Isoprenyl Side Chain Research Articles

Synthesis of Coenzyme Q10

Problem statement: CoQ10 is a key compound in ATP synthesis having wide number of health application especially for treating humans suffering from pathophysiological condition. The CoQ10 presently available in the market is solely derived from fermentation process. A commercially viable synthetic process is yet to be realized. Approach: The researchers described a new synthetic route for the preparation of CoQ10 (1). This new process utilized inexpensive isoprenol as a precursor for the synthesis of an early intermediate with a single isoprene unit. Another key step was the selective oxidation of trans methyl of isoprene unit as a prelude to the expansion of the side chain to decaprenyl group using solanesol. Results: Prenylation of 2, 3-dimethoxy-5-methylhydroquinone using isoprenol in presence of a Lewis acid, followed by selective oxidation of trans methyl group of isoprenyl side chain and subsequent allylic bromination yielded a bromide precursor (7). The p-toluenesulfination of the bromide followed by coupling with solanesyl bromide and de-p-toluenesulfination yielded dimethyl derivative of the CoQ10-quinol. Finally CAN oxidation of dimethyl quinol followed by purification yielded CoQ10 in 13% overall yield. Conclusion: The present process achieved CoQ10 starting from a relatively inexpensive precursor. Further improvement in the coupling reaction between 8 and solanesyl bromide may lead to a better and viable synthetic process.

Three Cyclized Isoprenylated Flavonoids from the Roots and Rhizomes of Sophora tonkinensis

AbstractTwo new flavanones, tonkinochromanes D (1) and E (2), and a new chalcone, tonkinochromane F (3), were isolated from the roots and rhizomes of Sophora tonkinensis. Their structures were elucidated by spectroscopic methods, including 2D‐NMR and circular‐dichroism (CD) techniques, in combination with HR‐MS analysis. Compounds 1–3, as well the previously reported tonkinochromanes A–C, were shown by LC‐MS analysis to be ‘artifacts’ resulting from acid‐catalyzed electrophilic cyclization of isoprenyl side chains during extraction.

Synthesis and structure–activity relationships of novel warfarin derivatives

4-Hydroxycoumarins such as warfarin 1 have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about the molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition of which produces a deficiency of vitamin K and consequently a deficiency of vitamin K-dependent proteins involved in thrombus formation. Using molecular probes, such as 4-sulfhydrylwarfarin 7 and 4-chlorowarfarin 10 it is shown in vitro that inhibition of VKER by warfarin is dependent on deprotonation of the 4-hydroxycoumarin moiety. In addition, the nature of the substituent on carbon 3 of the 4-hydroxycoumarin modulated inhibition. More specifically, a linear isoprenyl side chain increased inhibition of VKER when compared to cyclical substituents as present in warfarin. An example of a 4-hydroxycoumarin with an isoprenyl side chain is the natural product ferulenol 19 derived from Ferula communis. Ferulenol 19 confers ∼22 times more potent inhibition than warfarin and is ∼1.5 more potent than the rodenticide brodifacoum in this in vitro assay. Based on these data it is hypothesized that 4-hydroxycoumarins bind to the active site of VKER thereby mimicking the transition state of the elimination of water from substrate 2-hydroxyvitamin K.

Remarkable substrate‐specificity of CYP6AB3 in Depressaria pastinacella, a highly specialized caterpillar

