The action of lipoxygenase-1 on furan derivatives.

Several 2,5-disubstituted furans, which are known to react with peroxyacids, singlet oxygen and other active forms of oxygen were tested as potential inhibitors, co-oxidants, or substrates for soybean lipoxygenase. The furan, 10,13-epoxy-octadeca-10,12-dienoic acid, methyl ester (IV) was converted by lipoxygenase or singlet oxygen or peroxyacid to the acyclic product, methyl 10,13-dioxo-octadec-11-enoate. Apparently furan IV is able to interact with an active site of lipoxygenase (Km = 220 microM). 2,5-Dimethylfuran (I), 2,5-diphenylfuran (II) and 3-(5'-methyl-2'-furyl)propenoic acid (III) were neither substrates nor inhibitors of lipoxygenase activity. Lipoxygenase-catalyzed oxidation of furan (IV), which is inhibited by hydroquinone, is explained by a mechanism involving lipoxygenase-superoxide complex and furan-radical intermediates. Also described is the selective cleavage of furan rings by m-chloroperoxybenzoic acid to yield the 1,4-diketoethylene functional system.     

Sesquiterpenes from Russula sardonia

Three new sesquiterpenes, furanether A, furosardonin A and sardonialactone A (7-hydroxyblennin A), together with lactaral, vellerolactone, two known furan alcohols, lactarorufin A and cerevisterol, were isolated from Russula sardonia. Structures and stereochemistry were elucidated by spectral data and correlation to known compounds by chemical transformations.     

Kinetics of error generation in homologous B-family DNA polymerases

The kinetics of forming a proper Watson–Crick base pair as well incorporating bases opposite furan, an abasic site analog, have been well characterized for the B Family replicative DNA polymerase from bacteriophage T4. Structural studies of these reactions, however, have only been performed with the homologous enzyme from bacteriophage RB69. In this work, the homologous enzymes from RB69 and T4 were compared in parallel reactions to determine the relative abilities of the two polymerases to incorporate correct nucleotides as well as to form improper pairings. The kinetic rates for three different exonuclease mutants for each enzyme were measured for incorporation of an A opposite T and an A opposite furan as well as for the formation of A:C and T:T mismatches. The T4 exonuclease mutants were all ~2- to 7-fold more efficient than the corresponding RB69 exonuclease mutants depending on whether a T or furan was in the templating position and which exonuclease mutant was used. The rates for mismatch formation by T4 were significantly reduced compared with incorporation opposite furan, much more so than the corresponding RB69 mutant. These results show that there are kinetic differences between the two enzymes but they are not large enough to preclude structural assumptions for T4 DNA polymerase based on the known structure of the RB69 DNA polymerase.     

Influence of methoxy and nitro groups in the oxidative metabolism of naphtho[2,1-b]furan.

In the present study, we have investigated the role of methoxy and nitro groups in the oxidative metabolism of naphtho[2,1-b]furan. Hepatic microsomes were used to investigate the aerobic metabolism of naphtho[2,1-b]furan (compound A), 2-nitro-naphtho[2,1-b]furan (compound B) and 7-methoxy-naphtho [2,1-b]furan (compound C) and comparison of the metabolites formed was made using HPCL analysis and NMR, mass and UV-visible spectrometry. The different metabolic pathways investigated were compared with the previously reported metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan (compound D). Naphtho[2,1-b]furan yield metabolites of both the furan and benzene rings, while metabolites formed from 7-methoxy-naphtho[2,1-b]furan and 2-nitro-naphtho [2,1-b]furan were derived entirely as a result of enzymic attack on the first benzene ring.     

Furan fatty acids – Beneficial or harmful to health?

Furan fatty acids are found in plants, algae, and fish, and reported to have some positive health benefits, including anti-oxidant and anti-inflammatory activities, and inhibition of non-enzymatic lipid peroxidation. A major metabolite of furan fatty acids, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), has been reported to be increased in patients who progress from prediabetes to type 2 diabetes, although CMPF is not necessarily associated with impaired glucose metabolism. Other studies report that CMPF levels are lower in subjects with diabetes than control subjects. Plasma CMPF levels increase in subjects who consume fish or fish oil, and in patients with renal failure. It is not known where furan fatty acids are converted to CMPF and it is speculated that this might be a result of microbiome activity. The plasma levels reported for CMPF in healthy, diabetic and patients with renal disease vary by factors of more than 100-fold within each of these three groups, so measurement error appears to be limiting the ability to interpret studies. This review explores these controversies and raises questions about whether CMPF is a marker for healthy diets or indeed associated with diabetes and renal health. The review concludes that, on balance, furan fatty acids are beneficial for health.     

