Epoxide Moiety Research Articles

The juvenile hormone (JH) epoxide hydrolase gene in the honey bee ( Apis mellifera) genome encodes a protein which has negligible participation in JH degradation

Epoxide hydrolases are multifunctional enzymes that are best known in insects for their role in juvenile hormone (JH) degradation. Enzymes involved in JH catabolism can play major roles during metamorphosis and reproduction, such as the JH epoxide hydrolase (JHEH), which degrades JH through hydration of the epoxide moiety to form JH diol, and JH esterase (JHE), which hydrolyzes the methyl ester to produce JH acid. In the honey bee, JH has been co-opted for additional functions, mainly in caste differentiation and in age-related behavioral development of workers, where the activity of both enzymes could be important for JH titer regulation. Similarity searches for jheh candidate genes in the honey bee genome revealed a single Amjheh gene. Sequence analysis, quantification of Amjheh transcript levels and Western blot assays using an AmJHEH-specific antibody generated during this study revealed that the AmJHEH found in the fat body shares features with the microsomal JHEHs from several insect species. Using a partition assay we demonstrated that AmJHEH has a negligible role in JH degradation, which, in the honey bee, is thus performed primarily by JHE. High AmJHEH levels in larvae and adults were related to the ingestion of high loads of lipids, suggesting that AmJHEH has a role in dietary lipid catabolism.

Iron-Catalyzed Regio- and Stereoselective Substitution of γ,δ-Epoxy-α,β-unsaturated Esters and Amides with Grignard Reagents

When gamma,delta-epoxy-alpha,beta-unsaturated esters or amides were treated with 2 equiv of Grignard reagents in the presence of 10-24 mol % FeCl(2), regio- and stereoselective substitution of the epoxide moiety with the Grignard reagent occurred to give exclusively delta-hydroxy-gamma-alkyl or aryl-alpha,beta-unsaturated esters or amides in good yields.

Linking an insect enzyme to hypertension: angiotensin II–epoxide hydrolase interactions

Derived from arachidonic acid, epoxyeicosatrienoic acids function as antihypertensive and antihypertrophic mediators in the cardiovascular system. Epoxyeicosatrienoic acids are generated by soluble epoxide hydrolase, an enzyme hydrolyzing the epoxide moiety of juvenile hormones in insects, and are endothelium-derived hyperpolarizing factors that induce vessel dilation for cardioprotection. Pharmacological inhibition and genetic ablation of soluble epoxide hydrolase increases the level of epoxyeicosatrienoic acids. Recent findings suggest that the level of soluble epoxide hydrolase in the heart and endothelium is upregulated by angiotensin II in vitro in cultured cardiomyocytes and vascular endothelial cells and in vivo in rodent models. Treatment with soluble epoxide hydrolase-selective inhibitors in angiotensin II-infused hypertensive rats increases the level of epoxyeicosatrienoic acids, with attendant decrease in systolic blood pressure. Shear stress, the physiological stimulation of vessel dilation, downregulates soluble epoxide hydrolase and hence increases epoxyeicosatrienoic acid level in endothelial cells. Because of the close association of the angiotensin II/soluble epoxide hydrolase/epoxyeicosatrienoic acid system and blood pressure regulation, pharmacological inhibition of soluble epoxide hydrolase would be a useful approach to prevent and treat angiotensin II-induced cardiac hypertrophy and hypertension, as well as vascular impairments.

First Use of HEH in Oxazine Synthesis: Hydroxy-Substituted 2H-1,4-Benzoxazine Derivatives

The synthesis of 2H-1,4-benzoxazine derivatives from 1,2-epoxy-3-(2-nitroaryloxy)propanes in the presence of Hantzsch 1,4-dihydropyridine (HEH) and Pd/C as a catalyst was achieved. The nitro group was reduced before the epoxide functionality, leading to attack of the amino group on the epoxide moiety in a 6-exo-fashion. By introducing a methyl group at the 1-position, the 7-endo ring-closed product could also be formed.

