Mosquito Repellent Activity of the Methanol Extracts of Some Ascidian Species

The methanol extracts of seven marine ascidian species (Clavelina picta, Eudistoma obscuratum, Atriolum robustum, Didemnum sp., D. molle, Phallusia sp. and Aplidium sp.) from Malaysia were investigated for their repellency effects against four vector mosquitoes (Anopheles maculatus, Aedes aegypti, Ae. albopictus and Culex quinquefasciatus). Mosquito repellent activity was assessed by using the test cage described in the American Society for Testing and Materials standard E951-83. The extracts showed a significant degree of repellency against the mosquitoes with ED 50 values ranging from 0.0008 to 0.0746mgcm -2. The repellency effects were dose-dependent and selective as the ED 50 values showed variation towards the various mosquitoes. Amongst these, the extract of Didemnum sp., with an ED 50 of 0.0008 mgcm -2 against An. maculatus, was the most effective, comparable to the value obtained with the standard repellent, deet.     

Conformation of Amiodarone · HC1: A Solution and Solid State 13C-NMR Study

The comparison of ¹³C-NMR spectra of Amiodarone · HC1 in different solvents with the CPMAS spectrum and the crystal structure shows that the molecule adopts a single twist conformation both in the solid-state and in solution in nonpolar solvents.     

NMR analysis of ion pair formation between timolol and sorbic acid in ophthalmic preparations

Ion pair formation between timolol and sorbic acid was investigated using NMR spectroscopy in order to clarify their interactions within ophthalmic preparation. (13)C and (1)H NMR spectra of timolol, sorbic acid, and a mixture of the two were obtained, and the signal changes induced by pairing were observed. The carbon signals of the butylaminopropanol moiety of timolol were markedly shifted in the mixture, as were the carboxyl and conjugated carbons assigned to sorbic acid. The localizations of the changes in each molecule revealed the binding sites. The profiles of butylaminopropanol carbon chemical shifts plotted against a molar ratio of sorbate were synchronized, which suggested a single type of interaction with sorbic acid. The Job plot showed a typical pattern with a single-maximum at a mole function of 0.5, indicating the presence of a 1:1 complex of timolol and sorbic acid. The stability constants (K) of the timolol-sorbate and timolol-maleate pairs were 1.9x10(1) and 2.2x10(2)M(-1), respectively. The higher K value of the timolol-maleate interaction suggested that it was dominant to the timolol-sorbate interaction when maleate and sorbate coexisted within a timolol solution. Here, we demonstrated evidence of an interaction between timolol and sorbic acid using simple NMR measurements, which suggested the existence of ion pair formation derived from charge neutralization. Our analysis using NMR spectroscopy should advance the understanding and optimization of formulations that are based on ion pair.     

Analysis of illegally manufactured formulations of tadalafil (Cialis) by 1H NMR, 2D DOSY 1H NMR and Raman spectroscopy

Counterfeit and/or imitation medicines are becoming a major health problem not only in developing countries but also in wealthier countries. The need of new and easy analytical methods for quality control of drugs is essential. We describe the use of Raman spectroscopy, 1H nuclear magnetic resonance (NMR) and 2D diffusion-ordered spectroscopy (DOSY) NMR to analyse genuine Cialis and seven illegally manufactured formulations of this drug purchased via the internet. Seven out of the eight commercial formulations of tadalafil contain the active ingredient, measured by high performance liquid chromatography (HPLC), within 100+/-5% of stated concentration. Vardenafil and homosildenafil instead of tadalafil were found in the Chinese imitation. 2D DOSY NMR spectra clearly showed similarities and differences in the composition of the pharmaceutical formulations of tadalafil, thus giving a precise and global "signature" of the manufacturer. Our data show that the quality of the Cialis imitations manufactured in India and Syria is correct, whereas the Chinese formulation is adulterated with active pharmaceutical ingredients.     

Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration

Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP were examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-(13)C]1-BrP and [1-(14)C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO(2), urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or (14)CO(2) (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ( approximately 50%) and high ( approximately 71%) dose groups; while the percentage of the dose exhaled as (14)CO(2) decreased (19 to 10%). The molar ratio of exhaled (14)CO(2) to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [(14)C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (<2%), or retained in the tissues and carcass (<6%) of rats and mice administered i.v. 5 to 100 mg/kg [(14)C]1-BrP. Metabolites characterized in urine of rats and mice include N-acetyl-S-propylcysteine, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-S-(2-hydroxypropyl)cysteine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl)cysteine, and N-acetyl-3-[(2-oxopropyl)sulfinyl]alanine. These metabolites may be formed following oxidation of 1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats pretreated with 1-aminobenzotriazole (ABT), a potent inhibitor of P450 excreted less in urine (down 30%), exhaled as (14)CO2 (down 80%), or retained in liver (down 90%), with a concomitant increase in radioactivity expired as VOC (up 52%). Following ABT pretreatment, rat urinary metabolites were reduced in number from 10 to 1, N-acetyl-S-propylcysteine, which accounted for >90% of the total urinary radioactivity in ABT pretreated rats. Together, these data demonstrate a role for cytochrome P450 and glutathione in the dose-dependent metabolism and disposition of 1-BrP in the rat.     

Strategy for Imidazotetrazine Prodrugs with Anticancer Activity Independent of MGMT and MMR

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Characterization of Three Crystalline Forms (VIII,XI, and XII) and the Amorphous Form (V) of Delavirdine Mesylate Using 13C CP/MAS NMR

Purpose. The application of solid-state nuclear magnetic resonance (NMR) characterization of three crystalline forms (VIII, XI, XII) and the amorphous form V of delavirdine mesylate (DLV-M) is presented. Methods. Conventional ¹³C CP (cross-polarization)/MAS (magic angle spinning) NMR and related spectral editing methods were employed. NMR relaxation times (T_1pH, T_1H, and T_1C) were also measured. Results. Distinctly different spectral features among the four solid forms were observed, indicating high sensitivity of ¹³C NMR to the variations in solid structure. Assessment based on NMR data suggests that both anhydrous forms VIII and XI may contain one molecule per asymmetric unit. DLV may adopt a similar molecular conformation in the two forms. In contrast, form XII is found to consist of two molecules per asymmetric unit. Molecule conformation of DLV in forms VIII, XI, and XII is altered from the dominant conformer in solution. The amorphous form V may contain DLV molecules of a variety of conformations. NMR relaxation times (T_lpH, T_1H, and T_1C) provide valuable information about the motional characteristics in these solids. Values and the rank order of T_lpH, T_1H, and T_1C also reveal significant differences in local environments and the short range order among the four forms. Conclusions. Four solid forms of DLV-M (V, VIII, XI. and XII) can be distinctly differentiated by ¹³C CP/MAS NMR spectroscopy and their structural difference can be partially revealed without obtaining single crystal data. NMR relaxation times reveal motion dynamics and aid structural elucidation for these forms.     

Anticomplementary activity of ergosterol peroxide fromNaematoloma fasciculare and reassignment of NMR data

A very high content (at least 0.23%) of ergosterol peroxide was isolated fromNaematoloma fasciculare Karst. Not only ergosterol peroxide but also ergosterol showed very strong anticomplementary activity on the classical pathway, the IC₅₀ values being 5.0 μM and 1.0 μM, respectively. The¹H and¹³C NMR data of ergosterol peroxide were revised and completely assigned by DEPT,¹H-¹H COSY, HMQC and HMBC correlations.     

地黄中环烯醚萜类成分及其氢谱碳谱规律

我们对现有的600多个环烯醚萜类化合物进行比较,认为依据母核的不同,将环烯醚萜类化合物分为5大类便 加合理,地黄中已分得的环烯醚萜类化合物共32个,均属母核为9个碳,且C－10接在C－8上的第Ⅲ类骨架的化合物,本文试图结合已从其它植物中分得的第Ⅲ类骨架的环烯醚萜类化合物的^1H-NMR和^13C-NMR数据,对地黄中所分得的环烯萜类化合物的^1H-NMR和^13C-NMR规律作一总结。     

Anticancer cisplatin interactions with bilayers of total lipid extract from pig brain: A C, P and N solid-state NMR study

