Inhibitory effects of bis(2-aminohexyl)disulfide and its analogues on polymorphonuclear leukocyte functions in vitro.

Water soluble analogues of the anti-inflammatory compound, bis(2-aminopropyl)disulfide dihydrochloride (compd. I) with a butyl (II), phenyl (III), benzyl (IV) or pyrrolidinyl group (V) instead of the methyl group were synthesized, and their effects on the functions of cells related to inflammation were studied in vitro. Compounds II, III and IV showed much higher inhibitory activity than compd. I on formyl Met-Leu-Phe (FMLP)-induced O2(-)-generation of polymorphonuclear leukocytes (PMNs) and platelet aggregation. Compound II showed the strongest activity among the compounds (IC50 values: 2.6 microM). The inhibition of O2(-)-generation of PMNs by compd. II was the most effective when FMLP was used as a stimulant rather than when phorbol myristate acetate, A-23187 and opsonized zymosan were used. However, compd. II was not an O2(-)-scavenger. Compounds II, III and IV significantly inhibited a series of activation processes in PMNs, chemotaxis, phagocytosis and lysosomal enzyme release at doses ranging from 10 to 100 microM. Under these doses, compds II, III and IV did not affect the histamine release from mast cells or the hemolysis of erythrocytes. These results strongly suggest that the anti-inflammatory action caused by compd. II and its analogues was at least partly due to inhibition of several functions of PMNs and platelets.     

The effect of a cystamine derivative, bis[2-(E-2-hexenoylamino)ethyl] disulfide, on rat platelet aggregation

Bis[2-(E-2-alkenoylamino)ethyl] disulfides (compds. I), synthesized from cystamine and 2-trans fatty acids, inhibited collagen-induced rat and rabbit platelet aggregation. The most potent compound was bis[2-(E-2-hexenoylamino)ethyl] disulfide (compd. I-1), and this compound suppressed thromboxane B2 formation from arachidonic acid in rat platelets. The results suggested that compd. I-1 has an inhibitory effect on cyclooxygenase.     

Effects of 2-(E-2-decenoylamino)ethyl 2-(cyclohexylethyl) sulfide on various ulcer models in rats.

The effects of 2-(E-2-decenoylamino)ethyl 2-(cyclohexylethyl) sulfide (compd. III-1a) on various experimental ulcers were investigated. The oral administration of compd. III-1a at doses ranging from 30 to 300 mg/kg inhibited the acute gastric ulcerations induced by ethanol, HCl.aspirin and indomethacin in rats. Compound III-1a significantly inhibited the water immersion stress-induced gastric ulcer at doses of 3 mg/kg, p.o. The anti-ulcer activity of plaunotol as a reference drug was equivalent on an ethanol-induced ulcer to that of compd. III-1a, but weaker on HCl.aspirin, indomethacin and stress-induced ulcers than that of compd. III-1a. On indomethacin-produced gastric antral ulcer, compd. III-1a showed the same significant inhibitory activity as spizofurone did at a dose of 100 mg/kg, p.o. Compound III-1a also inhibited hemorrhagic shock-, diethyldithiocarbamic acid (DDC)-and platelet activating factor (PAF)-induced ulcers dose-dependently. Plaunotol only showed significant inhibitory activity on PAF-induced ulcer in these three ucler models. The consecutive administration of compd. III-1a (100 mg/kg, p.o.) twice a day significantly accelerated the healing of an acetic acid-induced ulcer and that of plaunotol (200 mg/kg, p.o.) showed the same activity. Moreover, orally administered compd. III-1a at a dose of 100 mg/kg decreased the gastric acid secretion in pylorus-ligated rats. The results in the present study suggest that compd. III-1a has the dual action on ulcer formation.     

