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At least 775 records · Page 43Linked to original sources
PubMed2005

Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action.

A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC(50) values of several compounds (11a, 11k-m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 muM, 5-10-fold lower than that of 1 but their cytotoxicities were only 2-4 times greater than that of 1. Compounds with a halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced antiplasmodial activity. In mice infected with P. berghei, the 7-bromo-2-chloro (11k) and 2-bromo-7-nitro (13) derivatives of 1 suppressed parasitemia by >90% at doses of 25 mg kg(-1) day(-1) with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated at several dose levels, and a dose-dependent suppression of parasitemia was seen (ED(90) = 21.6 mg kg(-1) day(-1)). The antimalarial mode of action of 1 appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. A number of analogues were assessed for their effects on the inhibition of beta-hematin (hemozoin) formation, and the results were compared with their antiplasmodial activities having taken account of their predicted accumulation into the acidic parasite food vacuole. No correlation was seen (r(2) = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.

Algorithms↗
PubMed2006

Compound-specific stable carbon isotope ratios (delta13C values) of the halogenated natural product 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (Q1).

Compound-specific isotope analysis using gas chromatography interfaced to isotope ratio mass spectrometry (GC/IRMS) was applied for the determination of delta13C values of the marine halogenated natural product 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (Q1). The delta13C value of a lab-made Q1 standard (-34.20 +/- 0.27 per thousand) was depleted in 13C by more than 11 per thousand relative to the residues of Q1 in dolphin blubber from Australia and skua liver from Antarctica. This clarified that the synthesized Q1 was not the source for Q1 in the biota samples. However, two Australian marine mammals showed a large variation in the delta13C value, which, in our experience, was implausible. Since the GC/IRMS system was connected to a conventional ion trap mass spectrometer by a post-column splitter, we were able to closely inspect the peak purity of Q1 in the respective samples. While the mass spectra of Q1 did not indicate any impurity, a fronting peak of PCB 101 was identified in one sample. This interference falsified the delta13C value of the respective sample. Once this sample was excluded, we found that the delta13C values of the remaining samples, i.e. liver of Antarctic brown skua (-21.47 +/- 1.47 per thousand) and blubber of Australian melon-headed whale (-22.80 +/- 0.33 per thousand), were in the same order. The standard deviation for Q1 was larger in the skua samples than in the standard and the whale blubber sample. This was due to lower amounts of skua sample available. It remained unclear if the Q1 residues originate from the same producer and location.

Adipose Tissue↗
PubMed1998

2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling.

3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligand with high affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, Ki values range from 11 to 210 pM, as measured by competition with (+/-)-[3H]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations demonstrate that the bulky substituents at position 2 cause notable changes in the molecular geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for developing radiohalogenated tracers to study nAChRs.

Animals↗
PubMed2006

Toward a protecting-group-free halogen-metal exchange reaction: practical, chemoselective metalation of functionalized aromatic halides using dianion-type zincate, tBu4ZnLi2.

A versatile preparation method for aromatic zincate compounds through a halogen-zinc exchange reaction using dilithium tetra-tert-butylzincate (tBu4ZnLi2) has been developed. This reagent permits efficient preparation of highly functionalized aromatic zincates, particularly, those with electrophilic functional groups, such as ester, amide, alcohol, and phenol. Halogen-zinc exchange reactions followed by electrophilic trapping (with allyl bromide or benzaldehyde) proved to be a powerful tool for C-C bond formation on functionalized aromatic rings. The functionalized aromatic zincate intermediate was also found to undergo copper- and palladium-catalyzed C-C bond-forming reactions with good yields and high chemoselectivity.

Anions↗
PubMed1989

Measurement of unscheduled DNA synthesis and S-phase synthesis in rodent hepatocytes following in vivo treatment: testing of 24 compounds.