Cisplatin (cis-diamminedichloroplatinum(II)) is used in chemotherapy and it is well established that cisplatin forms platinum-DNA adducts that initiate tumor cell death. Drawbacks are side effects such as neurotoxicity and cellular cisplatin resistance and it is possible that part of these effects are linked to cisplatin interaction with lipids and the phospholipid bilayer. 13C magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra of total lipid extract from pig brain with and without cisplatin show that the phosphatidylserine (PS) carboxyl resonance disappears in presence of cisplatin and that a new resonance of similar intensity appears at 185.5 ppm. Thus, indicating cisplatin interaction with the PS head-group. Static and MAS 31P NMR spectra of lipid extract with and without cisplatin show that the phospholipids to a large extent reside in a bilayer environment in pure lipid extract, and that the presence of cisplatin promotes isotropic and/or hexagonal lipid phases.     

Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61 y) who ingested a single dose (645 ± 20 μg/kg body weight) of ring-deuterated DEHP (DEHP-D₄). Concentrations of DEHP-D₄, of free ring-deuterated MEHP (MEHP-D₄), and the sum of free and glucuronidated MEHP-D₄ were measured in blood for up to 24 h; amounts of the monoesters MEHP-D₄, ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46 h after ingestion. The bioavailability of DEHP-D₄ was surprisingly high with an area under the concentration-time curve until 24 h (AUC) amounting to 50% of that of free MEHP-D₄. The AUC of free MEHP-D₄ normalized to DEHP-D₄ dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D₄ even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6 h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D₄ in blood, the parameter regarded as relevant for risk assessment.     

Quality assessment of fluoxetine and fluvoxamine pharmaceutical formulations purchased in different countries or via the Internet by 19F and 2D DOSY 1H NMR

A simple and selective (19)F NMR method has been validated for the quantitation of fluoxetine (FLX) and fluvoxamine (FLV) in methanol solutions and in human plasma and urine. The regression equations for FLX and FLV showed a good linearity in the range of 1.4-620 microg mL(-1) (3.3 x 10(-6)-1.8 x 10(-3) mol L(-1)) with a limit of detection of approximately 0.5 microg mL(-1) (1.3 x 10(-6) mol L(-1)) and a limit of quantification of approximately 2 microg mL(-1) (4.6 x 10(-6) mol L(-1)). The precision of the assay depends on the concentrations and is comprised between 1.5 and 9.5% for a range of concentrations between 1.2 x 10(-3) and 3.2 x 10(-6) mol L(-1). The accuracy evaluated through recovery studies ranged from approximately 96 to 103% in methanol solutions and in urine, and from approximately 93 to 104% in plasma, with standard deviations <7.5%. The low sensitivity of the method precludes its use for the assay of these antidepressants in biofluids at least at therapeutic doses as the ranges of FLX and FLV plasma levels are 0.15-0.5 microg mL(-1) and 0.15-0.25 microg mL(-1), respectively. The method was applied successfully to the determination of FLX and FLV contents in pharmaceutical samples (brand-named and generic) purchased in several countries or via the Internet. All the commercial formulations contain the active ingredient in the range 94-103% of stated concentration. A "signature" of the formulations (solid and liquid) was obtained with 2D Diffusion-Ordered SpectroscopY (DOSY) (1)H NMR which allowed the characterisation of the active ingredient and excipients present in the formulations studied. Finally, the DOSY separation of FLX and FLV whose molecular weights are very close was obtained by using beta-cyclodextrin as host-guest complexing agent.     

Quinoxaline chemistry. Part 15. 4-[2-Quinoxalylmethylenimino]-benzoylglutamates and -benzoates, 4-[2-quinoxalylmethyl-N-methylamino]-benzoylglutamates as analogues of classical antifolate agents. Synthesis,elucidation of structures and in vitro evaluation of antifolate and anticancer activities

