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PubMed1989

Polyene--sterol interaction and selective toxicity.

From permeability experiments carried out with series of amphotericin B derivatives in both biological and model membranes, it was concluded that derivatives, whose carboxyl group at the C18 position is blocked by substitution, are much more efficient at inducing permeability in ergosterol-containing than in cholesterol-containing membranes, whereas derivatives whose carboxyl group is free and ionizable are equally efficient in both membranes types. Binding measurements on erythrocyte membranes showed that all amphotericin B derivatives simply partition between membrane lipids and aqueous medium, according to their lipid solubility. There is no relationship between binding and efficiency in inducing permeability. Permeability studies carried out on lipidic vesicles containing various sterols showed that: 1) derivatives having their carboxyl free induced permeability of the 'channel' type, regardless of the sterol present, and no detectable permeability in sterol-free membranes; 2) derivatives whose carboxyl group is blocked induce channels only in membranes containing ergosterol or sterols having an alkyl side chain identical to that of ergosterol. In the presence of other sterols or in sterol-free membranes, their ionophoric activity is poor and always of the 'mobile-carrier' type. A model of polyene-sterol interaction is proposed, accounting for the data obtained with both biological and model membranes.

Amphotericin B↗
PubMed2006

Modulation of polyene antibiotics self-association by ions from the Hofmeister series.

The toxicity of the antifungal polyene antibiotic amphotericin B (AMB) has been related to its low solubility, more specifically to a self-associated form termed toxic aggregate. In addition, AMB in aqueous medium gives rise to concentration, ionic strength, and time-dependent polydisperse systems. For this reason different approaches, including the use of several lipid aggregates, have been used in attempts to improve the drug's solubility and increase its therapeutic index. In this context, understanding AMB's self-association properties should help in the preparation of less toxic formulations. Ions from the Hofmeister series alter water properties: while kosmotropes (water structure makers-sulfate, citrate, phosphate) decrease solute solubility, chaotropes (water structure breakers-perchlorate, thiocyanate, trichloroacetate, and the neutral molecule urea) have opposite effects. This work reports a study of the effect of Hofmeister ions and urea on the self-aggregation of AMB and some of its derivatives. Optical absorption and circular dichroism spectra were used to monitor monomeric and aggregated antibiotic. While kosmotropes increased aggregation in a concentration-dependent manner, the opposite was observed for chaotropes. It is shown, for the first time, that thiocyanate and trichloroacetate can induce complete AMB monomerization. The understanding of these processes at the physicochemical and molecular levels and the possibility of modulating the aggregation state of AMB and its derivatives should contribute to elucidate the mechanisms of action and toxicity of this widely used antibiotic and to develop more efficient and less toxic preparations.

Amphotericin B↗
PubMed2005

Generating novel polyene antifungal drugs.

In this issue of Chemistry & Biology, Francisco Malpartida and colleagues [1] report the formation of novel polyene amide derivatives upon transformation of the producer strain with SCP2*-derived vectors carrying the erythromycin resistance gene ermE. This unexpected finding provides a new tool for generating antifungal drugs by biotransformation.

Antifungal Agents↗
PubMed2006

High-performance liquid chromatography analysis of polyacetylenes and polyenes in Echinacea pallida by using a monolithic reversed-phase silica column.