Dendritic Polystyrene with Hydroxyl-Functionalized Branch Points by Convergent Living Anionic Polymerization

Dendritic polystyrene with hydroxyl functional groups at each branch point was synthesized using convergent living anionic polymerization. The polymer samples were formed by the slow addition of a 1/10 molar mixture of 4-vinylstyrene oxide/styrene to living polystyryllithium chains in a benzene/THF solution. The 4-vinylstyrene oxide contains both a vinyl group, which can undergo anionic vinyl addition polymerization, and an epoxide moiety, which can undergo a ring-opening addition reaction to result in an unreactive or terminated lithium alkoxide. The extent of generational growth for the dendritic polymers was calculated by molecular weight analysis and by titration of hydroxyl groups to determine generations as high as 3.8 and polymers with up to 14 hydroxyl groups situated at the branch points. Addition of LiCl to the benzene/THF solutions containing polystyryllithium chains resulted in the highest generational growth of the polymers. The polymers were characterized using gel permeation chromatography coupled with a MALLS detector, 1H NMR spectroscopy, and differential scanning calorimetry.

Microtubule Binding and Disruption and Induction of Premature Senescence by Disorazole C1

Disorazoles comprise a family of 29 macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. The major fermentation product, disorazole A(1), was found previously to irreversibly bind to tubulin and to have potent cytotoxic activity against tumor cells, possibly because of its highly electrophilic epoxide moiety. To test this hypothesis, we synthesized the epoxide-free disorazole C(1) and found it retained potent antiproliferative activity against tumor cells, causing prominent G(2)/M phase arrest and inhibition of in vitro tubulin polymerization. Furthermore, disorazole C(1) produced disorganized microtubules at interphase, misaligned chromosomes during mitosis, apoptosis, and premature senescence in the surviving cell populations. Using a tubulin polymerization assay, we found disorazole C(1) inhibited purified bovine tubulin polymerization, with an IC(50) of 11.8 +/- 0.4 microM, and inhibited [3H]vinblastine binding noncompetitively, with a K(i) of 4.5 +/- 0.6 microM. We also found noncompetitive inhibition of [3H]dolastatin 10 binding by disorazole C(1), with a K(i) of 10.6 +/- 1.5 microM, indicating that disorazole C(1) bound tubulin uniquely among known antimitotic agents. Disorazole C(1) could be a valuable chemical probe for studying the process of mitotic spindle disruption and its relationship to premature senescence.

Synthesis of Pluraflavin A “Aglycone”

The "aglycone" of pluraflavin A (2) has been synthesized. The key features of this synthesis include a 1,3-dipolar cycloaddition between a nitrile oxide (cf. 14) and an olefin (22) to yield an isoxazoline followed by subsequent conversion into the gamma-pyrone of pluraflavin A. The epoxide moiety linked to the pyrone is installed prior to Diels-Alder installation of the D ring, which allows access to a number of potentially active cytotoxic intermediates en route to the final compound. The preliminary in vitro results of two such compounds are also included with the racemic title compound exhibiting cytotoxicity in the nanomolar range.

Synthesis of Protected Hydroxyethylamine Transition-State Analogs of N-Ac-Muramyl-L-alanine

A novel N-acetyl-α-D-glucosamine derivative containing an epoxide moiety 5 has been synthesized and converted into a series of protected hydroxyethylamine transition-state analogs of N-Ac-muramyl-L-ala peptide 6a–e using a microwave-accelerated reaction.

The Potential of Soluble Epoxide Hydrolase Inhibition in the Treatment of Cardiac Hypertrophy

The Potential of Soluble Epoxide Hydrolase Inhibition in the Treatment of Cardiac Hypertrophy

Characterization of the Azinomycin B Biosynthetic Gene Cluster Revealing a Different Iterative Type I Polyketide Synthase for Naphthoate Biosynthesis

Azinomycin B is a complex natural product containing densely assembled functionalities with potent antitumor activity. Cloning and sequence analysis of the azi gene cluster revealed an iterative type I polyketide synthase (PKS) gene, five nonribosomal peptide synthetases (NRPSs) genes and numerous genes encoding the biosynthesis of unusual building blocks and tailoring steps for azinomycin B production. Characterization of AziB as a 5-methyl-naphthoic acid (NPA) synthase showed a distinct selective reduction pattern in aromatic polyketide biosynthesis governed by bacterial iterative type I PKSs. Heterologous expression established the PKS-post modification route from 5-methyl-NPA to reach the first building block 3-methoxy-5-methyl-NPA. This proposed azinomycin B biosynthetic pathway sets the stage to investigate the enzymatic mechanisms for building structurally unique and pharmaceutically important groups, including the unprecedented azabicyclic ring system and highly active epoxide moiety.

