Bromo Substitution Research Articles

Affinity for Thyroid Hormone and Estrogen Receptors of Hydroxylated Polybrominated Diphenyl Ethers

The affinity for thyroid hormone receptor (TR) of polybromodiphenyl ethers (PBDEs) and hydroxylated PBDEs was examined. 4-Hydroxy-2,2',3,4',5-pentabromodiphenyl ether (4-OH-BDE-90) and 3-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (3-OH-BDE-47) markedly inhibited the binding of triiodothyronine (1×10-10 M) to TR in the concentration range of 1×10-6-1×10-4 M. 2,3,4,5,6-Pentabromophenol (PBP) also showed an inhibitory effect at 1×10-5-1×10-4 M. However, 2,2',3,4,4',5'-hexabromodiphenyl ether (BDE-138), decabromodiphenyl ether (DBDE), 4-methoxy-2,2',3,4',5-pentabromodiphenyl ether (4-MeO-BDE-90), 4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether (4'-OHBDE-49), 4-hydroxy-2,2',3,4'-tetrabromodiphenyl ether (4-OH-BDE-42), 4'-hydroxy-2,2',4-tribromodiphenyl ether (4'-OH-BDE-17), 3'-hydroxy-2,4-dibromodiphenyl ether (3'-OH-BDE-7), 2,4,6-tribromophenol (TBP) and tetrabromohydroquinone (TBHQ) did not show affinity for TR. In contrast, 4'-OH-BDE-17 and 3'-OH-BDE-7 exhibited estrogenic activity in estrogen-responsive reporter assay using MCF-7 cells at the concentration of 1×10-5 M. However, adjacent bromo substitution of 3- or 4-hydroxylated PBDEs markedly decreased the estrogenic activity. These results suggest that hydroxylated PBDEs act as thyroid hormone-like agents, as well as estrogens, that a 4- or 3-hydroxyl group in PBDEs is essential for thyroid hormonal and estrogenic activities, and that adjacent dibromo substitution favors thyroid hormonal activity, but not estrogenic activity.

Naphthalene Core-Based Mesogens with Terminal Halogen Substituents: Synthesis and Mesomorphic Behavior

We report three series of naphthalene core-based mesogens obtained by varying two different terminal substituents. The flexibility in these systems is provided by attaching a straight alkoxy chain at the one end, while a halogen terminal substituent accounts for the polarity. To understand the structure–property relation, alkoxy tails (C1 to C8, C10, C12, C14, C16, and C18) as well as halogen atoms (F, Cl, and Br) have been varied. The molecular structures of these mesogens have been confirmed by spectroscopic and elemental analyses, whereas their thermal behavior was evaluated mainly by polarizing optical microscopic observations. The study shows that, in general, all the compounds display nematic and/or smectic A mesophases. In all three series of compounds, the lower and middle homologues exhibit the nematic phase only and higher homologues also display the smectic A phase. These compounds follow the general trend that with the increase in the length of alkoxy tail, the nematic to isotropic phase transition temperature decreases, which is reminiscent of a large number of reported homologues series. The transition temperatures of the compounds with fluro substituents are significantly lower when compared to the materials with chloro or bromo substitutions.

Influence of Functional Group Substitutions on the Carcinogenicity of Anthraquinone in Rats and Mice: Analysis of Long-Term Bioassays by the National Cancer Institute and the National Toxicology Program