In this study, a RP-HPLC method for the analysis of polyacetylenes and polyenes in Echinacea pallida roots and phytopharmaceuticals was developed. The reference compounds used for quantification were isolated from the plant material and their structures were determined on the basis of the analysis of UV, IR, NMR and MS data. The complete structure elucidation of three compounds, namely 8-hydroxy-tetradec-(9E)-ene-11,13-diyn-2-one (1), tetradec-(8Z)-ene-11,13-diyn-2-one (6) and pentadec-(8Z)-en-2-one (9) is described. In the analysis of the n-hexane extracts of E. pallida roots, the comparison between conventional and monolithic columns showed that the elution order in both cases is identical and the selectivity is equivalent. However, the retention times achieved by the monolithic column are shorter, resulting in a faster separation (20 min). Therefore, the analyses were carried out on a Chromolith Performance RP-18e (100 mm x 4.6 mm i.d.), with a gradient mobile phase composed by H(2)O and ACN at the flow rate of 2 mL/min. The column was thermostatted at 20 degrees C. The photodiode array detector monitored the eluent at 210 nm. The validation procedure confirmed that this technique affords reliable analysis of these components and is appropriate for the quality control of complex matrices, such as E. pallida roots and phytopharmaceuticals.

Chromatography, High Pressure Liquid↗
PubMed2006

Selective activity of polyene macrolides produced by genetically modified Streptomyces on Trypanosoma cruzi.

The growth inhibitory effects on Trypanosoma cruzi of several natural tetraene macrolides and their derivatives were studied and compared with that of amphotericin B. All tetraenes strongly inhibited in vitro multiplication. Proliferation of epimastigotes was arrested by all these drugs at < or =3.6 microM, which were also active on amastigotes proliferating in fibroblasts. Compared with amphotericin B, the compounds were less effective but also less toxic, showing no effect on the proliferation of J774 and NCTC 929 mammalian cells at concentrations active against the parasites. CE-108B (a polyene amide) appeared to be an especially potent trypanocidal compound, with strong in vivo trypanocidal activity and very low or no toxic side effects, and thus should be considered for further studies.

Amphotericin B↗
PubMed2003

Solution conformation of a nitrobenzoxadiazole derivative of the polyene antibiotic nystatin: a FRET study.

Nystatin is a polyene antibiotic frequently applied in the treatment of topical fungal infections. In this work, a 7-nitrobenz-2-oxa-1,3-diazole (NBD) hexanoyl amide derivative of nystatin was synthesized and its detailed photophysical characterization is presented. The average conformation of the labelled antibiotic in tetrahydrofuran, ethanol and methanol was determined by intramolecular (tetraene to NBD) fluorescence resonance energy transfer measurements. At variance with the literature [Can. J. Chem. 63 (1985) 77-85], it was concluded that there is no need to invoke a solvent-dependent conformational equilibrium between extended and closed conformers of the antibiotic, because the mean tetraene-to-NBD separating distance was found to remain constant (approximately 18 A) in all the solvents studied. In addition, the large solvent dependence of the fluorescence anisotropy observed for the non-derivatized nystatin, was rationalized on the basis of the prolate ellipsoidal geometry of the molecule. It was concluded that the rod shaped and amphipathic antibiotic remains monomeric in different solvents within the concentration range studied (2-20 microM).

Fluorescence Polarization↗
PubMed2005

Laetiporic acids, a family of non-carotenoid polyene pigments from fruit-bodies and liquid cultures of Laetiporus sulphureus (Polyporales, Fungi).

The non-isoprenoid polyene laetiporic acid A, recently described from fruit-bodies of the wood-rotting fungus Laetiporus sulphureus, was found to be the major orange pigment also in mycelium grown in liquid culture. Its formation was variable, ranging from 0.1 to 6.7 mg/g dry weight in three strains, all of which were identified as L. sulphureus by ITS rDNA sequence analysis. A second pigment, 2-dehydro-3-deoxylaetiporic acid A, is also described and fully characterized by NMR spectroscopy. Two further minor pigments, laetiporic acids B and C, were produced in liquid culture. These resemble laetiporic acid A but are enlarged by two and four carbon atoms, respectively, resulting in chromophores with 11 or 12 instead of 10 conjugated double bonds as described for laetiporic acid A. Since fruit-bodies of L. sulphureus are edible, laetiporic acids might hold potential as food colourants.

Molecular Structure↗
PubMed1992

Antileishmanial activity of hamycin: a polyene antibiotic.