Genotoxicity of furan in Big Blue rats

Furan is a multispecies liver carcinogen whose cancer mode of action (MOA) is unclear. A major metabolite of furan is a direct acting mutagen; however, it is not known if genotoxicity is a key step in the tumors that result from exposure to furan. In order to address this question, transgenic Big Blue rats were treated by gavage five times a week for 8 weeks with two concentrations of furan used in cancer bioassays (2 and 8mg/kg), and with two higher concentrations (16 and 30mg/kg). Peripheral blood samples taken 24h after the 5th dose (1 week of dosing) were used to assay for micronucleus (MN) frequency in normochromatic erythrocytes (NCEs) and reticulocytes (RETs), and Pig-a gene mutation in total red blood cells (RBCs). 24h after the last dose of the 8-week treatment schedule, the rats were euthanized, and their tissues were used to perform NCE and RET MN assays, the Pig-a RBC assay, Pig-a and Hprt lymphocyte gene mutation assays, the liver cII transgene mutation assay, and the liver Comet assay. The responses in the MN assays conducted at both sampling times, and all the gene mutation assays, were uniformly negative; however, the Comet assay was positive for the induction of liver DNA damage. As the positive responses in the Comet assay were seen only with doses in excess of the cancer bioassay doses, and at least one of these doses (30mg/kg) produced toxicity in the liver, the overall findings from the study are consistent with furan having a predominantly nongenotoxic MOA for cancer.     

Olefin cross-metathesis-based approaches to furans: procedures for the preparation of di- and trisubstituted variants

Olefin cross-metathesis (CM)-based protocols enable short, flexible and regiocontrolled access to substituted furan derivatives. Specifically, CM of allylic alcohol and enone components provides γ-hydroxyenone intermediates that are cycloaromatized to the final furan derivatives on exposure to either acid or a discrete Heck arylation step. This latter process concomitantly introduces an extra substituent onto the furan target with complete control of regiochemistry. The methodology described here serves as the basis for developing other CM-based entries to diverse heteroaromatic compounds. This protocol describes in detail the following stages of the furan procedures: (i) the tandem formation and acid-catalyzed cyclization of the γ-hydroxyenone to afford a 2,5-disubstituted furan directly; (ii) CM of an allylic alcohol with an enone to provide an isolated γ-hydroxyenone; and (iii) Heck arylation of this γ-hydroxyenone to afford a 2,3,5-trisubstituted furan. The reaction procedure given for the formation of the 2,5-disubstituted furan (option A) takes ～26.5 h to complete. The procedure described for the formation of the 2,3,5-trisubstituted furan (option B) takes ～52.5 h.     

应用生物技术降解木质纤维素水解液中呋喃醛

木质纤维素是地球上储量最为丰富的可再生有机碳资源,但由于其结构的复杂性,必须经过一系列预处理过程才能被微生物高效利用,这就不可避免地带来了呋喃醛等典型抑制物,严重阻碍了微生物的生长和后续发酵过程。认知微生物的呋喃醛代谢途径,并基于此开发耐受性和转化能力强的微生物菌株是生物炼制领域的重要研究内容。文中综述了呋喃醛抑制物的来源、呋喃醛对微生物的抑制机理以及微生物降解呋喃醛的代谢途径,并重点讨论了基于生物法降解呋喃醛抑制物的研究进展,涉及的主要技术手段包括传统的适应性进化工程和代谢工程,以及近年来新兴的微生物共培养系统和功能化材料辅助微生物脱除呋喃醛等。     

Synthetic studies of neoclerodane diterpenes from Salvia divinorum: selective modification of the furan ring

A synthetic sequence has been developed to selectively functionalize the furan ring of the natural product salvinorin A (2a). The synthetic routes described convert the furan ring in 2a into an N-sulfonylpyrrole, oxazole or an oxadiazole. In addition, a procedure has been found to remove the furan skeleton completely. Biological results indicate that replacement of the furan ring with an N-sulfonylpyrrole leads to reduced affinity and efficacy at kappa opioid receptors.     

Sesquiterpenes from Lactarius blennius

Six sesquiterpene lactones were isolated from Lactarius blennius. The structures of two new sesquiterpenes, blennin A and blennin B were determinated by spectroscopic methods and the structure of the seco-compound, blennin C, is revised. The two known furan sesquiterpenes and lactarorufin A were also identified.     

Novel γ-lactone derivatives from Trigonostemon heterophyllus with their potential antiproliferative activities

Two novel γ-lactone derivatives, trigoheterophines A (1) and B (2), together with four known furan derivatives (3–6), were isolated from the stems and leaves of Trigonostemon heterophyllus. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A (1) and B (2) represent an unusual type of γ-lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds (3–6) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–6 showed significant antiproliferative effects against various human cancer cell lines with IC₅₀ values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ-lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents.     