The parsnip webworm, Depressaria pastinacella, a specialist on two genera in Apiaceae, feeds exclusively on the furanocoumarin-containing reproductive structures of its host plants. This caterpillar relies principally on cytochrome P450-mediated detoxification for coping with the high concentrations of furanocoumarins in its diet. A cDNA encoding the furanocoumarin-inducible P450 CYP6AB3 from this species was coexpressed with house-fly NADPH P450 reductase in baculovirus-infected Sf9 cells and tested for binding and metabolism of the six furanocoumarins typically encountered in host plant tissues. Only imperatorin and bergapten bind in close proximity to the catalytic haem and only imperatorin is metabolized (V(max) and K(m) of 2.412 pmol/min per pmol P450 and 94.28 microm, respectively). Purification of the imperatorin metabolite by normal phase HPLC and characterization of its structure by MS-MS analysis indicate that CYP6AB3 initially epoxidizes the carbon-carbon pi-bond on the isoprenyl side chain on imperatorin. An improved molecular model for the CYP6AB3 protein based on this biochemical characterization and the recently defined mammalian CYP3A4 crystal structure provides insight into the remarkable substrate specificity of this protein.

Antimicrobial Butyrolactone I Derivatives from the Ecuadorian Soil Fungus Aspergillus terreus Thorn. var terreus

The fungus Aspergillus terreus Thorn var. terreus isolated from an Ecuador soil sample was cultured in liquid and solid media and yielded three main metabolites identified as terreic acid (1), butyrolactone I (2) and lovastatin (3). The natural products as well as three synthetic butyrolactone I derivatives were assessed for antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi as well as for seed germination and seedling growth. Furthermore, the compounds were assessed as inhibitors towards the enzymes acetylcholinesterase, β-glucosidase, and β-glucuronidase. Terreic acid, butyrolactone I, butyrolactone 4′,4′′-diacetate (2.1), and 3′-(3-methylbutyl)-butyrolactone II (2.2) were active towards the phytopathogenic bacteria Erwinia carotovora with IC50 of 5 and 4–18 μg/ml, respectively. Under the same experimental conditions, the IC50 of streptomycin was 1.9 μg/ml. 3′-(3-Methylbutyl)-butyrolactone II was moderately active against Pseudomonas syringae and Botrytis cinerea with IC50 of 21μg/ml and MIC of 15.6 μg/ml, respectively. Butyrolactone I also inhibited germination of the dicot Lactuca sativa with an IC50 of 5 × 10−5 M. The IC50 of reference herbicide acetochlor was 1 × 10−5 M. The effect of 2.2 and 2.3, known as butyrolactone III on Panicum millaceum germination and growth was stronger than that of 2 and 2.1. Reduction of the double bond in the isoprenyl side chain of butyrolactone I increased the antibacterial effect against E. carotovora as well as acetylation. To our best knowledge, this is the first report on the antibacterial effect of butyrolactone derivatives towards Erwinia carotovora and the phytopathogenic fungus Botrytis cinerea. The butyrolactone I derivative 2.2 presented a moderate inhibitory effect against the enzyme acetylcholinesterase with an IC50 of 47 μg/ml. Under the same experimental conditions, the reference inhibitor galanthamine had an IC50 of 3 μg/ml.

Acylphloroglucinol Derivatives from Mahurea palustris

Five new acylphloroglucinol derivatives, mahureones A-E (1, 3-6), have been isolated from the leaves of Mahurea palustris, and their structures determined by spectroscopic means. During the isolation process, several byproducts (7-9) were formed by reaction of one of the isoprenyl side chains with TFA, water, and acetonitrile. All the compounds were assayed for their ability to inhibit human DNA polymerase beta. The most active compounds, mahureones A (1) and D (5), exhibited IC50 values in the 10 microM range.

Electrogenic proton transfer in Rhodobacter sphaeroides reaction centers: effect of coenzyme Q 10 substitution by decylubiquinone in the Q B binding site

An electrometric technique was used to investigate the effect of coenzyme Q 10 (UQ), substitution by decylubiquinone (dQ) at the Q B binding site of reaction centers (UQ-RC and dQ-RC, respectively) on the electrogenic proton transfer kinetics upon Q B reduction in Rhodobacter sphaeroides chromatophores. Unlike dQ-RC, the kinetics of the second flash-induced proton uptake in UQ-RC clearly deviated from the mono-exponential one. The activation energy (about 30 kJ/mol) and the pH profile of the kinetics in dQ-RC were similar to those in UQ-RC, with the power law approximation used in the latter case. The interpretation of the data presumed the quinone translocation between the two binding positions within the Q B site. It is proposed that the native isoprenyl side chain (in contrast to decyl chain) favors the equilibrium binding of neutral quinone at the redox-active ‘proximal’ position, but causes a higher barrier for the hydroquinone movement from ‘proximal’ to ‘distal’ position.

