acetogenins and tetrahydrofuran

This paper describes the first total synthesis of the proposed structure for aromin, an annonaceous acetogenin possessing an unusual bis-THF ring system, and its 4S,7R-isomer. The key steps involve an oxidative cyclization of a couple of terminal-diene alcohols and an intermolecular metathesis of an alkenyl tetrahydrofuran with an enone carrying a tetrahydrofuranyl lactone. The spectral data of both samples did not match those of aromin. Re-examination of the NMR data using the CAST/CNMR Structure Elucidator and chemical derivations suggested that the real structure of aromin should be revised to be a tetrahydropyran acetogenin, montanacin D. Cytotoxicities in human solid tumor cell lines for synthetic samples were also evaluated.

Topics: Acetogenins; Annonaceae; Carbon-13 Magnetic Resonance Spectroscopy; Cell Line, Tumor; Cyclization; Drug Screening Assays, Antitumor; Furans; Humans; Mass Spectrometry; Molecular Structure; Oxidation-Reduction; Proton Magnetic Resonance Spectroscopy

Bioassay-guided fractionation of the fruit powder of graviola (Annona muricata) yielded three novel compounds: muricins J, K, and L. The compounds are all C35 Annonaceous acetogenins with a mono-tetrahydrofuran ring and four hydroxyls. Their structures were elucidated by spectral methods and chemical modification after isolation via chromatographic techniques and HPLC purification. These three acetogenins demonstrated an antiproliferative against human prostate cancer PC-3 cells.

Topics: Acetogenins; Annona; Antineoplastic Agents, Phytogenic; Cell Proliferation; Chromatography, High Pressure Liquid; Fruit; Furans; Humans; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Prostatic Neoplasms

Annonaceous acetogenins (ACGs) are one of the most powerful groups of mitochondrial complex I inhibitors. In this study, 24 ACGs with different chemical structures have been tested against mitochondrial complex I isolated in our laboratory. Molecular modelling study of the six mono-tetrahydrofuran (THF) ACGs in these 24 compounds has been performed to investigate the relationship between their inhibitory activity and chemical structures. IC50 of every ACGs against mitochondrial complex I was determined with a micro plate reader. The results show that every ACG can inhibit mitochondrial complex I and the six mono-THF ACGs' activities are in agreement with their molecular modelling results. It is suggested that proper length and flexibility of the alkyl spacer moiety, which links the THF and the α,β-unsaturated Q-lactone ring moieties, are essential for the potent activity. Both the number of hydroxyl groups and stereochemical structures of mono-THF ACGs impact the activity.

Topics: Acetogenins; Animals; Furans; Lactones; Liver; Mitochondria; Models, Molecular; Molecular Structure; Rats; Structure-Activity Relationship

Two types of trans-THF cores, present in acetogenins, have been synthesized by an intramolecular iodoetherification reaction. The starting alkenol was obtained in a few steps from a chiral cis-diol resulting from microbial oxidation of bromobenzene. The cyclization gave complete stereoselectivity for trans-THF cores with either (S,S) or (R,R) configurations at the THF chiral carbons.

Topics: Acetogenins; Alcohols; Annonaceae; Bromobenzenes; Cyclization; Furans; Molecular Structure; Oxidation-Reduction; Stereoisomerism; Structure-Activity Relationship

The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners.

Topics: Acetogenins; Antineoplastic Agents; Carbohydrates; Cell Line, Tumor; Cell Survival; Furans; HeLa Cells; Humans; Jurkat Cells; Light; Scattering, Radiation; Stereoisomerism; Structure-Activity Relationship

Topics: Acetogenins; Antineoplastic Agents; Apoptosis; Calcium; Cell Survival; Chelating Agents; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Furans; Hep G2 Cells; Humans; Models, Biological; Molecular Conformation; Organometallic Compounds; Stereoisomerism; Structure-Activity Relationship