Further studies on the pharmacological effect of the anti-inflammatory compound, bis[2-(E-2-octenoylamino)ethyl] disulfide

Further studies on the pharmacological effect of orally administered bis[2-(E-2-octenoyl-amino)ethyl] disulfide (compd. I-3) was examined by using several experimental models in vivo. Compound I-3 showed analgesic activity, inhibiting both acetic acid- and acetylcholine-induced writhings in mice. This compound also showed antipyretic activity against yeast-induced fever in rats, and significantly inhibited arachidonic acid-induced mortality in mice. However, it had no effect on serotonin-induced paw edema formation or platelet activating factor-acether-induced mortality in mice. The effects of compd. I-3 are suggested to be due to inhibition of prostaglandin biosynthesis.     

Antiedematogenic activity of two thiazolidine derivatives: N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28)

The search for new anti-inflammatory drugs has been constant in several research centers. The use of the Bioisostery concept allows the elaboration of new bioactive compounds with different properties through the introduction of substitute groups in one or more positions of a main molecule with known biological activity. Preliminary works accomplished at our laboratory with 2,4-thiazolidinedione isosters demonstrated inhibitory activity on edema formation for N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26). We verified the antiedematogenic and ulcerogenic activity of these two compounds in Wistar rats. The carrageenan induced paw edema suffered significant (p<0.05) inhibition (28.36% on average) for GS28 (100 mg/kg; v.o.) during the entire time of the experiment. GS26 (50 and 100 mg/kg; v.o.) significantly inhibited (p<0.05) the paw edema dextran induced (22.1 and 27.8%, for the respective doses) after 180 min. The compounds GS26 and GS28 did not show ulcerogenic activity on gastric mucous. The results suggest antiedematogenic action for both compounds without the appearance of gastric lesions.     

The inhibitory effect of bis[2-[(E)-2-octenoylamino]ethyl] disulfide on the cyclooxygenase pathway

Bis[2-[(E)-2-octenoylamino]ethyl] disulfide (compd. I-3) inhibited collagen- and arachidonic acid-induced rat platelet aggregation, although not adenosine 5'-diphosphate (ADP)-induced rat platelet aggregation. Based on these results, we then investigated the inhibitory effect of compd. I-3 on thromboxane B2 formation from arachidonic acid in rat platelets, and prostaglandin I2 formation in rat aortae. Compound I-3 inhibited both thromboxane B2 and prostaglandin I2 formation, suggesting that it has an inhibitory effect on cyclooxygenase. The inhibitory effect of compd. I-3 was confirmed in experiments using a crude preparation of sheep seminal vesicle microsomal prostaglandin synthetase. These findings suggested that compd. I-3 has an inhibitory effect on cyclooxygenase activity, like nonsteroidal anti-inflammatory drugs.     

Anti-inflammatory effects of low-level laser therapy (LLLT) with two different red wavelengths (660 nm and 684 nm) in carrageenan-induced rat paw edema

It has been suggested that low-level laser therapy (LLLT) can modulate inflammatory processes. The aim of this experiment was to investigate what effects red laser irradiation with two different wavelengths (660 nm and 684 nm) on carrageenan-induced rat paw edema and histology. Thirty two male Wistar rats were randomly divided into four groups. One group received a sterile saline injection, while inflammation was induced by a sub-plantar injection of carrageenan (1 mg/paw) in the three other groups. After 1 h, LLLT was administered to the paw in two of the carrageenan-injected groups. Continuous wave 660 nm and 684 nm red lasers respectively with mean optical outputs of 30 mW and doses of 7.5 J/cm(2) were used. The 660 nm and 684 nm laser groups developed significantly (p<0.01) less edema (0.58 ml [SE+/-0.17] ml and 0.76 ml [SE+/-0.10] respectively) than the control group (1.67 ml [SE+/-0.19]) at 4h after injections. Similarly, both laser groups showed a significantly lower number of inflammatory cells in the muscular and conjunctive sub-plantar tissues than the control group. We conclude that both 660 nm and 684 nm red wavelengths of LLLT are effective in reducing edema formation and inflammatory cell migration when a dose of 7.5 J/cm(2) is used.     