Structure of mangostin

The crystal structure of 1,3,6-trihydroxy-2,8-bis (3-methyl-2-butenyl)-9H-xanthen-9-one, Mangostin (C24H26O6) isolated from the fruit hulls of Garcinia mangostana, Guttiferae is reported. The compound crystallizes in space group $$P\bar 1 $$ , with cell parametersa = 11.194(5), b = 13.450(5), c = 9.875(5) A, α = 108.13(5), β = 108.13(5), γ = 99.64(5)°. The mean planes of the two isoprenyl side chains are oriented at an angle 49.6° in this structure while it is 159.8(2)° in mangostin acetate. The packing of the molecules is due to the solvent mediated network of hydrogen bonds. The conformation and packing of molecules are also different from mangostin acetate.

Structures and Properties of Ubiquinone-1 and Its Radical Anion from Hybrid Hartree−Fock/Density Functional Studies

Ubiquinones and their semiquinone radical anionselectron transfer cofactors vital for respiration and photosynthesisare typically characterized in proteins by measuring their vibrational or electron spin resonance spectra. This contribution presents calculated geometries and spin properties for ubiquinone-1 (UQ1) and its radical anion (UQ1•-), as well as vibrational frequencies for a model with the methyl groups on the isoprenyl side chain of UQ1 replaced by hydrogens (UQ and UQ•). Computations were done by using the hybrid Hartree−Fock/density functional B3LYP method with the 6-31G(d) and [632|41] basis sets. Bond distance changes upon reducing UQ1 to UQ1•- are qualitatively consistent with results for other p-benzoquinones. Proton and 13C hyperfine coupling constants calculated by using Chipman's [632|41] basis set agree exceptionally well with experimental measurements and reflect the distribution of unpaired spin. We suggest isotopic substitution experiments to resolve the nearly overlapping CO and CC stretching frequencies calculated for UQ and to shift methoxy and/or methyl CH bending modes away from one CO stretching band of UQ•-.

Novel prenylated hemes as cofactors of cytochrome oxidases. Archaea have modified hemes A and O.

A series of novel hemes with modifications of the isoprenyl side chain has been detected in archaea. Heme A(S) was isolated from cytochrome oxidases of the thermoacidophilic archaeon, Sulfolobus acidocaldarius. Heme A(S) has the same spectroscopic features as heme A but has a hydroxyethylgeranylgeranyl side chain instead of the hydroxyethylfarnesyl group. This variant is also present in other archaeal oxidases as well as in the cytochrome oxidases of a thermophilic eubacterium. Other archaea (Thermoplasma, Pyrobaculum) were also shown to have cytochrome oxidases. From these organisms, three novel prenylated heme variants (called OT, OP1, and OP2) were isolated. They are structurally related to heme O; OP2 has a hydroxyethylgeranylgeranyl instead of the hydroxyethylfarnesyl side chain. In OP1 and OT, the hydroxyethylprenyl group is altered to ethenylprenyl by elimination of a water molecule. Most probably, the novel hemes are cofactors binding to the binuclear reaction centers of archaeal cytochrome oxidases.