The carcinogenic activities of anthraquinone and six derivatives were compared and contrasted. Studies included representatives of amino, alkyl, nitro, hydroxy, or halogen-containing anthraquinones, with the purpose of uncovering general structure–activity relationships. Anthraquinone, 2-aminoanthraquinone, 1-amino-2-methylanthraquinone, 2-methyl-1-nitroanthraquinone, 1‐amino-2,4-dibromoanthraquinone, 1,4,5,8-tetraaminoanthraquinone, and 1,3,8-trihydroxy-6-methylanthraquinone (of varying purities) were administered via feed to Fischer 344/N rats and B6C3F1 mice. In rats, anthraquinone induced tumors in the liver, kidney, and urinary bladder. A 2-amino substitution narrowed the carcinogenicity to the liver, while multiple amino substitutions led to a carcinogenic response in the urinary bladder alone. A methyl substitution ortho to a 1-amino group preserved the hepatic and renal neoplasms seen with the parent anthraquinone, but did not induce urinary bladder tumors; amino or bromo substitutions para to a 1-amino group were related to urinary bladder neoplasms. The intestine may have been a target organ for bromine-substituted anthraquinones. The presence of a nitro group altered the targets of carcinogenicity, and skin tumors may have been associated with this particular functional group in both rats and mice. Overall for mice, the findings were somewhat different and limited by the small number of common target organs. The parent anthraquinone was clearly carcinogenic only to the liver. There were no other effects of single amino substitutions, in the presence or absence of an additional methyl group, on the carcinogenicity or the site of carcinogenesis of anthraquinone in mice. Multiple amino substitutions diminished, while bromine substitutions enhanced the carcinogenicity induced by anthraquinone and extended the target organs to include forestomach and lung. The authors are grateful to Drs. Tom Burka and James Huff for reviewing the manuscript of this article. The contribution of Dr. Doug Bristol is greatly appreciated. The authors also acknowledge the contribution of all study scientists and other personnel involved in the anthraquinone NCI and NTP studies.

N-Oxide analogs of WAY-100635: new high affinity 5-HT 1A receptor antagonists

WAY-100635 [ N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))- N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT 1A receptor antagonists, which when labeled with carbon-11 (β +; t 1/2 = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT 1A receptors with positron emission tomography (PET). In a search for new 5-HT 1A antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-oxide, was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine- N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4, a more lipophilic ( pyridinyl-6)-chloro derivative of 3, was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl- N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5, in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2, was prepared in five steps from 2-(chloroacetylamino)pyridine. N-Oxides 3– 5 were found to be high affinity antagonists at 5-HT 1A receptors, with 3 having the highest affinity and a K i value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (Log P = 1.87) is lower than that of 1 by 1.25 Log P units while TLC and reverse phase HPLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [ carbonyl- 11C] 3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT 1A receptors was obtained. Either 3 inadequately penetrates the blood–brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [ carbonyl- 11C] 3 appeared less rapidly than from the radioligands [ carbonyl- 11C] 1 and [ carbonyl- 11C] 2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging.

Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid.

(2S*,3R*)-1-(biphenyl-4-carbonyl)piperazine-2,3-dicarboxylic acid (PBPD) is a moderate affinity, competitive N-methyl-d-aspartate (NMDA) receptor antagonist with an atypical pattern of selectivity among NMDA receptor 2 subunit (NR2) subunits. We now describe the activity of several derivatives of PBPD tested at both rat brain NMDA receptors using l-[3H]-glutamate binding assays and at recombinant receptors expressed in Xenopus oocytes. Substituting various branched ring structures for the biphenyl group of PBPD reduced NMDA receptor activity. However, substituting linearly arranged ring structures - fluorenone or phenanthrene groups - retained or enhanced activity. Relative to PBPD, the phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) displayed a 30- to 78-fold increase in affinity for native NMDA receptors. At recombinant receptors, PPDA displayed a 16-fold (NR2B) to 94-fold (NR2C) increase in affinity over PBPD. Replacement of the biphenyl group of PBPD with a 9-oxofluorene ring system resulted in small changes in receptor affinity and subtype selectivity. 2'-Bromo substitution on the biphenyl group of PBPD reduced antagonist affinity 3- to 5-fold at NR2A-, NR2B- and NR2D-containing receptors, but had little effect on NR2C-containing receptors. In contrast, 4'-fluoro substitution of the biphenyl ring of PBPD selectively increased NR2A affinity. The aromatic rings of PBPD and PPDA increase antagonist affinity and appear to interact with a region of the NMDA receptor displaying subunit heterogeneity. PPDA is the most potent and selective NR2C/NR2D-preferring antagonist yet reported and thus may be useful in defining NR2C/NR2D function and developing related antagonists with improved NMDA receptor subtype selectivity. British Journal of Pharmacology (2004) 141, 508-516. doi:10.1038/sj.bjp.0705644