Biochemical characterization of the inhibition mechanism of Deltalac-acetogenins synthesized in our laboratory indicated that they are a new type of inhibitor of bovine heart mitochondrial NADH-ubiquinone oxidoreductase (complex I) [Murai, M., et al. (2006) Biochemistry 45, 9778-9787]. To identify the binding site of Deltalac-acetogenins with a photoaffinity labeling technique, we synthesized a photoreactive Deltalac-acetogenin ([(125)I]diazinylated Deltalac-acetogenin, [(125)I]DAA) which has a small photoreactive diazirine group attached to a pharmacophore, the bis-THF ring moiety. Characterization of the inhibitory effects of DAA on bovine complex I revealed unique features specific to, though not completely the same as those of, the original Deltalac-acetogenin. Using [(125)I]DAA, we carried out photoaffinity labeling with bovine heart submitochondrial particles. Analysis of the photo-cross-linked protein by Western blotting and immunoprecipitation revealed that [(125)I]DAA binds to the membrane subunit ND1 with high specificity. The photo-cross-linking to the ND1 subunit was suppressed by an exogenous short-chain ubiquinone (Q(2)) in a concentration-dependent manner. Careful examination of the fragmentation patterns of the cross-linked ND1 generated by limited proteolysis using lysylendopeptidase, endoprotease Asp-N, or trypsin and their changes in the presence of the original Deltalac-acetogenin strongly suggested that the cross-linked residues are located at two different sites in the third matrix-side loop connecting the fifth and sixth transmembrane helices.

Topics: Acetogenins; Amino Acid Sequence; Animals; Binding Sites; Binding, Competitive; Cattle; Diazomethane; Electron Transport Complex I; Furans; Hydrophobic and Hydrophilic Interactions; Iodine Radioisotopes; Membrane Proteins; Mitochondria, Heart; Molecular Sequence Data; NADH Dehydrogenase; Photoaffinity Labels; Protein Structure, Tertiary; Submitochondrial Particles

A total synthesis of annonacin (1) was accomplished by using versatile chiral building block 2 for synthesizing the mono-tetrahydrofuran (THF) annonaceous acetogenins.

Topics: Acetogenins; Annona; Furans; Lactones; Stereoisomerism

The bis-THF cores of annonaceous acetogenins were synthesized using (3R,4R)-1,5-hexadiene-3,4-diol (1) as the sole source of carbon atoms. The methylene acetal function was applied as a new linker/tether to facilitate the ring-closing metathesis.

Topics: Acetogenins; Cross-Linking Reagents; Furans; Molecular Structure; Stereoisomerism

Trienes and dienynes containing one electron-deficient double bond were shown to undergo regio- and stereoselective oxidative cyclization in the presence of permanganate ion to afford 2,5-bis-hydroxyalkyltetrahydrofurans (THF diols). The THF diols produced retained either alkene or alkyne functionalities, which provided convenient handles for the metal oxo-mediated introduction of an adjacent THF ring with overall control of relative and absolute stereochemistry. Adjacent bis-THFs possessing threo-cis-threo-trans-erythro, threo-cis-threo-trans-threo, threo-cis-threo-cis-erythro, threo-cis-erythro-cis-threo, or threo-cis-erythro-trans-threo relationships were synthesized by appropriate selection of alkene geometry and methodology for the closure of the second ring. The threo-cis-threo-cis-erythro stereochemical arrangement is embodied within the bis-THF core units of a number of Annonaceous acetogenins including membrarollin, while trilobacin has a threo-cis-erythro-trans-threo configured core. As an application of the selective oxidative cyclization approach, a total synthesis of membrarollin was completed in 17 linear steps from dodecyne. The C21,C22 double epimer of membrarollin was also synthesized in 15 linear steps and without recourse to the use of hydroxyl group protection.

Topics: Acetogenins; Alkynes; Annonaceae; Cyclization; Furans; Oxidation-Reduction; Polyenes

Five new C(15) acetogenin en-ynes (1-5) with a rare tetrahydrofuran moiety and a linear biosynthetic precursor (6) were isolated from an organic extract of Laurencia glandulifera, collected from the island of Crete in the south Aegean Sea. The structures of the new natural products, as well as their relative configuration, were established by means of spectroscopic data analysis. The cytotoxicity of the isolated natural products was evaluated against five human tumor cell lines.

Topics: Acetogenins; Alkynes; Drug Screening Assays, Antitumor; Furans; Greece; HeLa Cells; HT29 Cells; Humans; Laurencia; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular

A highly convergent synthesis of mono-tetrahydrofuran (THF) containing acetogenins, that is based on the cross-metathesis of THF and butenolide alkene precursors, was developed. This methodology was applied to the epimers of the C-9 alcohol of 4-deoxyannoreticuin, in an attempt to assign the configuration at this position in the naturally occurring material. Unfortunately, identification of one or the other epimeric structures with the natural product was not possible because of the closeness of the physical data for all three compounds. Both C-9 epimeric analogues showed similar cytotoxicity in the low micromolar range, against two human tumor cell lines PC-3 (prostate) and Jurkat (T-cell leukemia). This result contrasts to previous studies on closely related THF acetogenins, wherein configurational variation at analogous carbinol centers resulted in a significant effect on antitumor activity.

