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Preliminary SAR studies on the side chain of a new class of antiviral nucleosides have shown that terminal substitution in the side-chain, with a halogen atom, lead to potent and highly specific anti-VZV agents.
Substituted indole-3-acetic acid (IAA) derivatives, plant auxins with potential for use as prodrugs in enzyme-prodrug directed cancer therapies, were oxidised with horseradish peroxidase (HRP) and toxicity against V79 Chinese hamster lung fibroblasts was determined. Rate constants for oxidation by HRP compound I were also measured. Halogenated IAAs were found to be the most cytotoxic, with typical surviving fractions of <10(-3) after incubation for 2h with 100 microM prodrug and HRP.
In this report, we describe the synthesis of halogenated benzenesulfonamide compounds and their ability to inhibit the growth of HeLa, MCF-7 and MCF-7/ADR tumor cells in vitro. The multidrug resistance (MDR) phenotype of certain cells does not affect their sensitivity to these compounds. These agents belong to a family of compounds previously shown to bind irreversibly to cysteine-239 of beta-tubulin. Consistent with this mechanism of action, the cytotoxicities of these compounds appear to correlate with their ability to undergo nucleophilic aromatic substitution.
A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.
The reactivity and toxicity of metabolic intermediates that are generated by initial biotransformation reactions can be a major limiting factor for biodegradation of halogenated organic compounds. Recent work on the conversion of haloalkanes, chloroaromatics and chloroethenes indicates that microorganisms may become less sensitive to toxic effects either by using novel pathways that circumvent the generation of reactive intermediates or by producing modified enzymes that decrease the toxicity of such compounds.
With the aim of developing new radioligands for in vivo studies of substance P receptors using positron emission tomography or single photon emission computed tomography, 2- and 3-halo naphthyridone-6-carboxamide derivatives were synthesized. Their affinities toward the target receptors were evaluated on CHO cells and compared to the unsubstituted analogue EP 00652218 (IC(50) = 100 nM +/- 20). The IC(50) value was not altered in the case of 2-chloro compound 1 (IC(50) = 100 nM +/- 15) and only slightly reduced for the 2-fluoro and -iodo analogues 6 and 8 (IC(50) = 500 nM +/- 80). A drastic reduction in binding (IC(50) > 1000 nM) was observed for the halogenated compounds 2-5, 7, and 9.
We successfully prepared low viscosity, polar, and halogen-free ionic liquids as potential solvents for a wide range of polysaccharides. A series of 1,3-dialkylimidazolium formates were produced as liquids having strong hydrogen bond acceptability. These formates had significantly lower viscosity than previously reported polar ionic liquids, in particular 1-allyl-3-methylimidazolium formate (viscosity 66cP at 25 degrees C) and 1-allyl-3-ethylimidazolium formate (67cP at 25 degrees C). Because of their strong hydrogen bond ability, various polysaccharides including amylose and (scarcely soluble) cellulose were dissolved in high concentrations under mild condition.
The toxic effects from exposure to halogenated hydrocarbons (HAs), which are produced in large amounts and used in a variety of applications, are well-known. Previously, QSARs for the toxicity of a series of HAs in vitro have been studied extensively. In this work, using a composite toxicity metric calculated from a set of five in vitro hepatotoxicity endpoints determined for 20 HAs, we find that QSARs derived using quantum descriptors calculated from the neutral HA species are statistically similar to QSARs calculated from HA metabolites. In most cases, QSARs derived using descriptors calculated from both neutral HAs and metabolites are statistically superior to those derived using either neutral-HA descriptors or metabolite descriptors. However, to properly utilize metabolite descriptors, multiple QSARs, each of which utilizes a set of HAs that form unique metabolites, must be derived and toxicity values calculated therefrom must be averaged. These average toxicity values agree better with experiment than those calculated from the neutral-HA QSARs.