The in vivo-in vitro hepatocyte DNA repair assay has been shown to be useful for studying genotoxic hepatocarcinogens. In addition, measurement of S-phase synthesis (SPS) provides an indirect indicator of hepatocellular proliferation, which may be an important mechanism in rodent carcinogenesis. This assay was used to examine 24 chemicals for their ability to induce unscheduled DNA synthesis (UDS) or SPS in Fischer-344 rats or B6C3F1 mice following in vivo treatment. Hepatocytes were isolated by liver perfusion and incubated with 3H-thymidine following in vivo treatment by gavage. UDS was measured by quantitative autoradiography as net grains/nucleus (NG). Controls from both sexes of both species yielded less than 0.0 NG. Chemicals chosen for testing were from the National Toxicology Program (NTP) genetic toxicology testing program and most were also evaluated in long-term animal studies conducted by the NTP. 11-Aminoundecanoic acid, benzyl acetate, bis(2-chloro-1-methylethyl)ether (BCMEE), C.I. Solvent Yellow 14, cinnamaldehyde, cinnamyl anthranilate, dichloromethane, dichlorvos, glutaraldehyde, 4,4'-methylenedianiline (MDA), 4-nitrotoluene, 4,4'-oxydianiline, a polybrominated biphenyl mixture (PBB), reserpine, 1,1,2,2-tetrachloroethane, 1,1,2-trichloroethane, trichloroethylene, and 2,6-xylidine all failed to induce UDS in rats and/or mice. Dinitrotoluene and Michler's Ketone induced positive UDS response in rat, while N-nitrosodiethanolamine and selenium sulfide induced equivocal UDS results in mouse and rat, respectively. BCMEE, bromoform, chloroform, PBB, 1,1,2-trichloroethane, and trichloroethylene were all potent inducers of SPS in mouse liver, while C.I. Solvent Yellow 14, and 1,1,2,2-tetrachloroethane yielded equivocal SPS results in rat and mouse, respectively. These results indicate that most of the test compounds do not induce UDS in the liver; however, the significant S-phase responses induced by many of these compounds, especially the halogenated solvents, may be an important mechanism in their hepatocarcinogenicity.

Animals↗
PubMed1980

Metabolism and activation of chemical carcinogens.

A great deal of effort has gone into research on the mechanisms of action of chemical carcinogens. The action of the host on the carcinogen represents one approach--to determine what metabolic products may be involved. Study of the action of the carcinogen on the host requires a thorough comparison of changes wrought in cellular constituents by the carcinogen. Meshing of these two approaches increases the potential to discover the detailed mechanisms involved. Despite the increase in knowledge, many crucial molecular events and their consequences in the process of carcinogenesis still remain a mystery.

Aflatoxins↗
PubMed2001

Biodegradation and bioremediation of hydrocarbons in extreme environments.

Many hydrocarbon-contaminated environments are characterized by low or elevated temperatures, acidic or alkaline pH, high salt concentrations, or high pressure, Hydrocarbon-degrading microorganisms, adapted to grow and thrive in these environments, play an important role in the biological treatment of polluted extreme habitats. The biodegradation (transformation or mineralization) of a wide range of hydrocarbons, including aliphatic, aromatic, halogenated and nitrated compounds, has been shown to occur in various extreme habitats. The biodegradation of many components of petroleum hydrocarbons has been reported in a variety of terrestrial and marine cold ecosystems. Cold-adapted hydrocarbon degraders are also useful for wastewater treatment. The use of thermophiles for biodegradation of hydrocarbons with low water solubility is of interest, as solubility and thus bioavailability, are enhanced at elevated temperatures. Thermophiles, predominantly bacilli, possess a substantial potential for the degradation of environmental pollutants, including all major classes. Indigenous thermophilic hydrocarbon degraders are of special significance for the bioremediation of oil-polluted desert soil. Some studies have investigated composting as a bioremediation process. Hydrocarbon biodegradation in the presence of high salt concentrations is of interest for the bioremediation of oil-polluted salt marshes and industrial wastewaters, contaminated with aromatic hydrocarbons or with chlorinated hydrocarbons. Our knowledge of the biodegradation potential of acidophilic, alkaliphilic, or barophilic microorganisms is limited.