Investigations on the influence of headgroup substitution and isoprene side-chain length in the function of primary and secondary quinones of bacterial reaction centers

The contributions of headgroup and side-chain in the binding and function of the primary (Q A) and secondary (Q B) quinones of isolated reaction centers (RCs) from Rhodobacter sphaeroides were investigated. Various ubiquinones and structurally similar quinones were reconstituted into RCs depleted of one (1Q-RCs) or both (0Q-RCs) quinones. The influence of partition coefficients on the apparent binding affinities was minimized by expressing dissociation constants in terms of the mole fraction of quinone partitioned into the detergent. It was then apparent that the size of the isoprenyl side-chain was of little consequence in determining the binding affinity or the functional competence of either Q A or Q B, although an alkyl chain of equivalent size was a poor substitute. The degree of substitution of the headgroup, however, was a sensitive determinant of binding. For both quinone sites, the trisubstituted plastoquinones bound more weakly than the fully substituted ubiquinones. Similarly, for binding to the Q A site, duroquinone (tetramethylbenzoquinone) bound much more strongly than trimethylbenzoquinone. The affinity of the Q A site for ubiquinones was about 20-times stronger than the Q B site, but the Q B site is probably not more specific than the Q A site. However, Q B function depends on a suitable redox free-energy drop from Q A as well as binding, and of all the quinones tested only the ubiquinones simultaneously supported full Q A and Q B activity. Even plastoquinone-A, which fills both roles in Photosystem II, was unable to do so in bacterial RCs, although it did bind. The unique ability of ubiquinones to both bind and provide the appropriate redox span is discussed. The temperature dependence of binding of the isoprenyl ubiquinones at the Q A site changed markedly with chain length. For Q-10-Q-7, the binding enthalpy was positive and net binding was entirely driven by entropic factors. For the shorter-chain ubiquinones, Q-6-Q-1, both entropy and enthalpy of binding were favorable. This strong entropy-enthalpy compensation is suggested to arise from antagonistic interactions (anticooperativity) between headgroup and tail binding. For Q B function by hydrophobic quinones, the temperature dependence of the micelle properties prevented easy access to thermodynamic parameters. However, for water-soluble Q-0, binding to the Q B site was determined to be enthalpically driven. In the isoprenyl ubiquinone series, the electron transfer equilibrium for Q − AQ B ↔ Q AQ − B declined gradually as the side-chain was shortened from 7 to 1 isoprene unit, in both 0Q and 1Q-RCs, implying that the in situ redox midpoint potential in the Q B site decreased with decreasing side-chain length.

A rapid screening method for acute drug poisoning (II) : Hara A, Adachi S, Horiuchi T, et al. Jpn J Acute Med 1988;12:1641–1647

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id1"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id1"><ce:simple-para id="fsabs067" view="all">The term ubiquinone comprises fat-soluble benzoquinones differing in the length of the isoprenyl side chain. Ubiquinone-1O (Q10) is needed for the electron transport of oxidative phosphorylation, is a cofactor of pyrimidine nucleotide synthesis, aids nitric oxide recycling, and acts as an intracellular antioxidant. Most ubiquinone-l0 is consumed with meat and poultry, and some germ oils. Normally adequate amounts are synthesized endogenously requiring sufficient availability of tyrosine and unrestricted isoprenyl synthesis. Genetically low synthesis can cause muscle weakness, fatigability, mental impairment, and seizures. In some circumstances, such as heart failure and during treatment with HMG-CoA reductase inhibitors (statins), endogenous production may not be adequate, and additional dietary intakes of up to 30 mg/d may be beneficial. Supplementation with 100 mg ubiquinone-10/day has been used for up to six years without adverse effects. QI10 appears to be absorbed intact from the intestine, but neither the exact location nor the extent or mechanism is known. Complex I of the oxidative phosphorylation system is the electron-transferring-flavoprotein dehydrogenase, which catalyzes the electron transfer from primary flavoprotein dehydrogenases in the mitochondrial matrix to Q10 in the inner membrane.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