We report on an extension of our previous discovery of in vitro anticancer activity of trifluoromethylquinoxalines as analogues of classical and non-classical antifolic methotrexate and trimetrexate. In this case a small number of Schiff bases were obtained from the reaction of 2-bromethyl-3-R-6(7)trifluoromethylquinoxaline and ethyl p-aminobenzoylglutamate, ethyl p-aminobenzoate, p-toluidine instead of the expected 4-[2-quinoxalyl]methyl-N-methylanilino derivatives, which in turn formed with N-methylanilino derivatives. The reaction mechanism has been put forward. Structure elucidation of both Schiff bases and N-methylanilino analogues was achieved by a combination of 1H and 13C NMR spectra and hetcor experiments. Compounds 3a, 3b, 3c, 8, 11, 12, 13, Ie were tested in antifolic enzyme assay [Lactobacillus casei (LcTS), Leishmania major (LmTs), human Thymidylate synthase (hTs), human TS, human dihydrofolate reductase (hDHFR)] while compounds 3a, 3b, 3c were tested for anticancer activity. These results seem to indicate that the Schiff bases are somewhat active either as anticancer or as folate inhibitors, while compound Ie was selectively active against hDHFR with an inhibition constant (Ki) of 200 nM with a specificity of about 1000-folds with respect to hTS.     

Nuclear Magnetic Resonance (NMR) Spectroscopic Investigation of Interaction Energies of Ephedrine Stereoisomers in Noncrystalline Solids and Its Correlation with Thermodynamic Data

Equations relating the interaction energies of each of the binary mixtures of ephedrine from linear combinations of the energies of the individual isomers are presented. The interaction energies in the noncrystalline solid mixtures measured from NMR chemical shift data using cross-polarization magic angle spinning nuclear magnetic resonance ¹³C cross-polarization magic angle spinning nuclear magnetic resonance (¹³CP/MAS NMR) spectroscopy correlate strongly with interaction energy from thermodynamic data. The summation of changes in relative frequencies for structurally equivalent carbons is used as a measure of differences in electron shielding on mixing. The relative direction of polarization of individual stereoisomers is found to affect association in noncrystalline binary mixtures of solids. NMR chemical shift data of solids may be useful in confirming spectroscopically the interactions of stereoisomers observed thermodynamically.     

1H NMR Quantification of poly(Ethylene Glycol)-Phosphatidylethanolamine in Phospholipid Mixtures

Pharmaceutical Research -     

Synthesis and biological evaluation of N-substituted indole esters as inhibitors of cyclo-oxygenase-2 (COX-2)

A series of novel N-substituted indole carboxylic, acetic and propionic acid esters have been prepared as possible cyclo-oxygenase-2 (COX-2) enzyme inhibitors. Compounds 20, 23 were found slightly active against COX-2. The synthesis of indole carboxylic, acetic and propionic acid esters were furnished by using dicyclohexyl carbodiimide (DCC), dimethylamino pyridine (DMAP) as carboxylate activators. N-substitution of indole esters was verified with several benzyl and benzoyl group in presence of NaH in DMF, respectively.     

Search for Compounds with Hypoglycemic Activity in the Series of 1-[2-(1H-Tetrazol-5-yl)-R1-phenyl]-3-R2-phenyl(ethyl)ureas and R1-Tetrazolo[1,5-c]quinazolin-5(6H)-ones

Methods of 1-[2-(1H-tetrazol-5-yl)-R¹-phenyl]-3-R²-phenyl(ethyl)ureas and R¹-tetrazolo[1,5-c]quinazolin-5(6H)-ones synthesis were designed. IR, LC-MS, ¹H NMR, and elemental analysis data evaluated the structure and purity of the obtained compounds. Different products, depending on the reaction conditions, were distinguished and discussed. The preliminary hypoglycemic activity of 36 synthesized compounds was revealed. Docking studies to 11β-hydroxysteroid dehydrogenase 1, γ-peroxisome proliferator-activated receptor, and dipeptidyl peptidase-4 were conducted. Eight of these substances were further tested on glucocorticoid-induced insulin resistance models, namely glucose tolerance, oral rapid insulin, and adrenalin tests. One of the most active compounds turned out to be tetrazolo[1,5-c]quinazolin-5(6H)-one 3.1, exceeding the reference drugs Metformin (50 and 200 mg/kg) and Gliclazide (50 mg/kg).     

A Search for New 5-HT1A/5-HT2A Receptor Ligands. In Vitro and in vivo Studies of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones

A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT_1A/5-HT_2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT_1A (K_i = 2 – 44 nM) and/or 5-HT_2A affinity (K_i = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT_1A receptors. The 5-HT_2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT_1A/5-HT_2A affinity and an in vivo antagonistic activity towards both receptor subtypes.     

Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors

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