The in vitro micronucleus assay for detection of cytogenetic effects induced by mutagen-carcinogens: comparison with the in vitro sister-chromatid exchange assay

The sensitivity of a cytogenetic assay, as expressed by the in vitro induction of micronuclei (MN), was compared to the in vitro induction of sister-chromatid exchanges (SCEs). Chinese hamster lung (V79) cells were exposed to 3 known alkylating agents: methyl methanesulphonate (MMS), ethyl methanesulphonate (EMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and to 5 newly synthesized naphthofurans: 2-nitro-7-methoxynaphtho[2,1-b]furan (A), 2-nitro-8-methoxynaphtho[2,1-b]furan (B), 2-nitronaphtho[2,1-b]furan (C), 2-nitro-7-bromonaphtho[2,1-b]furan (D) and 7-methoxynaphtho[2,1-b]furan (E). The induction of MN only was also analysed after exposure of the cells to 4 alcohols: ethanol, methanol, butanol and propanol. The lowest dose at which a significant effect could be observed was determined. In both assays, MNNG, MMS and EMS were equally active with the following order of potency: MNNG greater than MMS greater than EMS, the latter being a very weak inducer of MN and SCE. Compounds A and B were also very effective in both assays. Compound C was a more active inducer of SCE than MN. Compounds D and E were not active in either assay. None of the 4 alcohols induced MN. Our results are compared with the previously published data on in vitro and in vivo induction of SCE and MN. We conclude that the MN in vitro assay which detects clastogens as well as agents affecting the spindle apparatus, is a good indicator of genotoxicity, though slightly less sensitive than the in vitro SCE test. It could provide a rapid, simple and inexpensive complementary short-term test for the evaluation of potentially mutagenic chemicals.     

Effects of Ca(OH)(2) treatments ("overliming") on the composition and toxicity of bagasse hemicellulose hydrolysates

Hemicellulose syrups from dilute sulfuric acid hydrolysates of hemicellulose contain inhibitors that prevent efficient fermentation by yeast or bacteria. It is well known that the toxicity of these hydrolysate syrups can be ameliorated by optimized "overliming" with Ca(OH)(2). We have investigated the optimization of overliming treatments for sugar cane bagasse hydrolysates (primarily pentose sugars) using recombinant Escherichia coli LY01 as the biocatalyst. A comparison of composition before and after optimal overliming revealed a substantial reduction in furfural, hydroxymethylfurfural, and three unidentified high-performance liquid chromatography (HPLC) peaks. Organic acids (acetic, formic, levulinic) were not affected. Similar changes have been reported after overliming of spruce hemicellulose hydrolysates (Larsson et al., 1999). Our studies further demonstrated that the extent of furan reduction correlated with increasing fermentability. However, furan reduction was not the sole cause for reduced toxicity. After optimal overliming, bagasse hydrolysate was rapidly and efficiently fermented (>90% yield) by LY01. During these studies, titration, and conductivity were found to be in excellent agreement as methods to estimate sulfuric acid content. Titration was also found to provide an estimate of total organic acids in hydrolysate, which agreed well with the sum of acetic, levulinic, and formic acids obtained by HPLC. Titration of acids, measurement of pH before and after treatment, and furan analyses are proposed as relatively simple methods to monitor the reproducibility of hydrolysate preparations and the effectiveness of overliming treatments.     

Furan in heat-treated foods: Formation, exposure, toxicity, and aspects of risk assessment

Furan is formed in a variety of heat-treated foods through thermal degradation of natural food constituents. Relatively high levels of furan contamination are found in ground roasted coffee, instant coffee, and processed baby foods. European exposure estimates suggest that mean dietary exposure to furan may be as high as 1.23 and 1.01 μg/kg bw/day for adults and 3- to 12-month-old infants, respectively. Furan is a potent hepatotoxin and hepatocarcinogen in rodents, causing hepatocellular adenomas and carcinomas in rats and mice, and high incidences of cholangiocarcinomas in rats at doses ≥2 mg/kg bw. There is therefore a relatively low margin of exposure between estimated human exposure and doses that cause a high tumor incidence in rodents. Since a genotoxic mode of action cannot be excluded for furan-induced tumor formation, the present exposures may indicate a risk to human health and need for mitigation. This review summarizes the current knowledge on mechanisms of furan formation in food, human dietary exposure to furan, and furan toxicity, and highlights the need to establish the risk resulting from the genotoxic and carcinogenic properties of furan at doses lower than 2 mg/kg bw.     