Copper‐Catalyzed Amidations of Bromo Substituted Furans and Thiophenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Planar or tetrahedral coordination in copper(II) complexes induced by bromo substitution

The diffraction study of bis(5-bromo- N- m-tolylsalicylaldiminate)copper(II) shows the copper atom in a centrosymmetric position and the two ligands displayed trans to each other in a planar environment. Two additional weak interactions due to Br atoms (Jahn-Teller effect) of neighboring units complete the coordination sphere, CuBr = 3.662(2) A ̊ , so that the comple is formally a polynuclear two-dimensional species. On the contrary, bis(3,5-dibromo- N- p-tolylsalicylaldiminate(copper(II) is mononuclear and shows only the two ligands coordinated and the geometry is distorted ‘tetrahedral’. The distortion is due to intramolecular repulsion interactions. Electronic spectra of these two compounds show a single asymmetric band at 700 nm for the former, and two bands located at 650 and 850 nm for the latter. Both compounds are monoclinic, space group P2 1/c with a = 9.919(2) A ̊ , b = 10.965(2) A ̊ , c = 12.283(2) A ̊ , β = 105.88(1)°, Z = 2 for the former, and a = 13.290(2) A ̊ , b = 12.195(2) A ̊ , c = 17.891(2) A ̊ , β = 105.38(1)°, Z = 4 for the latter.

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

AbstractFive previously undescribed trimetrexate analogues with bulky 2′‐bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2‐[2‐(2‐bromo‐3,4,5‐trimethoxyphenyl)ethyl]‐1,l‐dicyanopropene with sulfur in the presence of N,N‐diethylamine afforded 2‐amino‐5‐(2′‐bromo‐3′,4′,5′‐trimethoxybenzyl)‐4‐methyl‐thiophene‐3‐carbonitrile (15) and 2‐amino‐4‐[2‐(2′‐bromo‐3′,4′,5′‐trimethoxyphenyl)ethyl]thiophene‐3‐car‐bonitrile (16). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4‐diamino‐5‐(2′‐bromo‐3′,4′,5′‐trimethoxybenzyl)‐4‐methylthieno[2,3‐d]pyrimidine (8a) and 2,4‐diamino‐4‐[2‐(2′‐bromo‐3′,4′,5′‐trimethoxyphenyl)ethylthieno[2,3‐d]pyrimidine (12) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4‐diaminoquinazoline‐6(or 5)‐carbonitriles with 2‐bromo‐3,4,5‐trimethoxyaniline, were 2,4‐diamino‐6‐(2′‐bromo‐3′,4′,5′‐trimethoxyanilinomethyl)‐5‐chloro‐quinazoline (9a), 2,4‐diamino‐5‐(2′‐bromo‐3′,4′,5′‐trimethoxyanilinomethyl)quinazoline (10), and 2,4‐diamino‐6‐(2′‐bromo‐3′,4′,5′‐trimethoxyanilinomethyl)quinazoline (11). Enzyme inhibition assays revealed that space‐filling 2′‐bromo substitution in this limited series of dicyclic 2,4‐diaminopyrimidines with a 3′,4′,5′‐trimethoxyphenyl side chain and a CH2, CH2CH2, or CH2NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.

ChemInform Abstract: Detection of Elusive Chloro‐ and Bromo Substituted Ozonides by Nucleophilic Substitution Reactions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Detection of Elusive Chloro- and Bromo Substituted Ozonides by nucleophilic substitution reactions

Detection of Elusive Chloro- and Bromo Substituted Ozonides by nucleophilic substitution reactions

Studies on 1,4-naphthoquinones. 23. 2-3-Halogen-2-3-nitrophenyljuglone derivatives, synthesis and cytotoxic properties

Radical arylation of 1,4-naphthoquinones is possible by oxidative decarboxylation of 2- and 4-nitrobenzoic acid. With 2- and 3-halogenojuglone derivatives the 4-nitrophenyl compounds 10-13 are prepared in good, the 2-nitrophenyl analogues 14-17 only in poor yields. All compounds are inactive against the virus types HSV and HIV and their marked cytotoxicity in part depends on the substitution pattern. The 3-aryl and o-nitro derivatives are more active than their 2-aryl and p-nitro analogues and the influence of the chloro or bromo substitution is only remarkable in the case of 12/13.

Tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene in mouse skin and rat mammary gland.

Studies of the tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene (BP) can provide evidence about the role of the 6 position in the carcinogenic activation of BP. Female Swiss and A-strain mice were treated on the skin with BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-chlorobenzo[a]pyrene (6-C1BP), 6-bromobenzo[a]pyrene (6-BrBP) and 6-iodobenzo[a]pyrene (6-IBP) by repeated application, and in some cases by initiation-promotion. While BP was more potent than 6-FBP, only these two compounds exhibits tumor-initiating and carcinogenic activity in mouse skin. Female Sprague-Dawley rats were treated with BP, 6-FBP, 6-ClBP, and 6-BrBP by intramammillary injection. BP and 6-FBP induced high levels of mammary epithelial tumors and fibrosarcomas. 6-ClBP elicited only a high percentage of fibrosarcomas, whereas 6-BrBP induced a few adenocarcinomas. These results indicate that chloro or bromo substitution at C-6 in BP reduces or eliminates carcinogenic activity. Conversely, 6-FBP, from which the fluoro substituent has been chemically and metabolically removed by one-electron oxidation, displays a moderate carcinogenic activity which is consistent with activation by either one-electron oxidation or monooxygenation.

Effect of methyl and halogen substitutions in the αC position on the mutagenicity of cinnamaldehyde

Chloro or bromo substitution in the αC position of the naturally occurring, non-mutagenic cinnamaldehyde leads to derivatives that are strongly mutagenic for Salmonella typhimurium TA100. The mutagenicity, increasing from α-chlorocinnamaldehyde to α-bromocinnamaldehyde, is direct, i.e. addition of Aroclor-1254-induced rat-liver homogenate fraction (S9 mix) reduces the mutagenic potential. This is obviously due to both enzymatic and non-enzymatic interactions with S9 mix. The latter factor is proved by the influence of glutathione, which greatly reduces the mutagenecity of both substances. The addition of SK and F 525, an inhibitor of P450 oxygenase, and of 1,1,1-trichloropropen-2-oxide, an inhibitor of epoxide hydrolase, makes it likely that the metabolic reactions in the presence of S9 mix include the formation of a mutagenic epoxide intermediate. α-Methylcinnamaldehyde is non-mutagenic both in the presence and in the absence of S9 mix.

The effects of colchicine derivatives on humoral antibody response in mice

AbstractThe effects of colchicine and two of its chemical derivatives (propyl and bromo substitutions on the acetamido group) were investigated on the sheep red blood cell (SRBC) humoral antibody response in mice. These drugs were shown to suppress SRBC antibody titres. Immunosuppression was dependent upon temporal relationships of antigen/drug administration, as well as on the dosage profile of the drugs. In these studies bromocolchicine was the most active agent tested. Possible pharmacologic mechanisms are discussed.

Mesomorphic Properties of Bromo and Cyano Substituted Diarylethanes

Abstract Two homologous series of diarylethanes: 1-(4-alkoxy or alkyl-benzoyloxyphenyl)-2-(4′-bromo or cyanophenyl) ethanes (series I) and I-(4-alkoxy 3-bromo or cyanobenzoyloxyphenyl)-2-(4′-pentylphenyl) ethanes (series II) have been synthesized. The influence of the bromo or cyano group, in the meta or para position, on the mesomorphic range and the clearing point, is studied. In the series I, the bromo group induces a smectic polymorphism, whereas the cyano group induces nematic mesophases. In the series II, the larger the meta substituant, the lower the clearing point.