Topics: Acetogenins; Antineoplastic Agents; Drug Screening Assays, Antitumor; Furans; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Prostatic Neoplasms; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured

Side-chain analogs of Annonaceous acetogenins with a threo, trans, threo, trans, threo-bis-tetrahydrofuran core unit have been prepared and tested for cytotoxicity against HCT-116 human colon cancer cells.

Topics: Acetogenins; Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Screening Assays, Antitumor; Fatty Alcohols; Furans; Humans; Inhibitory Concentration 50; Lactones; Models, Chemical; Molecular Structure

A series of six 2,5-disubstituted adjacent bis(tetrahydrofuran) stereoisomers with trans/erythro/cis, trans/threo/trans, or cis/threo/cis relative stereochemistry have been synthesized from known dihydroxycyclooctenes via ring opening/cross metathesis and Pd(0)-mediated asymmetric double cycloetherification. The stereochemistry of four of these isomers has been found in the biologically active annonaceous acetogenin natural products. [reaction: see text].

Topics: Acetogenins; Annonaceae; Cyclization; Dioxanes; Ethers; Fatty Alcohols; Furans; Lactones; Magnetic Resonance Spectroscopy; Palladium; Solvents; Stereoisomerism

We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated gamma-lactone ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF rings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.

Topics: Acetogenins; Animals; Binding, Competitive; Cattle; Electron Transport Complex I; Enzyme Inhibitors; Fatty Alcohols; Furans; Lactones; Mitochondria, Heart; Protein Binding; Spectrometry, Fluorescence; Structure-Activity Relationship; Superoxides; Titrimetry

[Structure: See text] Double asymmetric [3 + 2]-annulation reactions of chiral beta-silyloxyallylsilanes with chiral 2-tetrahydrofuranyl carboxaldehydes have been studied, leading to the stereocontrolled synthesis of six diastereomeric bis-tetrahydrofuran structures corresponding to the core subunits of members of the Annonaceous acetogenin family of natural products. Transition-state models are proposed to account for the stereoselectivity of the double-stereodifferentiating [3 + 2]-annulation reactions.

Topics: Acetogenins; Aldehydes; Allyl Compounds; Chelating Agents; Fatty Alcohols; Furans; Indicators and Reagents; Lactones; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Silanes

The presence of two hydroxy groups adjacent to the THF ring(s) is a common structural feature of natural acetogenins. To elucidate the role of each hydroxy group in the inhibitory action of acetogenins, we synthesized three acetogenin analogues which lack either or both of the hydroxy groups, and investigated their inhibitory activities with bovine heart mitochondrial complex I. Our results indicate that the presence of either of the two hydroxy groups sufficiently sustains a potent inhibitory effect.

Topics: Acetogenins; Animals; Cattle; Electron Transport Complex I; Enzyme Inhibitors; Fatty Alcohols; Furans; Hydroxyl Radical; Lactones; Mitochondria, Heart; Molecular Conformation; Molecular Structure; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Structure-Activity Relationship

In this study we evaluated a mono-tetrahydrofuranic subgroup of natural acetogenins that had shown in previous enzyme inhibition studies different potency trends compared with the bis-tetrahydrofuranic acetogenin subgroup. The compounds were tested against colon, breast, lung, liver, and ovarian tumor cell lines. A drug-resistant ovarian cell line was also included in the panel. In general the compounds were more potent than doxorubicin. The goal was to determine how well the mitochondrial complex I inhibition correlates with the in vitro antitumor potency of these natural mono-tetrahydrofuranic acetogenins and of some derivatives. The results indicate that both the reduction of the terminal gamma-lactone after its translactonization and the introduction of an hydroxylimine group in the alkyl chain, near the mono-tetrahydrofuranic moiety, increased the antitumor activity, even against the doxorubicin-resistant cell line.

Topics: Acetogenins; Antineoplastic Agents; Cell Line, Tumor; Electron Transport Complex I; Fatty Alcohols; Furans; Humans; Inhibitory Concentration 50; Lactones; Molecular Structure; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Structure-Activity Relationship; Tetrazolium Salts; Thiazoles