Halogenated organic compounds (HOCs) such as 1,1'-dimethyl-3,3',4,4'-tetrabromo-5,5'-dichloro-2,2'-bipyrrole (DBP-Br4Cl2) and heptachloro-1'-methyl-1,2'-bipyrrole (Q1) have been detected worldwide, sometimes at high levels in Antarctic air, seabird eggs, the blubber of marine mammals, and, most notably, even human milk. To date, it has been difficult to determine whether these compounds are natural products or derived from industrial synthesis. Molecular-level 14C analysis of these compounds is particularly appealing because most industrial compounds are manufactured from petrochemicals (14C-free) and natural compounds should have "modern" or "contemporary" 14C levels. To investigate the source of DBP-Br4Cl2, we isolated 600 microg of this compound (150 microg of carbon) from marine animal extracts by employing gel permeation chromatography, Florisil column chromatography, and two-dimensional preparative capillary gas chromatography. The purified DBP-Br4Cl2 was split into two samples (75 microg of carbon each) and analyzed by accelerator mass spectrometry for 14C content. The delta14C values were -449 percent per thousand and -467 percent per thousand, corresponding to conventional 14C ages of 4740 and 5000 years before present (BP), respectively. The presence of detectable 14C in the DBP-Br4Cl2 strongly points to at least a natural or biogenic source. However, these delta14C values for DBP-Br4Cl2 are more depleted than expected for a recently synthesized natural product. Several explanations are discussed, but additional samples
Recent theoretical studies indicate that reactive organic iodocarbons such as CH2I2 would be extremely effective agents for tropospheric Arctic ozone depletion and that iodine compounds added to a Br2/BrCl mixture have a significantly greater ozone (and mercury) depletion effect than additional Br2 and BrCl molecules. Here we report the first observations of CH2I2, CH2IBr, and CH2ICl in Arctic air, as well as other reactive halocarbons including CHBr3, during spring at Kuujjuarapik, Hudson Bay. The organoiodine compounds were present atthe highest levels yet reported in air. The occurrence of the halocarbons was associated with northwesterly winds from the frozen bay, and, in the case of CHBr3, was anticorrelated with ozone and total gaseous mercury (TGM), suggesting a link between inorganic and organic halogens. The absence of local leads coupled with the extremely short atmospheric lifetime of CH2I2 indicates that production occurred in the surface of the sea-ice/overlying snowpack over the bay. We propose an abiotic mechanism for the production of polyhalogenated iodo- and bromocarbons, via reaction of HOI and/or HOBr with organic material on the quasi-liquid layer above sea-ice/snowpack, and report laboratory data to support this mechanism. CH2I2, CH2IBr, and other organic iodine compounds may therefore be a ubiquitous component of air above sea ice where they will increase the efficiency of bromine-initiated ozone and mercury depletion.
Selective 1,2-iodine, bromine, and chlorine migration in haloallenyl ketones in the presence of Au catalyst has been demonstrated. It was found that, depending on the nature of the Au catalyst used, either selective bromine migration or hydrogen shift occurs, leading to the formation of 3- or 2-bromofurans, respectively. Halirenium intermediate was proposed for the unusual 1,2-halogen migration. This cascade transformation allows for mild and efficient synthesis of various types of 3-halofurans.
A rapid transformation of eicosapentaenoic acid is initiated upon disintegration of cells of the marine diatom Stephanopyxis turris. In contrast to any other fatty acid cleaving activity known, this diatom releases a blend of chlorinated C8 hydrocarbons in addition to an unsaturated 12-oxo acid. Using labeled precursors, trapping experiments, and selective inhibition of enzyme activities, we were able to show that a lipoxygenase activates the C20 fatty acid to a hydroperoxide, which is subsequently cleaved by a new hydroperoxide halolyase to the C8 and C12 products. This adds a fundamentally new pathway to the limited set of halogenating enzymatic activities known from nature.
Concentrations of four naturally produced halogenated dimethyl bipyrroles (HDBPs) were quantitated in marine fish (n = 10), freshwater fish (n = 10), canned fish (n = 10), and shrimp composites (n = 10) collected from 1992 to 2002 for the Canadian Total Diet Study. Canned fish composites composed of epipelagic higher trophic level species contained the highest concentration of HDBPs (SigmaHDBP geometric mean +/- standard error = 880 +/- 690 pg/g of wet weight, n = 10), which was significantly higher than that found in the other three composites. There were no significant temporal trends of HDBP concentrations observed for any of the four composites. The estimated daily intake of HDBPs via consumption of fish and seafood was determined to be 53 pg/kg of body mass/day and 0.10 pg of TEQ/kg of body mass/day when transformed to 2,3,7,8-tetrachlorodibenzodioxin equivalents (TEQs). In the canned fish and shrimp composites collected in 1998, HDBPs accounted for approximately 98 and 19%, respectively, of the total quantitated TEQ (which included polychlorinated biphenyls, dioxins, and furans). The results of this study provide the first estimate of human exposure to naturally produced bioaccumulating organohalogens.