Synthesis and anti-inflammatory activity of 2,3-diaryl-4(3H)-quinazolinones

2,3-Diaryl-4(3H)-quinazolinones containing various substituents on diaryl rings have been synthesized and evaluated for their cyclooxygenase-2 inhibitory activity by the colorimetric COX (ovine) inhibitor screening assay and anti-inflammatory activity by the carrageenan-induced rat paw edema assay. 2-(4-Nitrophenyl)-3-(4-tolyl)-4(3H)-quinazolinone showed a maximum COX-2 inhibition of 27.72% at 22 μM concentration in the present series and exhibited a mild anti-inflammatory activity at a dose of 50 mg/kg in carrageenan-induced rat paw edema assay. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1198–1205, August, 2006.     

Polymorphic Characterization,Pharmacokinetics, and Anti-Inflammatory Activity of Ginsenoside Compound K Polymorphs

Polymorphism exhibits different physicochemical properties, which can impact the bioavailability and bioactivity of solid drugs. This study focused on identifying the polymorphs of ginsenoside compound K (CK) and studying their different behaviors in pharmacokinetics (PK) and pharmacodynamics (PD). Four CK polymorphs (form I, II, III, and IV) from organic solvents were characterized by scanning electron microscope (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD). A feasible LC-MS/MS method was exploited to determine the PK parameters. Form II displayed the most exposure, followed by form I, III, and IV. Notably, all forms showed sex dimorphism, and the bioavailability in the female group was about two-fold higher than in the male group. The PD properties were investigated in carrageenan-induced acute paw inflammation, and form II at 20 mg/kg showed significant inhibition of edema by 42.7%. This study clarified the polymorphic, PK, and PD characters of four crystal forms of CK, and the data suggested that form II had the best efficacy for drug development.     

Studies on medicinal resources from livestock. II. Anti-allergic effects of pig bile. (2)

Anti-allergic activities of lyophilized pig bile [( PB]) were examined in mice with picryl chloride-induced contact dermatitis (PC-CD), an experimental model of delayed-type hypersensitivity (DTH; type-IV allergy). PC-CD was markedly inhibited by an oral administration of [PB] within 4 h after but not during 8 to 16 h after challenge with picryl chloride. Anti-inflammatory activities of [PB] were also examined in acetic acid-induced mouse increased vascular permeability, hypotonic-hyperthermic lysis of rat erythrocytes and carrageenin-induced rat hind paw edema. [PB] had no effect on these models. The present study suggests that [PB] inhibits PC-CD through its immuno-modulation in the inductive phase of DTH rather than by an anti-inflammatory action.     

Kramecyne--a new anti-inflammatory compound isolated from Krameria cytisoides

In the present work we describe the structure and anti-inflammatory activity of a new compound, kramecyne, isolated from a methanol extract of Krameria cytisoides (Krameriaceae). The structure of kramecyne was determined by IR, NMR, MS, and elemental analysis, which indicated that the structure corresponded to a hexamer of cyclic peroxide monomers. This compound exhibited good anti-inflammatory activity in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema (51.8 ± 6.9% inhibition) and carrageenan-induced rat paw edema models at doses of 50 mg/kg. The compound significantly reduced edema to 63.1% after 1.0 h, and the effect was unchanged for 5 h. Kramecyne did not present acute toxicity, even at doses of 5,000 mg/kg.     

Design,synthesis and preclinical evaluations of (s)-2-((s)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-3-(4-isopropylphenyl)-2-methylpropanal (succ-5) as cardioprotective,hepatoprotective and lipid lowering molecule. in-vivo and in-silico approaches

