Manganese complexes of curcumin analogues: evaluation of hydroxyl radical scavenging ability, superoxide dismutase activity and stability towards hydrolysis

In order to improve the antioxidant property of curcumin and its analogue, diacetylcurcumin, manganese was incorporated into the structures in order to enhance superoxide dismutase (SOD) activity. Manganese (Mn) complexes of curcumin (CpCpx) and diacetylcurcumin (AcylCpCpx) were synthesized and firstly investigated for SOD activity and hydroxyl radical (HO*) scavenging ability. SOD activity was evaluated by both the nitroblue tetrazolium (NBT) reduction assay and electron paramagnetic resonance (EPR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trapping agent. CpCpx and AcylCpCpx inhibited the NBT reduction and decreased the DMPO/OOH adduct much greater than corresponding antioxidants or ligands, with IC50 values of 29.9 and 24.7 microM (NBT), and 1.09 and 2.40 mM (EPR), respectively. For EPR, potassium superoxide (KO2) was used as a source of O2- where qualitative results suggested that CpCpx and AcylCpCpx were SOD mimics, which catalyze the conversion of O2- to dioxygen and hydrogen peroxide (H2O2). Additionally, CpCpx and AcylCpCpx exhibited the great inhibition of DMPO/OH adduct formation with an IC50 of 0.57 and 0.37mM, respectively, which were comparable to that of curcumin (IC50 of 0.64 mM), indicating that both Mn complexes are also an effective HO* scavenger. The stability against hydrolysis in water, various buffers and human blood/serum was carried out in vitro. It was found that both Mn complexes were pH and salt concentration dependent, being more stable in basic pH. In the human blood/serum test, CpCpx was more stable against hydrolysis than AcylCpCpx with about 10 and 20% of free Mn2+ releasing, respectively.     

Manganese complexes of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity

In this study, three manganese complexes of curcumin (Cp) and related compounds, diacetylcurcumin (AcylCp) and ethylenediamine derivative (CpED), were synthesized and evaluated in vitro for antilipid peroxidation and superoxide dismutase activity. The manganese complexes exhibited a great capacity to protect brain lipids against peroxidation with IC₅₀ of 6.3–26.3 μM. All manganese complexes showed much greater SOD activity than their corresponding antioxidant ligands as well as trolox with IC₅₀ values of 8.9–29.9 μM. AcylCp and curcumin manganese complexes (AcylCpCpx and CpCpx) also gave the highest inhibitory activity to H₂O₂-induced cell damage (oxidative stress) at 0.1 μg/ml (< 0.2 μM) in NG108-15 cells, which were more potent than curcumin and related compounds. The neuropharmacological tests in mice supported the idea that the SOD mimicking complexes were able to penetrate to the brain as well as their role in the modulation of brain neurotransmitters under the aberrant conditions. The complexes significantly improved the learning and memory impairment induced by transient ischemic/reperfusion. AcylCpCpx, CpCpx, and CpEDCpx showed significant protection at 6.25, 25, and 50 mg/kg (i.p.), respectively, whereas manganese acetate and curcumin had no effect at doses of 50 mg/kg. In addition, treatment of AcylCpCpx and curcumin significantly attenuated MPTP-induced striatal dopamine depletion in mice, which was in accordance with the increase in the density of dopaminergic neurons when compared with MPTP-treated mice. These results support the important role of manganese in importing SOD activity and consequently, the enhancement of radical scavenging activity. AcylCpCpx and CpCpx seem to be the most promising neuroprotective agents for vascular dementia.     

Reduction of paraquat-induced renal cytotoxicity by manganese and copper complexes of EGTA and EHPG