The 3-D quantitative structure-activity relationships/comparative molecular field analysis (QSAR/CoMFA) paradigm, which considers the primary importance of the molecular fields in biological recognition, is now widely used to analyze and predict receptor-binding properties of various ligands. CoMFA was applied to build 3-D QSAR models of substituted estradiol-receptor interactions, employing 3-D molecular databases of more than 40 molecules. Ligands included the 17 alpha-ethynyl- and isomeric 17 alpha (20E/Z)-(iodovinyl)estradiols and their 7 alpha-, 11 beta-, and 12 beta-methyl (-methoxy) and -ethyl (-ethoxy) derivatives as well as selected 2- and 4-halogenated analogs. The influence of different CoMFA descriptors was studied in order to achieve the highest possible cross-validated r2, as derived from partial least-squares calculations. Special emphasis was put on the analysis of the nature of H-bonding (donor/acceptor) interactions. The model with the best predictive performance (r2 = 0.895) was used to visualize steric and electrostatic features of the QSAR (standard deviation*coefficient contour maps) and to predict receptor-binding affinities (RBA) of substituted estradiols other than those included in the original database. Twenty-seven test molecules were selected, including five which had previously been reported by other investigators. For the latter, a very good correlation with literature RBA values was obtained, which together with the high cross-validated r2 provides evidence for the high predictive capacity of the model. Among the unknown structures, the model suggests several new substitutions to derive at reasonable affinity ligands for the estrogen receptor.
Prealbumin is a major thyroxine binding protein in blood that has been well studied crystallographically and has also been proposed as a model for the thyroxine nuclear receptor in tissue. The high-affinity T4 binding site in prealbumin gave a linear plot on Scatchard analysis. The interactions of selected polychlorinated biphenyls (PCBs) with prealbumin have been studied with use of computer graphics and predictions made regarding relative binding affinities for such structures. These modeling predictions were tested by using competitive binding experiments involving selected PCBs and hydroxylated derivatives as soluble structural probes. The results are in excellent agreement with the modeling predictions and demonstrated that these compounds can be highly effective (3-8 times better than thyroxine itself) competitive binding ligands for thyroxine specific binding sites in prealbumin. Laterally (3,3',5,5'-) substituted PCBs show the highest binding activity and further substitution on nonlateral (2,2',6,6'-) positions lowers binding activity. Lateral chlorine substitution was common to all PCBs studied that showed high binding affinities. The binding model may also suggest a preference for a linear and symmetrical molecular shape. These structural requirements for binding are substantially consistent with the structure-toxicity relationship for closely related compounds of environmental interest. These specific binding interactions are likely to modulate the distribution of certain PCBs and related compounds and alter hormone-protein interactions that are responsible for the maintenance of normal thyroid status. Since prealbumin is also a model for the putative thyroxine nuclear receptor in tissue, our hypothesis that high toxicity of certain halogenated aromatic hydrocarbons is at least in part due to their thyromimetic properties is further supported.
Both homo- and mixed lithium di-alpha-(heteroatom)alkylcuprates readily dimerize upon addition of halogens (e.g., I(2), Br(2)) or N-halosuccinimides to afford the coupled products in excellent yields. Higher yields result when the requisite alpha-(heteroatom)alkyllithium reagents are generated via deprotonation rather than by transmetalation of the corresponding stannanes. Mixed lithium dialkyl- or alkyl(aryl)cuprate reagents containing one alpha-(heteroatom)alkyl ligand and one simple alkyl or aryl ligand give significantly lower yields of coupled product. Low enantioselectivity has been achieved in the oxidative coupling of lithium (n-Bu)(2-pyrrolidinyl)cuprate.
Previous studies of oxygen addition into an N12 cage framework revealed the possibility of stable high-energy density materials (HEDM) resulting from such additions. In the current study, nitrogen addition into N12 is studied as a means of generating stable HEDM. Nitrogen addition into N12 is shown to yield an N14H4(2+) ion, which is examined by theoretical calculations to determine its stability with respect to dissociation. Other variations on this ion are generated by substituting carbon for nitrogen and/or halogens for hydrogen. The cage structures will be compared with respect to stability, and factors that enhance stability will be discussed.
Para-halosubstituted thiophenols (X-TPs, where X is Br, Cl, or F) form ordered islands and monolayers on Cu(111) at temperatures as low as 81 K. At incomplete coverages, all X-TPs adsorb with the dehydrogenated thiol group attached to the substrate and the substituted ring inclined toward the surface, as verified experimentally and theoretically. The structure of ordered islands has a pronounced dependence on the nature of the halogen substituent: while unsubstituted TP and pentafluoro-TP molecules do not self-assemble into extended ordered patterns at 81 K, X-TP molecules form a range of different structures which depend both on the size and electronegativity of the substituent, as well as on the coverage.