In this study, the newly synthesized compound (Succ-5) was analyzed through spectral methods, seen for potential receptor targets via molecular docking, and pre-clinically evaluated for therapeutic effects and safety profile using biochemical and histopathological techniques. The biochemical analysis included assessment of cardiac biomarkers, hepatic enzymes, and lipid profiles, while histopathology included evaluation of cardiac and liver tissues. The toxic dose was determined pre-clinically, followed by dividing albino rats into five treatment groups (each having n = 6). The control group received oral saline for eight days. The 5-FU (5-Fluorouracil) group received oral saline for 8 days and 5-FU (150 mg/kg I.P.) on day 5. The atenolol group was administered with atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5. Two groups of rats were administered with the test compound (Succ-5) at doses of 5 mg/kg I.P and 10 mg/kg I.P (for 8-days), followed by 5-FU (150 mg/kg I.P.) on day 5. Elevated serum levels of CK-MB (creatinine kinase myocardial band), cTnI (troponin I), LDH (lactate dehydrogenase), lipid profile, and selected liver enzymes including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total) and BD (direct bilirubin) were associated with 5-FU toxicity. After administration of the test compound at the mentioned doses, these biomarkers significantly decreased. Likewise, histological examination revealed 5-FU damaged the heart and hepatic tissues, which were also considerably recovered following administration of the test compound. Immunohistochemistry of heart tissue also revealed the low expression of COX-2 and TNF-α in Succ-5 treated groups compared to toxic group. Dose-response evaluation showed that a dose of 10 mg/kg provided better results than 5 mg/kg. The analysis of binding energy values computed via docking simulations showed that Succ-5 interacts with the human beta2-adrenergic G protein-coupled receptor with a slightly stronger affinity than calcium channel T-type. In conclusion, the histological and biochemical findings revealed that the test compound had significant cardioprotective, hepatoprotective, and lipolytic effects in the 5-FU-induced toxicity.     

Effect of gambogenic acid in attenuating diethylnitrosamine (DEN)-induced hepatocellular carcinoma in rat model

Liver cancer, specifically hepatocellular carcinoma has been a widespread problem among general population. This study aims to investigate the modulating mechanism of gambogenic acid, a phenolic xanthonoid, in diethylnitrosamine (DEN)-induced liver cancer in rats. Male Wistar albino rats were clustered into four groups (n = 6). Group I served as control treated with normal saline. Hepatocellular carcinogenesis was induced in rats by single intraperitoneal (i.p.) administration of DEN in saline (200 mg/kg b.w.) for groups II and III. Group III received oral administration of gambogenic acid (20 mg/kg b.w.) one hour post DEN administration, whereas group IV received oral administration of gambogenic acid (20 mg/kg b.w.) alone. Rats were sacrificed after 16 weeks to determine the levels of hepatic biomarkers, oxidative stress markers, hematological profile and histopathological changes. Gambogenic acid significantly ameliorated the expressions of oxidative stress markers TBARS, GSH (P < 0.05), enzymatic antioxidants GPx, CAT, SOD, GST (P < 0.05), apoptosis mediators (P < 0.05), and serum biomarkers for liver damage and tumor formation (P < 0.05) compared with DEN-induced model group. Hepatocellular levels of 8-OHdG were significantly diminished (P < 0.05) by gambogenic acid against the damage incurred by DEN. Liver histopathological derangements caused by DEN were reversed by gambogenic acid. The results clearly impacted the effect of gambogenic acid in attenuating DEN-induced hepatocellular carcinoma in rats mediated through NF-kβ pathway and hepatocellular oxidative damage.     

Further studies on the anti-ulcerogenic effects of compound, 2-(E-2-decenoylamino)ethyl 2-(cyclohexylethyl) sulfide.