Superoxide anion generation plays an important role in the development of paraquat toxicity. Although superoxide dismutase mimetics (SODm) have provided protection against organ injury involving generation of superoxide anions, they often suffer problems, e.g., regarding their bioavailability or potential pro-oxidant activity. The aim here was to investigate and compare the therapeutic potential of two novel SODm, manganese(II) and copper(II) complexes of the calcium chelator ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) and of the contrast agent ethylenebis(hydroxyphenylglycine) (EHPG), against paraquat-induced renal toxicity in vitro. Incubation of renal NRK-52E cells with paraquat (1 mM) for 24 h produced submaximal, yet significant, reduction in cellular viability and cell death and produced significant increases in superoxide anion and hydroxyl radical generation. Manganese and copper complexes of EGTA (10-100 microM) and EHPG (30-100 microM) reduced paraquat-induced renal cell toxicity and reduced superoxide anion and hydroxyl radical generation significantly. Manganese complexes displayed greater efficacy than copper complexes and, at equivalent concentrations, manganese complexed with EHPG provided the greatest protection. Furthermore, these metal complexes did not interfere with the uptake of [methyl-(14)C]paraquat into NRK-52E cells, suggesting that they provided protection against paraquat cytotoxicity via intracellular mechanisms. These complexes did not display cytotoxicity at the concentrations examined. Together, these results suggest that manganese and copper complexes of EGTA and EHPG, and especially the manganese-EHPG complex, could provide benefit against paraquat nephrotoxicity.     

Protective effect of unsymmetrical dichalcogenide, a novel antioxidant agent, in vitro and an in vivo model of brain oxidative damage

Unsymmetrical dichalcogenides, a class of organoselenium compounds, were screened for antioxidant activity in rat brain homogenates in vitro. Unsymmetrical dichalcogenides (1-3) were tested against lipid peroxidation induced by sodium nitroprusside (SNP) or malonate, and reactive species (RS) production induced by sodium azide in rat brain homogenates. Compounds 1 (without a substituent at the phenyl group), 2 (chloro substituent at the phenyl group bounded to the sulfur atom) and 3 (chloro substituent at the phenyl group bounded to the selenium atom) protected against lipid peroxidation induced by SNP. The IC50 values followed the order 3<2<1. Lipid peroxidation induced by malonate was also reduced by dichalcogenides 1, 2 and 3. The IC50 values were 3相似文献   

Antioxidant properties of natural p-terphenyl derivatives from the mushroom Thelephora ganbajun

The antioxidant activity in vitro of three poly(phenylacetyloxy)-substituted 1,1':4',1"-terphenyl compounds from the edible mushroom Thelephora ganbajun were investigated. The IC50 values of compounds 1-3 for lipid peroxidation in rat liver homogenate were 400, 48, 54 microM, respectively. Compounds 1-3 increased superoxide dismutase (SOD) activity with EC50 values of 182, 74, 204 microM. They were also assessed on the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity with EC50 values of 49, 1233, 55 microM.     

Metalloporphyrins are potent inhibitors of lipid peroxidation

The objectives of these studies were to determine whether metalloporphyrins could inhibit lipid peroxidation, characterize factors that influence their potency and compare their potency to prototypical antioxidants. Lipid peroxidation was initiated with iron and ascorbate in rat brain homogenates and the formation of thiobarbituric acid reactive species was used as an index of lipid peroxidation. Metalloporphyrins were found to be a novel and potent class of lipid peroxidation inhibitors. Inhibition of lipid peroxidation by metalloporphyrins was dependent on the transition metal ligated to the porphyrin, indicating that metal centered redox chemistry was important to the mechanism of their antioxidant activities. Manganese porphyrins with the highest superoxide dismutase (SOD) activities, MnOBTM-4-PyP and MnTM-2-PyP (charges are omitted throughout text for clarity), were the most potent inhibitors of lipid peroxidation with calculated IC50s of 1.3 and 1.0 microM, respectively. These manganese porphyrins were 2 orders of magnitude more potent than either trolox (IC50 = 204 microM) or rutin (IC50 = 112 microM). The potencies of the manganese porphyrins were related not only to their redox potentials and SOD activities, but also to other factors that may contribute to their ability to act as electron acceptors. The broad array of antioxidant activities possessed by metalloporphyrins make them attractive therapeutic agents in disease states that involve the overproduction of reactive oxygen species.     

Antioxidant activities of three dihydrochalcone glucosides from leaves of Lithocarpus pachyphyllus

In vitro antioxidant activities of three sweet dihydrochalcone glucosides from the leaves of Lithocarpus pachyphyllus (Kurz) Rehd. (Fagaceae), trilobatin 2"-acetate (1), phloridzin (2) and trilobatin (3), were investigated. The IC50 (50% inhibitory concentration) values for compounds 1-3 of lipid peroxidation in rat liver homogenate were 261, 28, 88 microM, respectively. Compounds 1-3 increased superoxide dismutase (SOD) activity with EC50 (50% effective concentration) values of 575, 167, 128 microM, and glutathione peroxidase (GSH-Px) activity with EC50 values of 717, 347, 129 microM, respectively, and showed only weak DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity.     

