Simple brominated phenols in red algae

By using TLC and GLC-MS techniques, 23 species of red algae, representing nine orders, were analyzed for the presence of simple bromophenols. Ten bromophenols were detected, five of which might be artefacts. Furthermore, lanosol was identified in sea water from the Polysiphonia Brodiaei—zone. Bromophenols were detected in species from the families Ceramiaceae, Delesseriaceae, Bonnemaisoniaceae, Rhodophyllaceae, Corallinaceae and Rhodomelaceae.     

Bromophenol accumulation and sediment contamination by the marine annelids Notomastus lobatus and Thelepus crispus

The occurrence of bromophenols in Notomastus lobatus and Thelepus crispus and associated sediment and porewater was determined. 4-Bromophenol, 2,4-dibromophenol, and 2,4,6-tribromophenol were identified in N. lobatus with the highest concentrations occurring in the anterior and posterior abdomen and substantially less in the thorax (345, 209, and 6.6 μg/ml of worm, respectively). The concentration of dibromobenzyl alcohol was highest in the tail (last 15 setigers) of T. crispus (1.02 mg/ml of worm), but did not differ among body parts as the bromophenols did in N. lobatus. Concentrations in sediments were significantly reduced from those in the worms and decreased from the inner burrow lining out to 5 cm from N. lobatus burrows. Similarly for T. crispus, concentrations of dibromobenzyl alcohol in the surrounding sediments and porewater were low and increased with proximity to the burrow. For both species, concentrations in surface sediment (upper 1 cm) did not differ from those at 6 cm depth. Several lines of evidence indicate that these compounds are produced by the worms and hence their presence in sediments is derived from the worms. The contamination of sediment by these bromophenols has important implications for the structure and activities of benthic-associated communities.     

Bromochlorophenols and a brominated diphenylmethane in red algae

Identification of chlorinated bromophenols and a 2,3,2′,3′-tetrabromo-4,5,4′,5′-tetrahydroxydiphenylmethane in Polysiphonia nigrescens and Rhodomela confervoides was made by stepwise extraction followed by GC-MS analysis. Four different forms of the brominated and brominated-chlorinated benzyl alcohols in red algae are suggested (i) free phenols, (ii) sulphated potassium salts, (iii) constituents of brominated diphenylmethanes and (iv) part of the red pigment floridorubin.     

Metabolism of 4-hydroxybenzaldehyde, 3-bromo-4-hydroxybenzaldehyde and bromide by cell-free fractions of the marine red alga Odonthalia floccosa

Cell-free fractions from Odonthalia floccosa incubated with 4-hydroxybenzaldehyde-[U-¹⁴C], 3-bromo-4-hydroxybenzaldehyde-[U-¹⁴C] and ⁸²Br^? formed the dibromo-dihydroxybenzaldehyde derivatives of the bromophenols (brominated benzylalcohols) which were also identified as naturally occurring products.     

Synthesis and characterization of novel bromophenols: Determination of their anticholinergic,antidiabetic and antioxidant activities

In this paper, a series of novel bromophenol derivatives were synthesized and evaluated for their acetylcholinesterase and α-glycosidase enzymes inhibition properties and antioxidant activity. Diarylmethanones were synthesized and their bromination was carried out. During bromination, some compounds gave new bromophenols via regioselective O-demethylation. Demethylation of brominated diarylmethanones was also performed with BBr₃ to give novel bromophenols. In addition, we examines the antioxidant capacity of novel bromophenol derivatives using several in vitro bioanalytical methodologies such as 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS⋅⁺) and 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) radical scavenging activity, Fe³⁺ and Cu²⁺ reducing activities and ferrous (Fe²⁺) ions chelating activities. Also, novel bromophenols and methoxylated bromophenols derivatives were tested against acetylcholinesterase and α-glycosidase, which associated with some metabolic diseases. The novel bromophenols showed Ki values in range of 8.94 ± 0.73–59.45 ± 14.97 nM against AChE and 4.31 ± 1.93–44.14 ± 2.19 nM against α-glycosidase.     