Polyisoprenoid Epoxides Stimulate the Biosynthesis of Coenzyme Q and Inhibit Cholesterol Synthesis

In our search for compounds that up-regulate the biosynthesis of coenzyme Q (CoQ), we discovered that irradiation of CoQ with ultraviolet light results in the formation of a number of compounds that influence the synthesis of mevalonate pathway lipids by HepG2 cells. Among the compounds that potently stimulated CoQ synthesis while inhibiting cholesterol synthesis, derivatives of CoQ containing 1-4 epoxide moieties in their polyisoprenoid side chains were identified. Subsequently, chemical epoxidation of all-trans-polyprenols of different lengths revealed that the shorter farnesol and geranylgeraniol derivatives were without effect, whereas the longer derivatives of solanesol enhanced CoQ and markedly reduced cholesterol biosynthesis. In contrast, none of the modified trans-trans-poly-cis-polyprenols exerted noticeable effects. Tocotrienol epoxides were especially potent in our system; those with one epoxide moiety in the side-chain generally up-regulated CoQ biosynthesis by 200-300%, whereas those with two such moieties also decreased cholesterol synthesis by 50-90%. Prolonged treatment of HepG2 cells with tocotrienol epoxides for 26 days elevated their content of CoQ by 30%. In addition, the levels of mRNA encoding enzymes involved in CoQ biosynthesis were also elevated by the tocotrienol epoxides. The site of inhibition of cholesterol synthesis was shown to be oxidosqualene cyclase. In conclusion, epoxide derivatives of certain all-trans-polyisoprenoids cause pronounced stimulation of CoQ synthesis and, in some cases, simultaneous reduction of cholesterol biosynthesis by HepG2 cells.

Reactivity of Fullerene Epoxide: Preparation of Fullerene-Fused Thiirane, Tetrahydrothiazolidin-2-one, and 1,3-Dioxolane

The epoxide moiety in the fullerene-mixed peroxide C60(O)(OOtBu)4 1 reacts readily with aryl isocyanates ArNCS (Ar = Ph, Naph) to form both the thiirane derivative C60(S)(OOtBu)4 and fullerene-fused tetrahydrothiazolidin-2-one. The reaction of 1 with trimethylsilyl isothiocyanate TMSNCS yields the isothiocyanate derivative C60(NCS)(OH)(OOtBu)4, the isothiocyanate and hydroxyl moieties of which could be converted to a fullerene-fused tetrahydrothiazolidin-2-one ring with alumina quantitatively. Treating 1 with BF3.Et2O yields the fullerene-fused [1,3,2]-dioxoborolane derivative C60(O2BOH)(OOtBu)4. In the presence of aldehyde or acetone, BF3.Et2O catalyzes the conversion of epoxide to fullerene-fused 1,3-dioxolane derivatives. The products are characterized by spectroscopic data. Two of the compounds are also characterized by single-crystal X-ray analysis.

Regulating enzymatic activity with a photoswitchable affinity label.

Regulating enzymatic activity with a photoswitchable affinity label.

Total Synthesis of Junionone, a Natural Monoterpenoid from Juniperus communis L., and Determination of the Absolute Configuration of the Naturally Occurring Enantiomer by ROA Spectroscopy

Recently, we reported a novel access to 2,2-diethyl-3-[(E/Z)-prop-1-en-1-yl]cyclobutanone by an intramolecular nucleophilic substitution with allylic rearrangement (S(N)i') of (E)-6-chloro-3,3-diethylhept-4-en-2-one. The ring closure reaction was found to proceed with selective syn-displacement of the leaving group. This method was now applied to the total synthesis of junionone, an olfactorily interesting cyclobutane monoterpenoid isolated from Juniperus communis, L. S(N)i' Ring closure of the ketone enolate of (E)-3,3-dimethyl-5-[(2R,3R)-3-methyloxiran-2-yl]pent-4-en-2-one (R,R)-(E)-4' proceeded only after the epoxide moiety had been activated by Lewis acid and led to the junionone precursors (3R)- and (3S)-3-[(1E,3R)-3-hydroxybut-1-en-1-yl]-2,2-dimethylcyclobutanone (S/R,R)-(E)-3. The ratio of syn- and anti-conformers in the transitory molecular arrangement was found to depend on the nature of the Lewis acid. The absolute configuration of both the synthetic as well as the natural junionone, isolated from juniper berry oil, was determined by Raman Optical Activity (ROA) spectroscopy. Our experiments led to a novel synthetic route to both (+)- and (-)-junionone, the first determination of the absolute configuration of natural junionone, and to the development of a practical ROA procedure for measuring milligram quantities of volatile liquids.