3Beta-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity

6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3beta-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50 = 1.8 microM), similar to that of the commercially available steroid analogue U73122 (IC50 = 1-2.1 microM). Compound 1 exhibited significant growth inhibition effects (IC50 = 1.3 microM in each case) against MCF-7 and HT-29 cancer cells in in vitro cell culture. Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 microM, respectively. In vivo, compound 1, at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3beta-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50 = 16.2 microM).     

Mn2+, Co2+, Cu2+ and Zn2+ complexes with two macrocyclic ligands bearing L-lactate-like functions: potentiometric studies and evaluation of superoxide-scavenging properties of the Mn2+ complex

Some aerobic organisms devoid of SOD use Mn2+ chelates to scavenge the O2- radical. Since the Mn2+-bis(lactato)diaquo complex is known as having a high SOD-like activity, we prepared manganese(II) complexes with triazamacrocyclic ligands bearing L-lactate-like functions in order to obtain model compounds able to disproportionate the superoxide radical. Thus, two macrocyclic ligands, N,N',N"-tris[2(S)-hydroxybutyric acid]-1,4,7-triazacyclononane, L1, and N,N',N"-tris[2(S)-hydroxybutyric acid]-1,5,9-triazacyclododecane, L2, were prepared and their capacity to retain the Mn2+ ion in aqueous solution was determined from potentiometric experiments. The chelating properties in aqueous solution of each ligand towards Co2+, Cu2+ and Zn2+ ions were also determined. L1 forms complexes with Mn2+, Co2+, Cu2+ and Zn2+ ions with stability constants of 8.33(5), 15.78(5), 17.65(3) and 14.32(1), respectively. L2 forms complexes with Cu2+ and Zn2+ ions with stability constants of 10.67(1) and 6.98(3), respectively. But the constants related to the Mn2+ and Co2+ complexes were too low to be determined by the method used. The stability constants values calculated for L2 complexes are significantly lower than those for the corresponding complexes of L1. Additional spectroscopic measurements were carried out on the Mn2+-L1 system. The electronic spectrum of this system showed a pH-dependence that may be consistent with the formation of hydroxo-species as the ESR spectra recorded at 120 K did not show oxidation of the Mn2+ ion in the pH range studied. The superoxide-scavenging activity of the manganese(II)-L1 complex was investigated using the cytochrome c assay. The Mn2+-L1 system showed an IC50 value of 1.7 microM which indicates that it appears as a potent SOD mimic.     

Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class

Some novel 1-methyl-4-(2-(2-substitutedphenyl-1H-benzimidazol-1-yl)acetyl)thiosemicarbazides (16a-20a), 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl]-N-methyl-1,3,4-thiadiazol-2-amines (17b-20b), and 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (16c-20c) were synthesized and tested for antioxidant properties by using various in vitro systems. Compounds 16a-20a were found to be a good scavenger of DPPH radical (IC(50), 26 microM; IC(50), 30 microM; IC(50), 43 microM; IC(50), 55 microM; IC(50), 74 microM, respectively) when compared to BHT (IC(50), 54 microM). Noteworthy results could not be found on superoxide radical. Compound 19b, which is the most active derivative inhibited slightly lipid peroxidation (28%) at 10(-3)M concentration. Compound 17c inhibited the microsomal ethoxyresorufin O-deethylase (EROD) activity with an IC(50)=4.5 x 10(-4)M which is similarly better than the specific inhibitor caffeine IC(50)=5.2 x 10(-4)M.     