Tha anti-ulcerogenic mechanism of 2-(E-2-decenoylamino)ethyl 2-(cyclohexylethyl) sulfide (compd. III-1a) was investigated in various gastric defensive factors. Compound III-1a maintained the high molecular glycoprotein (relative content of Fr. I hexose) and accelerated hexosamine synthesis which were reduced by water immersion stress. But plaunotol did not have these actions. The lipid peroxide level in the gastric mucosa from water immersion stressed rat was lowered by the administration of compd. III-1a. Compound III-1a maintained prostaglandin E2 (PGE2) and PGI2 contents which were reduced in the early phase of the stress and accelerated PGs synthesis in the late phase of the stress. Furthermore, compd. III-1a maintained phospholipase A2 (PLA2) activity which was reduced by the stress. The plaunotol treated group showed the same tendency as the compd. III-1a treated group on the lipid peroxide level, PGE2 and PGI2 contents, and PLA2 activity, but the potency of plaunotol was less than that of compd. III-1a. Compound III-1a accelerated gastric cell proliferation in pyloric glands of hydrocortisone treated rats. Tetragastrin accelerated significantly the cell proliferation in fundic glands. The sucralfate treated group showed the same tendency as the compd. III-1a treated group but the potency of sucralfate was less than that of compd. III-1a. The results in the present study suggest that compd. III-1a has a protective action on gastric mucosa.     

1,1'-(四甲基二硅撑)双[环戊二烯基三羰基钼配合物]的合成及结构

1,2-二环戊二烯基四甲基二硅烷与正丁基锂作用生成(四甲基二硅撑)双[环戊二烯基负离子盐],后者随即与六羰基钼反应即形成1,1'-(四 甲基二硅撑)双[环戊二烯基三羰基钼负离子盐],分别与四种不同的卤化物反应,生成在钼原子上发生烃基化的产物与冰醋酸作用,随即分别与CCl~4及NBS反应,生成相应的钼氯化物和钼溴化物作用发生氧化偶联反应,生成Mo-Mo键断裂的钼碘化物,以元素分析、IR及^1HNMR表征了2-9的结构.并对5的单晶进行了X射线衍射分析.它的晶体属三斜晶系,PI空间群,晶体学数据:偏差因子R=0.043,R~W=0.055.     

Design, synthesis and preliminary pharmacological evaluation of new non-steroidal anti-inflammatory agents having a 4-(methylsulfonyl) aniline pharmacophore

A series of 4-(methylsulfonyl)aniline derivatives were synthesized in order to obtain new compounds as a potential anti-inflammatory agents with expected selectivity against COX-2 enzyme. In vivo acute anti-inflammatory activity of the final compounds 11-14 was evaluated in rat using an egg-white induced edema model of inflammation in a dose equivalent to 3 mg/Kg of diclofenac sodium. All tested compounds produced significant reduction of paw edema with respect to the effect of propylene glycol 50% v/v (control group). Moreover, the activity of compounds 11 and 14 was significantly higher than that of diclofenac sodium (at 3 mg/Kg) in the 120-300 minute time interval, while compound 12 expressed a comparable effect to that of diclofenac sodium in the 60-240 minute time interval time, and compound 13 showed a comparable effect to that of diclofenac sodium at all experimental times. The result of this study indicates that the incorporation of the 4-(methylsulfonyl)aniline pharamacophore into naproxen, indomethacine, diclofenac and mefanamic acid maintained their anti-inflammatory activity and may increase selectivity towards the COX-2 enzyme which will be confirmed in the future by assessing COX-2: COX-1 inhibitory ratios using a whole blood assay.     

Spectrophotometric determination of Fe(II) with 2,4,6-tri(2'-pyridyl)-1,3,5-triazine in the presence of large quantities of Fe(III) and complexing ions

A spectrophotometric method for the determination of Fe(II) in the presence of large amounts (up to 800 mg/l.) of Fe(III) is suggested. The Fe(III) is effectively masked by complexing with fluoride at pH 2.0-2.4 before development of the violet Fe(II) complex with 2,4,6-tri(2'-pyridyl)-1,3,5-triazine. The absorbance is measured at 595 nm. Various commonly occurring ions which complex with Fe(II) and/or Fe(III) do not interfere.     