Electrochemical impedance spectroscopy for the study of juvenile hormones - recombinant protein interactions

The interactions of recombinant juvenile hormone binding protein (His8-rJHBP) with juvenile hormones (JHs), methoprene and farnesol have been studied with electrochemical impedance spectroscopy (EIS). The protein was immobilized on the dodecanethiol (DDT) modified gold electrodes. Each step of electrode modification has been confirmed with cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The conformation changes of His8-rJHBP upon JHs and methoprene binding have been presented. The EIS determined association constants in the JHs analogs-immobilized His8-rJHBP system indicate that lack of the epoxide moiety in methoprene molecule is not critical for observed high affinity of this compound to the binding region of the His8-rJHBP protein.

Synthesis of the C3-C18 fragment of amphidinolides G and H.

A synthesis of an amphidinolides G and H C3-C18 subunits is reported. The C10-C18 segment 4 was prepared by a Negishi cross-coupling, whereas the synthesis of the C3-C9 fragment 5 employed an asymmetric cyanosilylation as the key step. The two segments were coupled by lithiation of iodide 4 and trapping of the anion with amide 5. The allylic epoxide moiety could be synthesized from the protected anti- mesylate 22.

シンコナアルカロイドの合成

This review summarizes the synthesis of cinchona alkaloids, especially quinine. First, the synthetic efforts done by Rabe, Prelog, and Woodward are briefly mentioned. Described next are the achievements of Uskokovic in 1970 s, who found useful stereoselective transformations, introduced key intermediates, and established transformation of homomeroquinene to quinine, though as a mixture with quinidine. Then, the first completely stereoselective synthesis of quinine published by Stork in 2001 is presented, in which the key step is a stereoselective reduction of the substituted tetrahydropyridine (imine) to the piperidine by using NaBH4. Finally, syntheses of quinine and quinidine published by Jacobsen and by us are presented, both of which feature the stereoselective formation of the epoxide moiety on one of the side chains attached to the piperidine and subsequent intramolecular epoxide ring opening with the piperidine nitrogen, while the construction of the piperidine ring and the stereoselectivities accompanied with are different each other.

Pt‐Catalyzed Tandem Epoxide Fragmentation/Pentannulation of Propargylic Esters.

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Isolation and Structure Elucidation of Anthraquinones from Barleria eranthemoides (Acanthaceae)

Barleria eranthemoides R. Br. (Acanthaceae) is used in traditional medicine in the Bunda district, Tanzania. Root decoctions or infusions of pounded leaves are drunk for treatment of dysentery and against infectious diseases. Whereas phytochemical and biological investigations on the 80% methanolic extract of roots of B. eranthemoides are still in progress, a series of anthraquinone derivatives have been obtained from the n-hexane extract, which was investigated for its antiprotozoal activity. In addition to barleriaquinone (1), reported before from Barleria buxifolia, and the other known anthraquinones chrysophanol (2), isochrysophanol (3), digitopurpone (4), and 2-methoxy-7-methylanthraquinone (5), a new unusual anthraquinone derivative containing an epoxide moiety (6) was obtained. Structures were elucidated by means of 1D (1H, 13C, DEPT) and 2D (COSY, HSQC and HMBC) NMR and mass spectroscopy.

Exploring the S4 and S1 Prime Subsite Specificities in Caspase-3 with Aza-Peptide Epoxide Inhibitors,

Caspase-3 is a prototypic executioner caspase that plays a central role in apoptosis. Aza-peptide epoxides are a novel class of irreversible inhibitors that are highly specific for clan CD cysteine proteases. The five crystal structures of caspase-3-aza-peptide epoxide inhibitor complexes reported here reveal the structural basis for the mechanism of inhibition and the specificities at the S1' and the S4 subsites. Unlike the clan CA cysteine proteases, the catalytic histidine in caspase-3 plays a critical role during protonation and subsequent ring opening of the epoxide moiety and facilitates the nucleophilic attack by the active site cysteine. The nucleophilic attack takes place on the C3 carbon atom of the epoxide and results in an irreversible alkylation of the active site cysteine residue. A favorable network of hydrogen bonds involving the oxyanion hole, catalytic histidine, and the atoms in the prime site of the inhibitor enhance the binding affinity and specificity of the aza-peptide epoxide inhibitors toward caspase-3. The studies also reveal that subtle movements of the N-terminal loop of the beta-subunit occur when the P4 Asp is replaced by a P4 Ile, whereas the N-terminal loop and the safety catch Asp179 are completely disordered when the P4 Asp is replaced by P4 Cbz group.