Trypanocidal activity of (-)-cubebin derivatives against free amastigote forms of Trypanosoma cruzi

Five (-)-cubebin derivative compounds, (-)-O-acetyl cubebin (3), (-)-O-benzyl cubebin (4), (-)-O-(N,N-dimethylaminoethyl)-cubebin (5), (-)-hinokinin (6) and (-)-6,6'-dinitrohinokinin (7), previously synthesised by our research group, were evaluated on in vitro assay against free amastigote forms of Trypanosoma cruzi, the asogic agent of Chagas' disease. It was observed that 6 was the most active compound (IC(50)=0.7 microM), and that 4 and 5 displayed moderate activity against the parasite, giving IC(50) values of 5.7 and 4.7 microM, respectively. In contrast, it was observed that compound 3 was inactive and that 7 displayed low activity with IC(50) values of congruent with 1.5 x 10(4) and 95.3 microM, respectively.     

Chroman amide 12P inhibition of lipid peroxidation and protection against learning and memory impairment

Structure modification of the cerebroprotective chroman amide 12 to improve the drug delivery to the target organ by protecting the active hydroxy functional group was carried out in this study. Chroman amide 12P, which the O-acetyl group was served to protect the active group to be delivered to the target organ, was synthesized. Ex vivo antilipid peroxidation activity of 12P was significantly greater than the activity of 12 while the in vitro inhibition of 12P was found to be lower. These indicated that 12P with protected active group effectively reached the brain, the target site, but in vitro, 12P was unable to release its parent or released slowly. Neuropharmacological effect of 12P was investigated in mice. 12 and 12P (50-100 mg/kg, i.p.) showed significant suppression on the hypermotility induced by methamphetamine. 12P (100 mg/kg, i.p.) was more potent than 12, 54.36% and 38.73% suppression, respectively. The result suggested the enhancement of brain delivery and the antagonism against aberrant dopamine release. In the water maze test, 12P (200 mg/kg) as well as tacrine (3 mg/kg) significantly reduced the learning and memory impairment induced by scopolamine (0.5 mg/kg). The results support the enhanced brain delivery and the additional role of radical scavengers in the modulation of brain neurotransmitters in the aberrant condition.     

Synthesis and in vitro antioxidant properties of manganese(III) beta-octabromo-meso-tetrakis(4-carboxyphenyl)porphyrin

Manganese(III) meso-tetrakis(4-carboxypheny)porphyrin (MnTBAP) is a readily available and widely used agent to scavenge reactive oxygen species. A major limitation of MnTBAP is its relatively weak potency due to its low metal centered redox potential. The goal of these studies was to prepare a more potent analog of MnTBAP by increasing its redox potential through beta-substitution on the porphyrin ring by bromination. Manganese(III) beta-octabromo-meso-tetrakis(4-carboxyphenyl)porphyrin (MnBr(8)TBAP) was prepared in three steps starting from the methyl ester of the free ligand meso-tetrakis(4-carboxyphenyl)porphyrin, with an overall yield of 50%. The superoxide dismutase (SOD)-like activity of MnBr(8)TBAP (IC(50)=0.7 microM) was the same as manganese(III) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (MnTM-4-PyP(5+)), while the metal-centered redox potential of the first was considerably higher than the second (E(1/2)=+128 and 0 mV vs. normal hydrogen electrode, respectively). However, a number of these cationic Mn-porphyrins (such as MnTM-4-PyP(5+)) redox-cycle with cytochrome P450 reductase in the presence of oxygen and NADPH whereas MnTBAP and its halogenated analog, MnBr(8)TBAP do not. The enhanced ability of MnBr(8)TBAP to inhibit paraquat- and hypoxia-induced injuries in vitro is also reported. In these in vitro models, in which cationic Mn-porphyrins exhibit very low activity, MnBr(8)TBAP appears to be at least eightfold more active than the non-brominated analog MnTBAP.     

Selective ABTS radical-scavenging activity of prenylated flavonoids from Cudrania tricuspidata

The antioxidative properties of five prenylated flavonoids, including new flavanone (2), from the root bark of Cudrania tricuspidata were examined against the ABTS, DPPH, and hydroxyl radicals. In most of the assays to determine their antioxidative properties, the ABTS activity was strongly correlated with DPPH because both methods are responsible for the same chemical property of hydrogen- or electron-donation to the antioxidant. On the other hand, the prenylated flavonoids (1-5) acted differently with both methods; namely, all the prenylated flavonoids strongly scavenged the ABTS radical (IC(50) < 10 microM), while they were inactive against the DPPH radical (IC(50) > 300 microM). Even though isolated 5,7,2',4',-tetrahydroxy-6,5'-diprenylflavanone (3) showed weak reducing power (746 mV) by cyclic voltammetry when compared to quercetin (394 mV), both had similar ABTS activity (IC(50) < 5 microM).     