Potent alpha-glucosidase inhibitors purified from the red alga Grateloupia elliptica

Diabetes mellitus is a most serious and chronic disease whose incidence rates are increasing with incidences of obesity and aging of the general population over the world. One therapeutic approach for decreasing postprandial hyperglycemia is to retard absorption of glucose by inhibition of α-glucosidase. Two bromophenols, 2,4,6-tribromophenol and 2,4-dibromophenol, were purified from the red alga Grateloupia elliptica. IC₅₀ values of 2,4,6-tribromophenol and 2,4-dibromophenol were 60.3 and 110.4 μM against Saccharomyces cerevisiae α-glucosidase, and 130.3 and 230.3 μM against Bacillus stearothermophilus α-glucosidase, respectively. In addition, both mildly inhibited rat-intestinal sucrase (IC₅₀ of 4.2 and 3.6 mM) and rat-intestinal maltase (IC₅₀ of 5.0 and 4.8 mM). Therefore, bromophenols of G. elliptica have potential as natural nutraceuticals to prevent diabetes mellitus because of their high α-glucosidase inhibitory activity.     

Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols including natural products

(2-Bromo-3,4-dimethoxyphenyl) (3,4-dimethoxyphenyl)methanone (10) and its derivatives with Br, one dibromide and isomeric three tribromides, were synthesized. Demethylation of these compounds afforded a series of new bromophenols. Inhibition of human cytosolic carbonic anhydrase II (hCA II) isozyme by these new bromophenols and naturally occurring 3,4,6-tribromo-5-(2,5-dibromo-3,4-dihydroxybenzyl)benzene-1,2-diol (3), and 5,5'-methylenebis(3,4,6-tribromo-benzene-1,2-diol) (4) was investigated. The synthesized compounds showed carbonic anhydrase inhibitory capacities with IC(50) values in the range of 0.7-372 μM against hCA II. Some bromophenols investigated here showed effective hCA II inhibitory activity and might be used as leads for generating novel carbonic anhydrase inhibitors which are valuable drug candidates for the treatment of glaucoma, epilepsy, gastric and duodenal ulcers, neurological disorders, or osteoporosis.     

Bromine, Bromophenols and Floridorubin in the Red Alga Lenormandia prolifera

The pigment floridorunin was localized to the cuticle of the red alga Lenormandia prolifera (C. Ag.) J. Agardh by x-ray micro-analysis in Ihe transmission electron microscope and by its colour reactions in the light microscope. The pigment was set free from the cell wall by a pectinase. Bromine was also identified in the chloro-plasts. the middle lamellae, the intercellulars and the pore plugs of the alga. The content of bromophenols in the alga increases with increasing age. The cell walls of old plants are stratified and their outer parts are apparently shed. The bromophenols could have a function as regulators of the epiphytes or the shedding of parts of the outer cell wall.     

Correlations between primary and secondary metabolites in Ceramiales (Rhodophyta)

A correlation between the presence of terpenes and floridosides and between the presence of bromophenols and digeneaside was observed in species of red algae belonging to the order Ceramiales. This observation suggests a division in Ceramiales that can be easily detected through the presence of the secondary metabolites, terpenes and bromophenols.     

Synthesis and Biological Activity of Some Bromophenols and Their Derivatives Including Natural Products

In addition to the first synthesis of the natural bromophenol butyl 2-(3,5-dibromo-4-hydroxyphenyl)acetate ( 1 ), indene derivatives 34 and 35 were synthesized from 3-phenylpropenal derivatives in BBr₃ medium. Five known natural bromophenols and some derivatives were synthesized by known methods. Cholinesterase (ChEs) inhibitors reduce the breakdown of acetylcholine and are used in the treatment of Alzheimer's disease (AD) and dementia symptoms. The inhibition effects of all obtained compounds were examined towards acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glycosidase enzymes. All synthesized compounds demonstrated the strong inhibition effects against both cholinergic enzymes. For determination of Ki values of novel bromophenols Lineweaver-Burk graphs were obtained. Ki values were found in the ranging of 0.13–14.74 nM for AChE, 5.11–23.95 nM for BChE, and 63.96–206.78 nM for α-glycosidase, respectively. All bromophenols and their derivatives exhibit effective inhibition profile when compared to positive controls.     

Antimicrobial activities of the bromophenols from the red alga Odonthalia corymbifera and some synthetic derivatives

A series of bromophenols was obtained by isolation from red alga Odonthalia corymbifera and by reactions of bis(hydroxyphenyl)methanes with bromine. New bromophenols including 3,3',5,5'-tetrabromo-2,2',4,4'-tetrahydroxydiphenylmethane (10), a regioisomer of the potent antimicrobial natural product, together with known derivatives were synthesized in high yield. All of the isolated and synthesized compounds were tested for antimicrobial activity against gram-negative, gram-positive bacteria and fungi. The preliminary structure-activity relationship, to elucidate the essential structure requirements for antimicrobial activity, has been described. Among the isolated natural products 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxydiphenylmethane (4) was found to be the most active derivative against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, and Trichophyton mentagrophytes. The synthetic bromophenols 3,3'-dibromo-6,6'-dihydroxydiphenylmethane (13) and 3,3',5,5'-tetrabromo-6,6'-dihydroxydiphenylmethane (14) showed potent antibacterial effect against Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Proteus vulgaris, and Salmonella typhimurium.     