Hamycin, a polyene antibiotic, now in extensive use in the treatment of candidiasis and otomycosis, is found to be remarkably effective in killing Leishmania donovani promastigotes in a liquid medium at a concentration of 0.2 microgram/ml. The glucose stimulated respiration and the uptake of 2-deoxy-D[U-14C]-glucose was inhibited in cells treated with the drug at a growth inhibitory concentration. An immediate release of isotopic glucose from preloaded cells could be demonstrated after exposure to hamycin. All the above effects could be effectively prevented in the presence of ergosterol. The primary site of action of hamycin on L. donovani promastigote cells appears to be membrane sterols that result in the loss of the permeability barrier to small metabolites. The lower minimum inhibitory concentration of hamycin compared to other established drugs warrants further study in the context of increasing reports of clinical resistance to pentavalent antimonials.

Amphotericin B↗
PubMed1975

Quantitative thin-layer spectrodensitometric determination of the components of polyene macrolide antibiotice complexes.

A direct spectrodensitometric method for quantitating the components of polyene macrolide complexes after separation by thin-layer chromatography is described. Resolution of the components of the candidin and candihexin complexes was good up to 2.5 and 10 mu-g/spot, respectively. The peak areas were linear with the amount spotted up to the same levels. Maximum peak areas for the components of the candidin and candihexin complexes were obtained using light wavelengths of 360 and 340 nm, respectively. Spotting errors rather than instrumental parameters were responsible for the variance of repeated determinations. Minimal relative standard deviation values were found at intermediate concentration levels in the linear range.

Anti-Bacterial Agents↗
PubMed1999

Experimental studies (in vitro) on polyene macrolide antibiotics with special reference to hamycin against Malassezia ovale.

Hamycin activity (in vitro) against Malassezia ovale was studied and compared with old and newly discovered polyene antifungal antibiotics. Hamycin showed a marked anti-M. ovale activity which was enhanced in the presence of divalent cations like Cu++ and Zn++. Furthermore, the absorption of hamycin onto the cell membrane or cell surface of M. ovale was also increased in the presence of divalent cations. It is suggested that hamycin alone or along with metal ions, specifically Cu++ may be useful clinically in the treatment of dandruff or seborrheic dermatitis.

Amphotericin B↗
PubMed1984

Fibroblasts from patients with myotonic muscular dystrophy: cholesterol requirement for proliferation and sensitivity to polyene antibiotics.

The genetic defect in myotonic muscular dystrophy (MMD) remains obscure. From the evidence that drugs blocking cholesterol biosynthesis induce myotonia and increased serum concentrations of deoxycholic acids are common among patients with MMD, evidence of the abnormal sterol metabolism in MMD fibroblasts was sought by comparing them with fibroblasts from control individuals and patients with Duchenne muscular dystrophy (DMD). Although early-onset type MMD and DMD fibroblasts have lower maximal cell densities than fibroblasts from age-matched control individuals do in medium containing 10% fetal bovine serum, we could not reveal any abnormalities in exogeneous cholesterol requirements for proliferation of MMD fibroblasts. This suggests that the sterol biosynthetic pathway in MMD fibroblasts is grossly intact. Furthermore, no difference were observed in sensitivities to polyene antibiotics, which bind to membrane sterols and presumably damage the cell membrane.

Adolescent↗
PubMed1996

Polyenes and vision.

Polyenes are important for vision in all sighted species. The visual pigments (the rhodopsins) all use 11-cis-retinal as the chromophore; some possible reasons for the importance of this isomer are now emerging. New results on the involvement of xanthophils in the maintenance of the retina are also discussed.

Humans↗
PubMed2006

Acetonitrile covalent adduct chemical ionization mass spectrometry for double bond localization in non-methylene-interrupted polyene fatty acid methyl esters.