Aminothiol multidentate chelators against Chagas disease

Three compounds of an aminothiol family of iron chelators were examined for activity against trypomastigote (human) and epimastigote (vector) forms of Trypanosoma cruzi: tetraethyl and tetramethyl derivatives of ethane-1,2-bis (N-1-amino-3-ethyl butyl-3-thiol) (BAT-TE and BAT-TM) and N',N',N'-tris-(2-methyl-2-mercaptopriopyl)- 1,4,7-triazacyclonane (TAT). BAT-TE at 270 microM completely arrested the growth of trypomastigote forms in mouse blood stored at 4 degrees C for 24 h (IC(50) 67.7+/-7 microM), while BAT-TM arrested growth at 630 microM (IC(50) 158+/-17 microM) and TAT at concentrations >800 microM (IC(50) 415+/-55 microM). In T. cruzi-infected mice, BAT-TE and BAT-TM had no anti-trypanosomal activity in doses up to 200 mg/kg, whether the route of administration was intraperitoneal or oral, and TAT was not tested due to insufficient quantity. TAT had an IC(50) of 52+/-7 microM against the epimastigote forms while BAT-TM and BAT-TE were inhibitory only at concentrations >250 microM. The trypanocidal activity of BAT derivatives in blood stored at 4 degrees C makes these compounds potential candidates for the purpose of clearing donated blood of trypomastigotes.     

Phytoestrogens as inhibitors of fungal 17beta-hydroxysteroid dehydrogenase

Different phytoestrogens were tested as inhibitors of 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl), a member of the short-chain dehydrogenase/reductase superfamily. Phytoestrogens inhibited the oxidation of 100 microM 17beta-hydroxyestra-4-en-3-one and the reduction of 100 microM estra-4-en-3,17-dione, the best substrate pair known. The best inhibitors of oxidation, with IC(50) below 1 microM, were flavones hydroxylated at positions 3, 5 and 7: 3-hydroxyflavone, 3,7-dihydroxyflavone, 5,7-dihydroxyflavone (chrysin) and 5-hydroxyflavone, together with 5-methoxyflavone. The best inhibitors of reduction were less potent; 3-hydroxyflavone, 5-methoxyflavone, coumestrol, 3,5,7,4'-tetrahydroxyflavone (kaempferol) and 5-hydroxyflavone all had IC(50) values between 1 and 5 microM. Docking the representative inhibitors chrysin and kaempferol into the active site of 17beta-HSDcl revealed the possible binding mode, in which they are sandwiched between the nicotinamide moiety and Tyr212. The structural features of phytoestrogens, inhibitors of both oxidation and reduction catalyzed by the fungal 17beta-HSD, are similar to the reported structural features of phytoestrogen inhibitors of human 17beta-HSD types 1 and 2.     

Phytoestrogens as inhibitors of fungal 17beta-hydroxysteroid dehydrogenase

Different phytoestrogens were tested as inhibitors of 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl), a member of the short-chain dehydrogenase/reductase superfamily. Phytoestrogens inhibited the oxidation of 100microM 17beta-hydroxyestra-4-en-3-one and the reduction of 100microM estra-4-en-3,17-dione, the best substrate pair known. The best inhibitors of oxidation, with IC(50) below 1microM, were flavones hydroxylated at positions 3, 5 and 7: 3-hydroxyflavone, 3,7-dihydroxyflavone, 5,7-dihydroxyflavone (chrysin) and 5-hydroxyflavone, together with 5-methoxyflavone. The best inhibitors of reduction were less potent; 3-hydroxyflavone, 5-methoxyflavone, coumestrol, 3,5,7,4'-tetrahydroxyflavone (kaempferol) and 5-hydroxyflavone, all had IC(50) values between 1 and 5microM. Docking the representative inhibitors chrysin and kaempferol into the active site of 17beta-HSDcl revealed the possible binding mode, in which they are sandwiched between the nicotinamide moiety and Tyr212. The structural features of phytoestrogens, inhibitors of both oxidation and reduction catalyzed by the fungal 17beta-HSD, are similar to the reported structural features of phytoestrogen inhibitors of human 17beta-HSD types 1 and 2.     

