acetic acid as well as to a 10-fold excess of trifluoromethane sulfonic acid in trifluoro-acetic acid. The behaviours of ⁺H₂-Gly-Phe-Leu-OBzl-SO^-₃ and the corresponding methyl, benzyl and 4-nitrobenzyl esters were compared under various conditions.     

Nicotinic Acid and Pyridoxine Modulate Arachidonic Acid Metabolism in vitro and ex vivo in Man

Abstract: The in vitro effects of nicotinic acid (10–1000 μM), pyridoxine (0.1–500 μM) and pyridoxal-5′-phosphate (0.1–500 μM) and the ex vivo effects of nicotinic acid (2500 mg orally during 12 h) and pyridoxine (600 mg orally daily for seven days) on arachidonic acid metabolism were investigated in calcium ionophore A23187 (calcimycin)-stimulated human whole blood. In vitro nicotinic acid stimulated prostaglandin E₂, thromboxane B₂ and leukotriene E₄ synthesis. Pyridoxine at all concentrations and pyridoxal-5′-phosphate at the highest concentration stimulated prostaglandin E₂ and thromboxane B₂ production, but had no effect on leukotriene E₄ synthesis. Nicotinic acid treatment increased ex vivo prostaglandin E₂, thromboxane B₂ and leukotriene E₄ synthesis to 185%, 165% and 175% of the initial values, respectively. In the pyridoxine-treated subjects, ex vivo prostaglandin E₂, thromboxane B₂ and leukotriene E₄ synthesis was decreased after seven days to 75%, 65% and 45% of the initial values, respectively. In the present study the effects of nicotinic acid on the 5-lipoxygenase pathway in arachidonic acid metabolism were studied for the first time and the drug was found to stimulate this pathway in vitro and ex vivo. In vitro pyridoxine and pyridoxal-5′-phosphate had no effect on the 5-lipoxygenase pathway. The inhibition of leukotriene synthesis by pyridoxine ex vivo might be of therapeutic importance.     

Synthesis of the lipid peroxidation product 4‐hydroxy‐2(E)‐nonenal with 13C stable isotope incorporation

The aim of this work was to synthesize ¹³C internal standards for the quantification of 4‐hydroxy‐2(E)‐nonenal (HNE), a lipid peroxidation product, and of the etheno‐adducts possibly formed by HNE damage to DNA nucleobases. We designed an eight‐step synthesis starting from ethyl 2‐bromoacetate and giving access to 4‐[(tetrahydro‐2H‐pyran‐2‐yl)oxy]‐2(E)‐nonenal. This compound is a precursor of HNE. The scheme was then used to produce the ¹³C precursor [1,2‐¹³C₂]‐4‐[(tetrahydro‐2H‐pyran‐2‐yl)oxy]‐2(E)‐nonenal. [1,2‐¹³C₂]‐HNE was obtained by acid deprotection. All the intermediary and final compounds were fully characterized by IR, HRMS, ¹H and ¹³C NMR. It is the first synthesis of HNE which enables the incorporation of two ¹³C labels at determined positions. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis,characterization, and antimicrobial activity of some new coumarin derivatives

A number of new [(4-methyl-2-oxo-2H-chromen-7-yl)amino]methylcoumarins (5a–c), benzofuran (6), and benzoxazol (7) were synthesized through the reaction of 7-amino-4-methylcoumarin (1) with a number of organic halides. In addition, series of N-substituted 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a–h) and (12a–d) were prepared from the reaction of 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corresponding heteroaryl/alkyl halides (2–4, 9, and 10). The synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry and were tested for their in vitro antimicrobial activity. The newly synthesized compounds exerted significant inhibitory activity against the growth of tested bacterial strains and a few of them are found to be potent antimicrobial agents.     

Intestinal site-dependent susceptibility to chronic indomethacin in the rat: a morphological and biochemical study

Background: The cyclo-oxygenase inhibitor indomethacin induces a pattern of gastrointestinal injury in the rat that is site-dependent. This study compared the extent of injury to different regions of the rat intestine (small intestine, caecum and colon) with the corresponding changes in arachidonic acid metabolism in these areas, following long-term, low-dose indomethachin. Methods: Rats (eight per group) received either indomethacin (3 mg.kg/day) or control diet for either 6 or 12 weeks. At termination animals were bled, examined both macroscopically and microscopically for ulcers, and assayed for blood thromboxane B₂, intestinal tissue prostaglandin E₂ content and production of leukotriene B₄. In a further eight animals luminal indomethacin concentrations from the small intestine, caecum and colon were measured following 6 weeks of chronic drug ingestion. Results: At 6 weeks, macroscopic ulcers were observed in 2/8 (small intestine), 3/8 (caecum) and 1/8 (colon) animals. The corresponding ratios at 12 weeks were 5/8, 8/8 and 0/8. In control animals, a site-dependent gradient of the prostaglandin E₂ concentration was found. In indomethacin-dosed animals the intestinal prostaglandin E₂ content was reduced significantly in the caecum at 6 weeks, and in all tissues at 12 weeks. An increased leukotriene B₄ production was observed in the caecum only, at 12 weeks (P < 0.01), and the blood thromboxane B₂ was reduced at both time points (P < 0.05). Conclusion: There is a site-dependent gradient of the prostaglandin E₂ concentration in the rat intestine. The rat caecum is particularly sensitive to long-term low-dose indomethacin, both in terms of chronic intestinal inflammation and changes in prostanoid metabolism. This site-dependent degree of injury may be associated with a local cyclo-oxygenase inhibition.     