Antinociceptive profile of 2,3,6-trisubstituted piperidine alkaloids: 3-O-acetyl-spectaline and semi-synthetic derivatives of (-)-spectaline

In early studies, we have reported the antinociceptive profile of (-)-spectaline, a piperidine alkaloid from Cassia spectabilis. The present study describes the synthesis, the antinociceptive and anti-inflammatory activities of a series of 2,3,6-trialkyl-piperidine alkaloids: the natural (-)-3-O-acetyl-spectaline (LASSBio-755) and ten semi-synthetic spectaline derivatives. Structure-activity relationship (SARs) studies were performed. The structures of all synthesized derivatives were confirmed by means of nuclear magnetic resonance. Compounds were evaluated for their analgesic (acetic acid-induced mouse abdominal constrictions, hot-plate test, formalin-induced pain test) and some of them for the anti-inflammatory activities (carrageenan-induced rat paw edema test). The pharmacological results showed that several of the new compounds given orally at a dose of 100 micromol/kg significantly inhibited the acetic acid-induced abdominal constrictions, but they were less active than (-)-spectaline. LASSBio-755 and LASSBio-776 were the most actives with 37% and 31.7% of inhibition. In the formalin-induced pain only LASSBio-776 was able to inhibit by 34.4% the paw licking response of the inflammatory phase, (-)-spectaline and LASSBio-755 did show any activity. In the carrageenan-induced rat paw edema, only (-)-spectaline exhibited an anti-inflammatory profile, showing an ED(50) value of 56.6 micromol/kg. Our results suggest different mechanisms of action for the analgesic activity observed for LASSBio-776 (3-O-Boc-spectaline), LASSBio-755 (3-O-acetyl-spectaline) and (-)-spectaline (LASSBio-754). The antinociceptive profile of some of the semi-synthetic spectaline derivatives extends our research concerning the chemical and pharmacological optimization of isolated natural products in the search of new drug candidates from Brazilian biodiversity.     

Anti-Inflammatory and Analgesic Activity of Total Flavone of <em>Cunninghamia lanceolata</em>

The present study was undertaken to investigate the anti-inflammatory and analgesic activity of total flavone of branches and leaves of Cunninghamia lanceolata (TFC) to provide a scientific basis for its clinical use and resource development. TFC was evaluated for anti-inflammatory and analgesic activity in mice or rats using chemical and thermal models of nociception, including acetic acid-induced writhing test, hot plate latency test, formalin test and carrageenan induced paw oedema test. Results showed that TFC given orally can significantly attenuate acetic acid-induced writhing in mice in a dose-dependent manner. In the hot plate latency test, TFC showed common activity in prolonging duration time only at the highest dose (400 mg/kg). Each dose of TFC could not significantly inhibit the first phase but was active in the later phase of formalin-induced pain, whereas morphine showed notable activity in the two phases. In the carrageenan-induced paw oedema model, TFC could significantly and dose-dependently reduce the carrageenan-induced paw edema at the third and fifth hour, and decrease the content of PEG₂ in paw edema tissue and that of COX-2 in blood serum. It may be concluded that TFC showed both anti-inflammatory and analgesic effects, showing that it can be of importance in drug development, especially in the field of pain and inflammation.     

Hypotensive effects on spontaneously hypertensive rats and antifungal activity on various species of Fusarium oxysporum of diethylstilbestrol-related compounds

The diethylstilbestrol-related compounds 3,3'-dihydroxy-alpha, beta-diethyldiphenylethane (I), diethylstilbestrol (II) and hexestrol (III) showed hypotensive effects on spontaneously hypertensive rats (SHR) and antifungal activities against all Fusarium oxysporum sp. tested. As previously reported, I had strong hypotensive action on normotensive rats at the dose of 10 mg/kg, while II and III showed weak hypotensive effects on these rats at the same dose. In this work, all three compounds also had hypotensive actions on SHR at the same dose. I showed the strongest hypotensive effect (-80.0 +/- 5.0 mmHg, 10 mg/kg, i.v.) on both SHR and normotensive rats. The three compounds also had antifungal activities against five kinds of Fusarium oxysporum sp. tested. Especially, II strongly inhibited the growth of Fusarium oxysporum f. sp. raphani IFO-9972 (minimum inhibitory concentration (MIC): 1.0 micrograms/ml).