E.P.R. and zero-field odmr studies of theT1states of halogen-containing benzonitriles, anisoles and anilines

The magnetic and dynamic properties of bromo and chloro substituted benzonitriles, anisoles and anilines were studied by means of E.P.R. and zero-field odmr at 1·2–4·2 K. Single-crystal E.P.R. studies showed that the zero-field splitting parameter D of bromo substituted molecules are positive as in other aromatic molecules. It was also shown that para bromo substitution depresses the energies of the Tx and Ty sublevels preferentially. This indicates that the second-order effect of the spin-orbit mixing of the T 1 state with the 3 nπ* state is the most important in affecting the zero-field splitting. Single-crystal E.P.R. spectra of 4-bromobenzonitrile and 4-bromoanisole gave resolved hyperfine splittings at certain orientations. The analysis of the in-plane hyperfine structure of 4-bromobenzonitrile gives Azz = 16 G and Ayy = 13 G, which are considerably different from the values expected from the spin densities in benzonitrile and the 81Br hyperfine coupling of α-bromomaleic acid. The large value of Axx indicates considerable delocalization of the π electron onto the bromine atom. Hyperfine data were also used to ascertain the zero-field sublevel schemes and the directions of the principal axes of the zero-field tensor. It was found that the Tz sublevel is radiatively active at the electronic origin in most of the systems studied here. Possible causes of this activity are considered. In particular, mixing of the 3nπ* and 1nπ* states with the T 1 state is suggested as the possible cause of the radiative activity of the Tz sublevel.

Beta-Adrenoceptor blocking activity of halogenated thienylethanolamine derivatives.

The synthesis of a number of ring-halogenated N-isopropyl- and N-tert-butyl-2-amino-1-(2-thienyl)ethanols has been carried out in order to ascertain the influence of chloro or bromo substitution at the thiophene moiety on their blocking beta-adrenoceptor activity. It was found that chloro- and bromo-substituted compounds exhibited a similar activity. Monohalo substitution at positions C4 or C5 of the thiophene ring resulted in comparable blocking potency, whereas C3 halo-substituted compounds were practically devoid of activity. The highest activity in these series was observed with compounds dihalogenated at C4 and C5, their effect on myocardial beta-receptors being comparable to that of propranolol.

Pharmacological effects of cyclic nucleotides and their derivatives on tracheal smooth muscle

The relationship between structure and tracheal relaxing activity of cyclic-3′,5′-adenosine monophosphate (cAMP), cyclic-3′,5′-guanosine monophosphate (cGMP) and cyclic-3′,5′-inosine monophosphate (GIMP) derivatives has been studied. The results obtained indicate that the 8 position of the cyclic nucleotides plays an important role in the relaxing activity of these compounds. Experiments have also shown that the Bromo substitution of cGMP increases the tracehal relaxing activity both in vitro and in vivo.

Specificity of thyroxine action on oxygen uptake of kidney slices during prolonged incubation.

The effect of a number of thyroxine analogs has been evaluated using kidney tissue respiration during prolonged incubation. Thyroxine was found to be the most active compound studied. All substances with marked thyroxinelikc activity had a skeletal structure of a diphenyl ether with at least three substitutions on the rings. lodo, methyl, bromo, chloro and nitro substitutions activated with decreasing effectiveness in that order. Variation in the number of carbon atoms, alteration of the optical configuration of the alanine side chain or its replacement by a short-chain fatty acid caused only slight reduction of the activity of an analog, as did the replacement of the ether oxygen with a sulfur. The results can be correlated with those from in vivo experiments and suggest that the thyroxine effect on tissue respiration in this type of system may yield information of value in explaining the hormone’s mechanism of action in whole animals.

Bromination of cyclic 1,3-diketone monoenolates with N-bromosucinimide. II.

The position of the substituted bromine in bromination of 1, 3-cyclohexanedione monoenolate with N-bromosuccinimide was investigated. 1, 3-Cyclohexanedione-3-monoenolates, which have two alkyl substituents at their 5-position, were found to be brominated at positions other than 2. From the data obtained in infrared spectra, the stereochemical situations of the bromo substitution were discussed. In this reaction dibromo compounds were obtained as by-products which were not found in a similar reaction for 1, 3-cyclohexanedione monoenolates having no or one aryl substituent at their 5-positions.