Bacteria↗
PubMed2000

Transformation of the sydnone ring into oxadiazolinones. A convenient one-pot synthesis of 3-aryl-5-methyl-1,3,4-oxadiazolin-2-ones from 3-arylsydnones and their antimicrobial activity.

3-Arylsydnones (Ia-u) have been converted into the corresponding 3-aryl-5-methyl-1,3,4-oxadiazolin-2-ones (IIIa-u) by a single-step reaction with bromine in acetic anhydride. In the preliminary screening of all these compounds, the halogen-substituted derivatives have shown antimicrobial activities equal to those of the standard drugs used.

Anti-Infective Agents↗
PubMed1999

[Adsorption of carbon dioxide gas].

OBJECTIVES: To analyse the various methods for carbon dioxide absorption in anaesthesia, the available absorbents and their modes of use. DATA SOURCES: We searched the Medline and Internet databases for papers using the key words: carbon dioxide absorption, soda-lime, zeolite. We also had correspondence and contacts with soda lime manufacturers. STUDY SELECTION: All types of articles containing data on CO2 absorption. DATA EXTRACTION: The articles were analysed for the benefits and adverse effects of the various absorbents. DATA SYNTHESIS: Carbon dioxide absorption enables the use of low flow anaesthesia, and a decreased consumption of medical gases and halogenated anaesthetics, as well as reduced pollution. Chemical absorbents (soda-lime and barium hydroxide lime (Baralyme) may produce toxic compounds: carbon monoxide with all halogenated anaesthetics and compound A with sevoflurane. Simple measures against desiccation of the lime prevent carbon monoxide production. The toxicity of compound A, shown in the rat, has not been proven in clinical anaesthesia. Recent improvements in manufacture processes have decreased the powdering of lime. Moreover, filters inserted between the anaesthesia circuit and the patient abolish the risk for powder inhalation.

Anesthesia, Inhalation↗
PubMed2003

Chlorine kinetic isotope effects on enzymatic dehalogenations.

Enzymatic dehalogenation reactions are important for the bioremediation of the environment because of the increasing anthropogenic pollution with halogen-containing organic compounds. Chlorine kinetic isotope effects have been measured for four hydrolytic dehalogenases. On the basis of these isotope effects, several details of the mechanisms of the enzymatic dehalogenation reactions have been revealed.

Chlorine↗
PubMed2000

Chemistry and insulin-mimetic properties of bis(acetylacetonate)oxovanadium(IV) and derivatives.

The syntheses and the solid state structural and spectroscopic solution characterizations of VO(Me-acac)2 and VO(Et-acac)2 (where Me-acac is 3-methyl-2,4-pentanedionato and Et-acac is 3-ethyl-2,4-pentanedionato) have been conducted since both VO(acac)2 and VO(Et-acac)2 have long-term in vivo insulin-mimetic effects in streptozotocin-induced diabetic Wistar rats. X-ray structural characterizations of VO(Me-acac)2 and VO(Et-acac)2 show that both contain five-coordinate vanadium similar to the parent VO(acac)2. The unit cells for VO(Et-acac)2 and VO(Me-acac)2 are both triclinic, P1, with a = 9.29970(10) A, b = 13.6117(2) A, c = 13.6642(2) A, alpha = 94.1770(10) degrees, beta = 106.4770(10) degrees, gamma = 106.6350(10) degrees for VO(Et-acac)2 and a = 7.72969(4) A, b = 8.1856(5) A, c = 11.9029(6) A, alpha = 79.927(2) degrees, beta = 73.988(2)degrees, gamma = 65.1790(10)degrees for VO(Me-acac)2. The total concentration of EPR-observable vanadium(IV) species for VO(acac)2 and derivatives in water solution at 20 degreesC was determined by double integration of the EPR spectra and apportioned between individual species on the basis of computer simulations of the spectra. Three species were observed, and the concentrations were found to be time, pH, temperature, and salt dependent. The three complexes are assigned as the trans-VO(acac)2.H2O adduct, cis-VO(acac)2.H2O adduct, and a hydrolysis product containing one vanadium atom and one R-acac- group. The reaction rate for conversion of species was slower for VO(acac)2 than for VO(malto)2, VO(Et-acac)2, and VO(Me-acac)2; however, in aqueous solution the rates for all of these species are slow compared to those of other vanadium species. The concentration of vanadium(V) species was determined by 51V NMR. The visible spectra were time dependent, consistent with the changes in species concentrations that were observed in the EPR and NMR spectra. EPR and visible spectroscopic studies of solutions prepared as for administration to diabetic rats documented both a salt effect on speciation and formation of a new halogen-containing complex. Compound efficacy with respect to long-term lowering of plasma glucose levels in diabetic rats traces the concentration of the hydrolysis product in the administration solution.