A new cytotoxic coumarin, 7-[(<Emphasis Type="Italic">E</Emphasis>)-3′,7′-dimethyl-6′-oxo-2′,7′-octadienyl] oxy Coumarin,from the leaves of <Emphasis Type="Italic">Zanthoxylum schinifolium</Emphasis>

A new coumarin, 7-[(E)-3′,7′-Dimethyl-6′-oxo-2′,7′-octadienyl]oxy coumarin (1), together with three known compounds, schinilenol (2), schinindiol (3) and 7-[(E)-7′-hydroxy-3′,7′-dimethylocta-2′,5′-dienyloxy]-coumarin (4) were isolated from the methylene chloride fraction of Z. schinifolium by normal and reverse phase column chromatographies. Their structures were determined on the basis of physical and spectroscopic evidences. Compound 1 (IC₅₀ 8.10 μM) showed potent cytotoxicity compared to auraptene (IC₅₀ 55.36 μM) against Jurkat T cells. The other isolated compounds 2 and 4 exhibited weak cytotoxicities.     

Inhibition of LTB4 biosynthesis in situ by CGS 23885, a potent 5-lipoxygenase inhibitor, correlates with its pleural fluid concentrations in an experimentally induced rat pleurisy model

An intrapleural injection of carrageenan in rats induced LTB₄ and LTC₄/D₄/E₄ biosynthesis, exudate formation, and cellular influx in the pleural cavity. An injection of calcium ionophore (A23187, 100nmol) 16–18h after carrageenan injection augmented leukotriene biosynthesis and exudate formation, but not cellular influx. The carrageenan-induced pleurisy model modifid by A23187 administration was used to study the oral effect of CGS 23885 (N-hydroxy-N-[(6-phenoxy-2H-1-benzopyran-3-yl)-methyl]urea), a potent 5-lipoxygenase (5-LO) inhibitor, on inflammatory parameters. CGS 23885 dose-dependently (1 to 30mg/kg) inhibited the enhanced LTB₄ and LTC₄/D₄/E₄ (1 to 10mg/kg) biosynthesis, but had no effect on enhanced exudate formation. An inhibitory effect of CGS 23885 of small magnitude on cellular influx due to carrageenan stimulation was seen at 30mg/kg. The concentrations of CGS 23885 in the pleural fluid were dose-related, and a positive correlation (r ²=0.989) between pleural fluid concentration of LTB₄ and CGS 23885 was observed. The results confirm that CGS 23885 is a specific, orally active 5-LO inhibitor which can achieve concentrations in the pleural cavity sufficient to inhibit production of LTB₄ and LTC₄/D₄/E₄ in an ongoing inflammatory response. Received: 9 February 1995 / Accepted: 20 December 1996     

Peptide formation in the presence of metal ion protecting groups

A quantitative study of the degree of racemization induced by the [(NH₃)₅Co-(III)-] protecting group when bound to the C-terminal of the amino acids Leu, Phe, and His, as has been carried out. Racemization was determined by forming the diastereomeric cobalt dipeptides [(Leu)(AA)Co(III)(NH3)₅] where AA = L-Leu, L-Phe, and L-His; after cobalt removal (using NaBH₄), the peptide diastereomers were analyzed quantitatively using an amino acid analyzer. No racemization was observed within experimental error (0.3%) as a result of the substitution of the [(NH3)₅Co(III)-] group on the amino acids and peptides studied.     

肿瘤的化学治疗 ⅩⅩⅢ.若干[双-(β-卤乙基)-氨基]-吲■-2-羧酸及其乙酯的合成

由5(及7)-[双-(β-羥乙基)-氨基]吲(口朶)-2-羧酸乙酯(Ⅶ_a,b)合成了5(及7)-[双-(β-氯乙基)-氨基]吲(口朶)-2-羧酸乙酯(Ⅱ_a和Ⅱ_b)、5(及7)-[双-(β-溴乙基)-氨基]-吲(口朶)-2-羧酸乙酯(Ⅱ_c和Ⅱ_d)以及5(及7)-[双-(β-碘乙基)-氨基]-吲(口朶)-2-羧酸乙酯(Ⅱ_e和Ⅱ_f)。再經水解制得其相应的羧酸(I_a-f)。此外又合成了5(及7)-乙氧羰氨基-吲(口朶)-2-羧酸乙酯(IX_a,b)和5-乙氧基-7-[双-(β-氯乙基)-氨基]-吲(口朶)-2-羧酸乙酯(Ⅶ)。化合物I_a,I_b,I_c,Ⅱ_a,Ⅱ_b,Ⅱ_c,Ⅱ_e和Ⅱ_f对組織培养Hela細胞有明显的抑制作用。化合物Ⅰ_a,Ⅰ_b,Ⅱ_a和Ⅱ_b口服时对小鼠肉瘤180有明显的抑制作用。化合物Ⅰ_e,Ⅰ_f和Ⅻ对肉瘤180具有中度的抑制作用。