Structure based design of compounds from natural sources for diabetes and inflammation

Medicinal plants and marine sources are important elements of indigenous medical systems worldwide. The natural drugs from medicinal plants and marine sources have received considerable interest in treatment of diabetes and inflammation. Based on literature, alpha glucosidase, aldose reductase and PTP1B enzymes were chosen as anti-diabetes targets and PLA₂ was chosen for the anti-inflammatory target. In our study, plant and bromophenols (BPs) inhibitors were screened using High Throughput Virtual screening (HTVS) followed by Induced Fit Docking (IFD) studies were carried out against diabetes and inflammation targets. The IFD result of natural inhibitors has showed favorable docking score, glide energy and hydrogen bonds interactions with the active site residues. Some of the natural inhibitors successively satisfied all the in silico parameters among the others and seem to be potent inhibitors against diabetes and inflammation.     

Synthesis and antioxidant properties of diphenylmethane derivative bromophenols including a natural product

Bromination of bis(3,4-dimethoxyphenyl)methanone (5) gave four products (6–9) with mono, di, tri, and tetra Br under different conditions. Reduction and demethylation reactions of product 9 with tetra Br were performed, consecutively and a natural product, 5,5′-methylene bis(3,4-dibrombenzene-1,2-diol) (1), was obtained with a 53% yield. Five derivatives, (13–17) (bromophenols), of 1 were also synthesised. The antioxidant and radical scavenging activities of bromophenols 1 and 13–17 were determined by employing various in vitro assays such as 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH^?), 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid (ABTS^?+), N,N-dimethyl-p-phenylenediamine dihydrochloride radical cation (DMPD^?+), and superoxide anion radical (O₂^?-) scavenging, reducing ability determination by the Fe³⁺-Fe²⁺ and Cu²⁺-Cu⁺ cupric reducing antioxidant capacity (CUPRAC) transformation methods, hydrogen peroxide scavenging, and ferrous ion (Fe²⁺) chelating activities. Moreover, these activities were compared to those of synthetic standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol, and trolox. The results showed that the synthesised bromophenols had effective antioxidant power.     

Bromophenols as Candida albicans isocitrate lyase inhibitors

A new series of bromophenols was synthesized by reactions of corresponding phenol analogs with bromine. The synthesized compounds were tested for inhibitory activity against isocitrate lyase (ICL) of Candida albicans and antimicrobial activity against gram-positive and, gram-negative bacteria and fungi. Among the synthesized bromophenols, bis(3-bromo-4,5-dihydroxyphenyl)methanone (11) and (3-bromo-4,5-dihydroxyphenyl)(2,3-dibromo-4,5-dihydroxyphenyl)methanone (12) displayed potent inhibitory activities against ICL, showing a stronger inhibitory effects than were found with natural bromophenol 1. The preliminary structure-activity relationships were investigated in order to determine the essential structural requirements for the inhibitory activities of these compounds against ICL of C. albicans.     

Synthesis and biological activity of halophenols as potent antioxidant and cytoprotective agents

A series of new bromophenols and chlorophenols were prepared by a practical route. The in vitro antioxidative activity of the halophenols was evaluated by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay, and their cytoprotective activity was also tested on hydrogen peroxide (H₂O₂)-induced injury in human umbilical vein endothelial cells (HUVEC). All halophenols tested displayed moderate to good DPPH radical-scavenging activity, and two bromophenols, 2,3′-dibromo-4,5,6′-trihydroxydiphenylmethanone (16c) and 2,3-dibromo-4,5-dihydroxydiphenylmethanone (17c) exhibited high protective activity against H₂O₂-induced injury in HUVEC with EC₅₀ values of 0.4 and 0.8 μM, respectively. The preliminary structure–activity relationships of these compounds were also investigated in order to determine the essential structures required for their bioactivities.     