Animals↗
PubMed1989

Antitumor and antiviral activity of synthetic alpha- and beta-ribonucleosides of certain substituted pyrimido[5,4-d]pyrimidines: a new synthetic strategy for exocyclic aminonucleosides.

A novel and direct synthesis of the antiviral and antitumor agent 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (ARPP, 8) and its alpha-anomer (11) has been developed. Treatment of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (1) with 2,3-O-isopropylidene-D-ribofuranosylamine gave an anomeric mixture of 2,4,6-trichloro-8-(2,3-O-isopropylidene-beta- and -alpha-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidines (3 and 4) in a ratio of 1.0:0.7. A nucleophilic displacement of the 4-chloro group of 3 and 4 with NH3 furnished 4-amino-2,6-dichloro-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino ] pyrimido[5,4-d]pyrimidine (6) and its alpha-anomer (9), respectively. Catalytic hydrogenation of 6 and 9, followed by deisopropylidenation gave ARPP (8) and the alpha-anomer 11, respectively. Similarly, 3 and 4 have been transformed to 4-methoxy-8-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine (MRPP, 14) and its alpha-anomer (17). Application of this procedure to 3 with NH2Me or NHMe2 resulted in the synthesis of 4-(methylamino)- and 4-(dimethylamino)-8-(beta-D-ribofuranosylamino)pyrimido [5,4-d]pyrimidine (24 and 27, respectively). A synthesis of 8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidin-4(3H)-one (21) has also been accomplished from 3 in three steps. Selective hydrogenation of 6 furnished 4-amino-6-chloro-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino] pyrimido[5,4-d]pyrimidine (36), the structure of which was established by single-crystal X-ray diffraction analysis. Deisopropylidenation of 36 gave 6-chloro-ARPP (37). Extended treatment of 36 with NH3 furnished 4,6-diamino-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino]pyrimido [5,4-d]pyrimidine (34), which on deisopropylidenation gave 6-amino-ARPP (35). An unambiguous synthesis of 34 and 36 has also been accomplished by the reaction of 4,6,8-trichloropyrimido[5,4-d]pyrimidine (28) with 2, followed by the treatment with NH3. Nucleophilic displacement studies with 1, 6, and 28 indicated the reactivity of the halogens in these compounds is in the order of 8 greater than 4 greater than 6 greater than 2. The structures of 3 and 9 have been assigned on the basis of 1H NMR data and further confirmed by single-crystal X-ray diffraction analysis. The exocyclic aminonucleosides synthesized during this study were tested for their activity against several RNA and DNA viruses in vitro and against L1210, WI-L2, and LoVo/L in cell culture. The effect of these compounds on the de novo nucleic acid biosynthesis has been studied. Compound 14 (MRPP) exhibited enhanced activity against L1210 in vivo, when compared to ARPP (8).

Animals↗
PubMed2006

Mechanism of formation of biocidal imidazolidin-4-one derivatives: an Ab initio density-functional theory study.