Covalent adduct chemical ionization (CACI) using a product of acetonitrile self-reaction, (1-methyleneimino)-1-ethenylium (MIE; CH2=C=N+=CH2), has been investigated as a method for localizing double bonds in a series of 16 non-methylene-interrupted fatty acid methyl esters (NMI-FAME) of polyenes with three and more double bonds. As with polyunsaturated homoallylic (methylene-interrupted) FAME and conjugated dienes, MIE (m/z 54) reacts across double bonds to yield molecular ions 54 mass units above the parent analyte. [M + 54]+ ions of several 20- and 22-carbon FAME that include one double bond in the C2-C3 position separated by two to five methylene units from a three, four, or five C homoallylic system dissociated according to rules for the homoallylic system, with an additional fragment corresponding to cleavage between the lone double bond and the carboxyl group and defining the position of the lone double bond. Triene FAME with both methylene and ethylene interruption yielded characteristic fragments distinguishable from homoallylic trienes. Fragmentation of fully conjugated trienes in the MS-1 spectra yields ratios of [M + 54]+/[M + 54 - 32]+ (loss of methanol) near unity, which distinguishes them from homoallylic FAME having a ratio of 8 or more; collisionally activated dissociation of [M + 54]+ yields a series of ions, including some rearrangement products, indicative of double bond position. Unlike conjugated dienes, fully conjugated triene diagnostic ion signal ratios did not follow any pattern based on double bond geometry. Partially conjugated trienes behave similarly to monoenes and conjugated dienes, yielding [M + 54]+/[M + 54 - 32]+ of 2-3 and, permitting them to be assigned as partially conjugated FAME using the MS-1 spectrum. They yield unique MS/MS spectra with weaker but assignable fragment ions, along with a diagnostic fragment that locates the lone double bond and permits 6,10,12-octatrienoate to be distinguished from 6,8,12-octatrienoate. The presence of a triple bond did not affect fragment formation in a methylene-interrupted yne-ene but did change fragments in a conjugated yne-ene. These data extend the principle of double bond localization by acetonitrile CACI-MS/MS to double bond structure in complex FAME found in nature.

Acetonitriles↗
PubMed1977

Conjugated polyene fatty acids on fluorescent probes: spectroscopic characterization.

This paper is the first in a series which extends introductory studies of parinaric acid and its phospholipid derivatives as membrane probes (Sklar, L.A., Hudson, B., and Simoni, R.D. (1975), Proc. Natl. Acad. Sci. after U.S.A. 72, 1649; (1976), J. Supramol. Struct. 4, 449). Parinaric acid has a conjugated tetraene chromophore and exhibits many spectroscopic properties common to linear polyenes. Its absorption spectrum is characterized by a strong near-ultraviolet transition with vibronic structure, which is strongly affected by solvent polarizability. The fluorescence emission occurs at considerably lower energy than the absorption and the wavelength of the emission is nearly independent of the solvent. The fluorescence quantum yield and lifetime are strongly affected by temperature and solvent. These spectral features are interpreted in terms of an excited electronic-state order such that a weak transition occurs at longer wavelengths than the strongly allowed transition which dominates the absorption. The sensitivity of the fluorescence quantum yield an lifetime to environment is shown to be due primarily to variations in the nonradiative rate, although changes in the radiative rate constant are also observed and interpreted. The absorption spectrum (epsilon max greater than 65 000) is in the 300-320-nm range, a region relatively free of absorption due to intrinsic biological chromophores. Shifts of several nanometers are characteristic of different environments. These shifts are compared to similar effects observed for a series of diphenylpolyenes for which new data are given and are correlated using a simple but adequate theory of solvent shifts. The intrinsic (or radiative) fluorescence lifetime is near 100 ns in a wide variety of environments. This is much longer than the intrinsic lifetime calculated from the absorption spectrum and strongly supports the proposed excited-state order.

Fatty Acids, Unsaturated↗
PubMed1977

Conjugated polyene fatty acids as fluorescent probes: synthetic phospholipid membrane studies.