Screening marine algae from China for their antitumor activities

Thirty-nine species of marine algae collected from the coast of China were screened for their antitumor activities, and eight species Leathesia difformes, Polysiphonia urcedata, Scytosiphon lomentarius, Gloiopeliis furcata, Punctaria latifolia, Symphyocladia latiuscula, Rhodomela confervoides and Ulva pertusa showed potent cytotoxic activities. Three, Rhodomela confervoides, Scytosiphon lomentarius and Gloiopeliis furcata, were used for further investigation. More than 30 compounds were isolated and purified, and 14 bromophenols, 1 steroid and 1 carotene were identified by advanced spectroscopic methods including IR, MS, and NMR techniques. Amongst the 16 identified compounds, 7 showed vigorously selective activities against KB, Bel7402 and A549 cancer cells, and 6 bromophenols were new compounds.     

Crystal structures of cyclomaltohexaose (alpha-cyclodextrin) complexes with p-bromophenol and m-bromophenol.

Crystal structures of cyclomaltohexose (alpha-cyclodextrin) complexes with p-bromophenol and m-bromophenol have been determined by single-crystal X-ray diffraction. The space group of the alpha-cyclodextrin-p-bromophenol complex is P2(1)2(1)2(1) with unit cell dimensions of a = 15.318(3), b = 24.733(3), c = 13.457(2) A, and that of the alpha-cyclodextrin-m-bromophenol complex is P2(1)2(1)2 with unit cell dimensions of a = 25.858(7), b = 27.263(8), c = 8.145(3) A. In crystals, the alpha-cyclodextrin-p-bromophenol complex and the alpha-cyclodextrin-m-bromophenol complex form a layer-type and a channel-type molecular packing structure, respectively. The intermolecular hydrogen-bond interactions of the hydroxyl groups of bromophenols are closely related to the molecular packing structure.     

Specificity of Reductive Dehalogenation of Substituted ortho-Chlorophenols by Desulfitobacterium dehalogenans JW/IU-DC1

Volume 61, no. 1, abstract, lines 4 and 5: "2,6-dichloro-4-R-phenols, where . . ." should read "2,6-dichloro-4-R-phenols (2,6-DCl-4-RPs, where R is -H, -F, -Cl, -NO(inf2), -CO(inf2)(sup-), or -COOCH(inf3)) . . ." Line 6: ". . . bromophenols (2-BrP, 2,6-DBrP, and 2-Br-4ClP)" should read ". . . the bromophenols 2-BrP, 2,6-DBrP, and 2-Br-4-ClP." [This corrects the article on p. 346 in vol. 61.].     

Extracellular secretion of phenolic substances from living brown algae

The chemical structures of ultraviolet (UV)- absorbing substances secreted from the healthy living brown algae, Eisenia bicyclis and Ecklonia kurome, were demonstrated. The living activity of algal cells was critically examined using a confocal laser-scanning microscope after incorporation of fluorescein diacetate (FDA) into the cells. Using thin-layer chromatography (TLC), reversed-phase three-dimensional high-performance liquid chromatography (RP-3D-HPLC) and gas chromatography-mass spectrometry (GC-MS), it was found that the UV-absorbing substances (λ_max 265–270 nm) secreted from the living brown algae mainly consisted of the three monomeric bromophenols, 2,4-dibromophenol, 2,4,6-tribromophenol and dibromo-iodophenol, but not phloroglucinol or phlorotannins. The other minor compounds detected in the secretions were as follows: benzothiazole, fatty acids (14:1, 16:0 and 18:0 acids), franesol, 3-hydroxy-2,4,4-trimethylpentyl 2-methylpropanoate and squalene. Exudation of phloroglucinol and phlorotannins was ascertained to take place only after the cell death of these algae. These results indicate that, whilst the algae are alive, polymeric phlorotannins are strictly kept within the algal body, and only monomeric bromophenols are secreted into the seawater medium.     

Synthesis and paroxonase activities of novel bromophenols

Three novel bromophenols 10–12 were synthesized. Acylation of veratrole (4) with 2,3-dimethoxy benzoic acid (5) gave a kown diarylmethanone 6. Bromination of 6 with different equivalents of molecular bromine afforded new di and tribrominated compounds 7–9 which were converted to their corresponding bromophenols 10–12 via O-demethylation with BBr₃. Paraoxonase-1 (PON1) was purified from human serum with approximately 42% and 3584?U × mg^?1 specific activity. The synthesized compounds 6–12 showed inhibitory effects on paraoxonase-1 (PON1) which is an organophosphate (OP) hydrolyser and an antioxidant bioscavenger enzyme. IC₅₀ values were determined in the range of 0.123–1.212?mM.

Graphical abstract