3,5-dibenzoyl-1,4-dihydropyridines: synthesis and MDR reversal in tumor cells

Fifteen 4-phenyl-3,5-dibenzoyl-1,4-dihydropyridines (BzDHPs) (1-15) substituted at the 4-phenyl ring were synthesized and compared to their cytotoxic activity and multidrug resistance (MDR)-reversing activity in in vitro assay systems. Among them, 2-CF3 (5) (IC50=8.7 microM), 2-Cl (11) (IC50=7.0 microM) and 3-Cl (12) (IC50=7.0 microM) derivatives showed the highest cytotoxic activity against human oral squamous carcinoma (HSC-2) cells. The activity of P-glycoprotein (Pgp) response for MDR in tumor cells was reduced by some of derivatives (3, 4, 8, 12), verapamil (VP) and nifedipine (NP). These data suggest that 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (12) can be recommended as a new drug candidate for MDR cancer treatment.     

Prostaglandin-H-synthase (PGHS)-1 and -2 microtiter assays for the testing of herbal drugs and in vitro inhibition of PGHS-isoenzyms by polyunsaturated fatty acids from Platycodi radix

In order to test inhibition of prostaglandin-H-synthase-1 and -2 (PGHS-1 and -2) by plant extracts, we have established two enzyme based in vitro assays with enzyme immunoassay (EIA) evaluation. The assays have been evaluated with known synthetic inhibitors and with plant extracts. In a screening of traditionally used Chinese herbs for anti-inflammatory activity, a series of n-hexane and dichloromethane extracts showed significant inhibitory effect in comparison with the known specific PGHS-2 inhibitors NS-398 (IC(50) = 2.6 microM) and nimesulide (IC(50) = 36 microM). The lipophilic extracts of the Chinese drug Jiengeng, the dried roots of Platycodon grandiflorum (Jacq.) A. DC. (Campanulaceae), showed good inhibitory activity against both PGHS isoenzymes. The directly prepared DCM-extract exhibited better activity against PGHS-2 (IC(50) = 4.0 microg/ml) than against PGHS-1 (IC(50) = 17.6 microg/ml). We identified fatty acids as main active constituents and quantified them. Linoleic acid showed the highest content (ca. 20% of the dried extract) and a high and preferential PGHS-2 inhibitory activity (IC(50) (PGHS-1) = 20 microM; IC(50) (PGHS-2) = 2 microM). The comparison of the concentration of linoleic acid and the inhibitory activity of the direct DCM-extract showed, that linoleic acid is mainly responsible for the in vitro activity of the extract on PGHS-2.     

In vitro antiplasmodial activities of semisynthetic N,N'-spacer-linked oligomeric ergolines

Starting from three monomeric ergolines (terguride 1, festuclavine 2, pergolide 3) N,N'-spacer-linked oligomeric derivatives were prepared using different aliphatic or arylalkyl spacers. The compounds have been evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive strain poW and the chloroquine-resistant clone Dd2 of Plasmodium falciparum. Additionally, the cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro, and human hepatocytes were evaluated. All monomers displayed only a weak antiplasmodial effect, but N-1,N-1'-spacer-linked dimerization substantially enhanced their antiplasmodial activity. The best activities were observed for compounds showing a distance of six carbon atoms between two monomers, which can be obtained by aliphatic or p-xylene linkers. The N-6,N-6'-spacer-linked depropylpergolide dimer 3i exhibited the highest antiplasmodial activity of all compounds tested (IC(50) values: 0.14 and 0.13 microM against poW and Dd2, respectively). Unfortunately, it displayed toxic effects against the mouse fibroblast cell line NIH 3T3 (IC(50): 0.1+/-0.09 microM) and also against human hepatocytes at 100 microM (LDH-leakage: 15.58+/-0.87 microkat/L; GSH-level: 8.15+/-0.78 nmol/10(6) cells). However, the N-1,N-1'-spacer-linked trimer of festuclavine (2f), and also the N-1,N-1'-spacer-linked tetramer of terguride (1g) possessed remarkable antiplasmodial activities (IC(50): 0.54 and 1.53 microM, respectively, against Dd2) lacking cytotoxicity.