Vitamin K composition of anaerobic gut bacteria

The menaquinone (vitamin K2) composition of a wide range of obligately anaerobic bacteria was investigated using chromatographic and physicochemical techniques. Members of the genera Bifidobacterium, Butyrivibrio, Clostridium, Fusobacterium, Lachnospira, Megasphaera, Propionispira, Ruminococcus, Selenomonas, Succinovibrio and Succinomonas were found to lack menaquinones, In contrast, all species of the genera Actinomyces, Arachnia, Bacteroides, Propionibacterium, Veillonella and Wolinella examined possessed menaquinones. Considerable variation in length and degree of saturation of the C-3 isoprenyl side-chains of the menaquinones isolated from these taxa were evident. In addition to menaquinone, strains of Wolinella and Eubacterium lentum contained methylated menaquinones. The possible contribution of bacterial menaquinones to the total pool of vitamin K in the human gut is discussed.

Vitamin K composition of anaerobic gut bacteria

The menaquinone (vitamin K2) composition of a wide range of obligately anaerobic bacteria was investigated using chromatographic and physicochemical techniques. Members of the genera Bifidobacterium, Butyrivibrio, Clostridium, Fusobacterium, Lachnospira, Megasphaera, Propionispira, Ruminococcus, Selenomonas, Succinovibrio and Succinomonas were found to lack menaquinones, In contrast, all species of the genera Actinomyces, Arachnia, Bacteroides, Propionibacterium, Veillonella and Wolinella examined possessed menaquinones. Considerable variation in length and degree of saturation of the C-3 isoprenyl side-chains of the menaquinones isolated from these taxa were evident. In addition to menaquinone, strains of Wolinella and Eubacterium lentum contained methylated menaquinones. The possible contribution of bacterial menaquinones to the total pool of vitamin K in the human gut is discussed.

New members of the Coenzyme Q series from the Legionellaceae

Since the discovery of Legionella pneumophila, the causative agent of Legionnaires disease, two other groups of fastidious bacteria have been isolated which share many phenotypic characteristics with L. pneumophila [1-7] which have been referred to as Atypical Legionella-Like Organisms (ALLO) [2]. One group contains strains known as the Pittsburgh pneumonia agent (PPA) [6] and the Tatlock strain [8], for which the name Tatlockia micdadei has been proposed [4]. Members of the second group are serologically and genetically more diverse [2,3,7]. The name Fluoribacter [4] has been proposed for the latter group, and presently three species F. bozemanae, F. dumoffii and F. gormanii are recognised [4,7]. The taxonomic interrelationships of Legionella, Tatlockia and Fluoribacter are, however, equivocal, and additional criteria are required to tighten the generic and species descriptions. Ubiquinones (Coenzyme Q) are constituents of bacterial plasma membranes, and play an important role in electron transport and oxidative phosphorylation. Furthermore, recent studies have indicated that the structural variations exhibited by these compounds are of value in bacterial classification (see [9] for review). Ubiquinones, 2,3-dimethoxy-5-methyl-6-polyprenyl1,4-benzoquinones form a relatively large homologous series in which the length of the C-6 isoprenyl side-chain may vary from 1 to up to 12 isoprene units (Fig. 1). The major constituents of bacterial ubiquinones have been shown however to possess between 7 and 10 isoprene units (i.e. n = 7 to 10, Fig. 1) [9]. Recently, Finnerty et al. [10] reported Legionella pneumophila possessed ubiquinones as its sole respiratory quinones. Although the detailed structure of the ubiquinones of L. pneumophila was not determined, the authors noted that it possessed a side-chain containing more than 10 isoprene units [10]. This report is of considerable interest, as ubiquinone isoprenologues with more than 10 isoprene units have been found previously only in small amounts in a Pseudomonas sp. [11] and trace amounts in certain photosynthetic bacteria [ 12,13]. In this paper we report the structure of the ubiquinones of L. pneumophila. The opportunity was taken to also determine the ubiquinone content of other Legionella species, and representatives of the genera Fluoribacter and Tatlockia.