The preparation of polyene fatty acid membrane probes cis- and trans-parinaric acid and parinaroylphosphatidylcholines and their use in studies of several one- and two- component lipid systems are described. The fluorescence quantum yield of trans-parinaric acid in dipalmitoylphosphatidylcholine at 20 degrees C is approximately 0.3; the quantum yield in aqueous solution is negligibly small. Thermal-phase transitions in single-component phospholipid dispersions are monitored with absorption and fluorescence excitation peak position, fluorescence intensity, lifetime, and polarization. The transition temperatures observed are consistent with previous determinations. Shifts in the absorption peak position are related to the bilayer expansion as it undergoes the gel to liquid-crystalline transition, while fluorescence depolarization provides semiquantitative information concerning molecular motion of the probe in the bilayer. A long fluorescence lifetime component is observed for parinaric acid in the solid phase (up to 50 ns), and a short lifetime component is observed (ca. 5 ns) in the fluid phase of dipalmitoylphosphatidylcholine; both lifetime components are observed in the transition region. In most phospholipids, cis-parinaric acid detects the melting transition at about 1 degree C lower than trans-parinaric acid. Partitioning experiments involving mixed populations of phospholipid vesicles show that trans-parinaric acid preferentially associates with solid-phase lipids, while cis-parinaric acid shows a more equal distribution between solid and fluid lipids. The binding of cis-parinaric acid to dipalmitoylphosphatidylcholine at 25 degrees C is described as partitioning of parinaric acid between lipid vesicles and the aqueous phase with a partition coefficient of 5 X 10(5). Several rates are observed in the binding process which are interpreted as rapid outer monolayer uptake and a much slower process of interlamellar exchange. The phase diagram of the binary lipid mixture dipalmitoylphosphatidylcholine-dipalmitoylphosphatidylethanolamine has also been examined and found to be essentially identical to the one constructed using a nitroxide probe.

Fatty Acids, Unsaturated↗
PubMed2002

Relative orientation between the beta-ionone ring and the polyene chain for the chromophore of rhodopsin in native membranes.

Rotational resonance solid state nuclear magnetic resonance has been used to determine the relative orientation of the beta-ionone ring and the polyene chain of the chromophore 11-Z-retinylidene of rhodopsin in rod outer segment membranes from bovine retina. The bleached protein was regenerated with either 11-Z-[8,18-(13)C(2)]retinal or 11-Z-[8,16/17(13)C(2)]retinal, the latter having only one (13)C label at either of the chemically equivalent positions 16 and 17. Observation of (13)C selectively enriched in the ring methyl groups, C16/17, revealed alternative conformational states for the ring. Minor spectral components comprised around 26% of the chromophore. The major conformation (approximately 74%) has the chemical shift resolution required for measuring internuclear distances to (13)C in the retinal chain (C8) separately from each of these methyl groups. The resulting distance constraints, C8 to C16 and C17 (4.05 +/- 0.25 A) and from C8 to C18 (2.95 +/- 0.15 A), show that the major portion of retinylidene in rhodopsin has a twisted 6-s-cis conformation. The more precise distance measurement made here between C8 and C18 (2.95 A) predicts that the chain is twisted out-of-plane with respect to the ring by a modest amount (C5-C6-C7-C8 torsion angle = -28 +/- 7 degrees ).

Animals↗
PubMed2006

Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

Animals↗
PubMed2003

Structure elucidation of polyene systems with extensive charge delocalization-carbocations from allylic carotenols.

[structure: see text] The structures of two diastereomeric cations, readily prepared from beta, beta-caroten-4-ol (1) by treatment with trifluoroacetic acid, have been determined by NIR and NMR spectroscopy, resulting in the complete structure elucidation of the most extensively delocalized carbocations so far described. Higher partial charge was observed toward the center of the polyene chain (larger filled red circles). Bond reversion occurs in the central region of the molecule.

Carotenoids↗