N-halamine chemistry has been a research topic of considerable importance in these laboratories for over 2 decades because N-halamine compounds are very useful in preparing biocidal materials. To understand the utility of these compounds, the stabilities and mechanism of halogenation of cyclic N-halamine compounds should be resolved. The important precursor biocidal compound, 2,2,5,5-tetramethylimidazolidin-4-one (TMIO) was considered as a model in this theoretical study. The thermodynamic and kinetic products of monohalogenation were investigated along with tautomerization of TMIO and succinimide theoretically at the level of B3LYP/6-311+G(2d,p). Solvation effects (water and chloroform) were included using the CPCM solvation model with UAKS cavities. Several mechanisms have been proposed for the chlorine migration from the 3-position (kinetic product) to the 1-position (thermodynamic product) of the TMIO ring. The results are in agreement with experimental NMR data.

Crystallography, X-Ray↗
PubMed2003

An approach to the total synthesis of the marine ascidian metabolite perophoramidine via a halogen-selective tandem Heck/carbonylation strategy.

A halogen-selective tandem intramolecular Heck/carbonylation reaction has been developed for the construction of the C,E,F-ring system and the C20 quaternary center found in perophoramidine (1). This process can be effected in good yields in the presence of both the chlorine and bromine atoms found in the natural product. In addition, it is possible to introduce the quaternary center at C4 in a stereoselective manner by a lactone enolate alkylation, using NaH and allyl bromide. [reaction: see text]

Alkylation↗
PubMed2005

New route to 1-thia-closo-dodecaborane(11), closo-1-SB11H11, and its halogenation reactions. The effect of the halogen on the dipole moments and the NMR spectra and the importance of spin-orbit coupling for the 11B chemical shifts.

Reaction between nido-B10H14 (1) and elemental sulfur in CHCl3 in the presence of Et3N at room temperature, followed by treatment with Et3N.BH3 at 170-190 degrees C, resulted in the isolation of closo-1-SB11H11 (2) in 50% yield. Selected electrophilic halogenation reactions of compound led to the isolation of a series of monohalogenated derivatives of general constitution 12-X-closo-1-SB11H10 (12-X-, where X = Cl, Br, and I). The structures of 12-Cl- and 12-I- were determined by an X-ray diffraction analysis and the structures of all compounds were geometry optimised at the RMP2(fc)/6-31G* level. The constitution of all compounds is consistent with the results of mass spectrometry and multinuclear (1H and 11B) spectroscopy complemented by two-dimensional [11B-11B]-COSY and 1H{11B(selective)} NMR measurements. Experimental 11B chemical shifts generally show acceptable agreement with theoretical values calculated by GIAO methods, but spin-orbit coupling must be included for nuclei bearing heavy-atom substituents such as Br or I. The dipole moments determined for the B12-X bonds show similarities to those of aliphatic C-X bonds and confirm unambiguously the B12 --> S dipole moment orientation in the SB11 cage.

Journal Article↗
PubMed2006

Enantioselective formation and ring-opening of epoxides catalysed by halohydrin dehalogenases.

Halohydrin dehalogenases catalyse the conversion of vicinal halohydrins into their corresponding epoxides, while releasing halide ions. They can be found in several bacteria that use halogenated alcohols or compounds that are degraded via halohydrins as a carbon source for growth. Biochemical and structural studies have shown that halohydrin dehalogenases are evolutionarily and mechanistically related to enzymes of the SDR (short-chain dehydrogenase/reductase) superfamily. In the reverse reaction, which is epoxide-ring opening, different nucleophiles can be accepted, including azide, nitrite and cyanide. This remarkable catalytic promiscuity allows the enzymatic production of a broad range of beta-substituted alcohols from epoxides. In these oxirane-ring-opening reactions, the halohydrin dehalogenase from Agrobacterium radiobacter displays high enantioselectivity, making it possible to use the enzyme for the preparation of enantiopure building blocks for fine chemicals.

Catalysis↗