Rings D-seco and B,D-seco tetranortriterpenoids from root bark of Entandrophragma angolense

Investigation of the root bark extract of Entandrophragma angolense led to identification of two gedunin-type limonoids 5-hydroxy-7-deacetoxy-7-oxogedunin and 5,6-dehydro-7-deacetoxy-7-oxogedunin, and three methyl angolensate derivatives, 6-deacetoxydomesticulide D, 6-deacetoxydomesticulide D 21-methylether, and entangosin, together with known compounds, methyl angolensate, 6-acetoxymethyl angolensate and secomahoganin. Their structures were established by extensive NMR experiments in conjunction with mass spectrometry. Entangosin is a rare example of a limonoid derivative having a fully O-substituted furan moiety.     

Studies on furan fatty acids of salmon roe phospholipids

Mature salmon roe lipids were found to consist of triacylglycerols (63%), phospholipids (30%), sterols (4.2%), steryl esters (0.7%), and other minor components. In the steryl esters and phospholipids, furan fatty acids were detected instead of the triacylglycerols of the testes lipids in male fish. The representative 12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid (F6) amounted to 3.8% and 0.6% of the total fatty acids in each fraction, respectively. However, the absolute amount of the acid in the phospholipid was much more than that contained in the steryl esters. The characteristic distribution of the furan acids found in the phospholipids was common to the steryl esters in the liver. Large amounts of furan acids were contained in phosphatidylcholine (PC) rather than in phosphatidylethanolamine. For positional analysis of furan fatty acids in PC, furan-containing species in the molecule were concentrated fourteenfold by using selective hydrogenation and repeated silica gel column chromatography. A series of furan fatty acids in PC was found to be exclusively linked to the sn-1 position. The amount of the acids in the roe exclusively linked to the sn-1 position. The amount of the acids in the roe phospholipids was comparable with that in the testes triacylglycerols. The physiological roles of furan fatty acids are discussed.     

Genotoxic activity of two furan analogues of benzo[a]pyrene and their 2-nitro derivatives

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS Chromotest (an assay for SOS induction in E. coli), of two pairs of isomeric furan analogues of benzo[a]pyrene: pyreno[1,2-b]furan (R7490) and pyreno[2,1-b]furan (R7692) and their 2-nitro derivatives, 8-nitro-pyreno[1,2-b]furan (R7489) and 8-nitro-pyreno[2,1-b]furan (R7691). We found that: For all 4 compounds, the responses were correlated in the two tests. For the 2-nitro derivatives, R7489 and R7691, the responses were extremely high, reaching SOS-inducing potencies of 5.2 X 10(3) and 10(5)/nmole in the SOS Chromotest and mutagenic potencies of 6.3 X 10(4) and 3.7 X 10(7) revertants/nmole in the Salmonella/histidine assay (strain TA98), respectively; the responses were only slightly decreased in nitroreductase-deficient strains. The responses to the two pyrenofurans were increased in the presence of an "activating mixture" but were still lower than that to benzo[a]pyrene. In contrast to benzo[a]pyrene and pyreno[2,1-b]furan (R7692), pyreno[1,2-b]furan (R7490) also gave a response in the absence of an "activating mixture". (5) Compounds with the oxygen heteroatom within the "bay region" gave lower responses than their isomers with the oxygen heteroatom outside the "bay region".     

DFT study of conductive properties of three polymers formed by bicyclic furans

Density functional theory methods were employed to study the electronic, structural and conductive properties of classical bicyclic furans. In this paper, studies of monomers, oligomers and polymers of furo[3,4-b]furan, furo[2,3-b]furan and furo[3,2-b]furan are presented. To gain detailed information on conjugational degree, we selected the nucleus-independent chemical shift as a method for examining the changes in conjugational degree. Furthermore, three parameters of density of state, effective mass (m*) and kinetic model of mobility (μ) were also investigated. The variable trends of all parameters from monomers to tetramers indicate that poly(4,4′-bifuro[3,4-b]furan), poly(trans-2,2′-bifuro[3,2-b]furan) and poly(cis-2,2′-bifuro[3,2-b]furan) are good candidates for conductive materials, which are consistent with band structure analyses showing that the three polymers had narrower band gaps (1.21, 1.93 and 1.89 eV, respectively) than other polymers.     

Two new butanolides from the roots of Litsea acuminata

Two new butanolides, licunolides A (1) and B (2), were isolated from the roots of Litsea acuminata, together with three known compounds: isolancifolide (3), longifolin (4), and sesquirose furan (5). The structures of compounds 1 and 2 were determined by spectroscopic studies (IR, MS, 1D and 2D NMR) and chemical evidence. This is the first report of 4-hydroxy-5-methylbutanolides with a C₁₀-side chain from a natural source. Longifolin (4) and sesquirose furan (5) showed a significant cytotoxicity against HeLa cell lines in vitro.