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C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH-ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The first total synthesis of (+)-giganin and its unnatural diastereoisomer (+)-C10-epi-giganin has been completed in a total of 13 linear steps, and 7 % and 8 % overall yield, respectively (see scheme; (-)-sp= (-)-sparteine, (+)-sps=(+)-sparteine surrogate). Lithiation-borylation methodology has been successfully applied in the key step, to couple together advanced intermediates with very high diastereoselectivity, thus demonstrating its power as a tool for total synthesis., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Total synthesis of Debilisone C, a lactone containing conjugated endiyne has been achieved. The adopted strategy involves the stereoselective construction of the five membered lactone ring and the C20 endiyne chain followed by regioselective coupling of both the parts. The lactone was obtained from the oxidative cleavage of the hydroxy olefin which was derived from the benzyl protected S-epichlorohydrine by regioselective epoxide opening with allyl trimethyl silane in presence of a Lewis acid at -78 °C. Takai olefination, Pd(0)/Ag(1) catalyzed cross-coupling reaction and selective substitution of trimethylsilyl groups were successfully utilized to establish the C20 polyyne chain. The final coupling of both the parts have been carried out by alkyl coupling using LDA in THF-DMPU (1 : 1).

In addition to 13 known compounds, four new bisabolane sesquiterpenes, okamurenes A-D (1-4), a new chamigrane derivative, okamurene E (5), and a new C₁₂-acetogenin, okamuragenin (6), were isolated from the marine red alga Laurencia okamurai. The structures of these compounds were determined through detailed spectroscopic analyses. Of these, okamurenes A and B (1 and 2) are the first examples of bromobisabolane sesquiterpenes possessing a phenyl moiety among Laurencia-derived sesquiterpenes, while okamuragenin (6) was the first acetogenin aldehyde possessing a C₁₂-carbon skeleton. Each of the isolated compounds was evaluated for the brine shrimp (Artemia salina) lethal assay and 7-hydroxylaurene displayed potent lethality with LD₅₀ 1.8 μM.

Custard apple (Annona squamosa L.) is an edible tropical fruit, and its seeds had been used in south China as a folk medicine to treat "malignant sore" (cancer) and as an insecticide. Phytochemical investigation of the ethanol fraction of custard apple seeds led to the isolation of six new annonaceous acetogenins: annosquacins A-D (1-4), annosquatin A (5) and annosquatin B (6). Their structures were elucidated by spectroscopic analysis. Compounds 1-4 are adjacent bistetrahydrofuran annonaceous acetogenins. Compounds 5 and 6 are non-adjacent bistetrahydrofuran annonaceous acetogenins and the first examples in which the tetrahydrofuran ring system is located between C-9 and C-20. The absolute configurations of 1-6 were defined by the application of the Mosher method. Compounds 1-6 exhibited potent cytotoxic activity in vitro against five human tumour cell lines. Compounds 5 and 6 showed a high selectivity toward the MCF-7 and A-549 cell line respectively., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Transannular O-heterocyclization is applied as a key step in a total synthesis. This highly stereoselective and metal-free transformation introduces four stereocenters in one step. It was chosen to be the pivotal step in the synthesis of Murisolin and 16,19-cis-Murisolin, two annonaceous acetogenins. The efficiency of this synthesis is further illustrated by a stereodivergent late-stage separation of both synthetic routes.

A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C(15)-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species.

Annonaceous acetogenins (AAGs) are a homogenous class of polyketides proposed as environmental neurotoxins. Previous dereplication studies of AAGs were limited by the use of low-resolution mass spectrometers. Only poor information in terms of structures was provided due to the limited fragmentation of protonated or sodium cationized species. An innovative approach, using reversed-phase high-performance liquid chromatography coupled to a hybrid linear ion trap/orbitrap mass spectrometer (LTQ-Orbitrap®), was therefore performed. Sensitivity was enhanced by post-column infusion of lithium, since AAGs have a high affinity for this cation. High level of structural information was obtained from low-energy-collision-induced dissociation fragmentation experiments of lithium-cationized AAGs ([M + Li](+) ions) as demonstrated with purified standards. The method was then applied to a total ethyl-acetate extract prepared from commercial soursop nectar (Annona muricata L.). The sensitivity, mass accuracy and specific fragmentation patterns proved to be particularly useful for characterization of the AAGs. Typical structural identification procedure and unexpected observations for specific structural types are illustrated, with major and minor compounds., (Copyright © 2012 John Wiley & Sons, Ltd.)

The interactions were studied by FTIR and DSC of the terminal lactone of annonaceous acetogenins (ACGs) and synthetic analogues, such as THF, with POPC bilayers, as well as the toxic effect produced by these compounds on Spodoptera frugiperda larvae. The aim of this work was to find a relationship between ACG insecticidal properties and the specific sites of interaction with lipid membranes. ACGs interact to different extents with the phosphate of lipid membranes and differences in the antisymmetric stretching of the phosphate groups were found in the presence of water that indicate water loss and further hydrogen bonding.The ACG tested produced more than 70% larval mortality. Rolliniastatin-1 (3) proved to have the most toxic effects (100%) on early larval instars when incorporated in the larval diet at a dose of 100 microg per g of diet. Additionally, it produced a significant decrease in growth rate (GR) and consumption index (CI), and reduced the efficiency with which larvae converted ingested food into biomass (ECI). The destabilization that occurs in the membrane due to dehydration around the phosphate groups caused by interaction with ACGs and their synthetic analogues would account for ACGs' insecticidal action.

Acetogenins are cell-membrane permeable, naturally occurring secondary metabolites of plants such as Annonaceae, Lauraceae and other related phylogenic families. They belong to the chemical derivatives of polyketides, which are synthesized from fatty acid precursors. Although acetogenins have displayed diverse biological activities, the anti-proliferative effect on human cancer cells has been widely reported. Acetogenins are inhibitors of complex I in the electron transport chain therefore they interrupt ATP synthesis in mitochondria. We tested a new acetogenins-enriched extract from the seed of Persea americana in order to investigate if any toxicity was induced on cardiac tissue and determine the involved mechanism. In isolated perfused heart we found that contractility was completely inhibited at an accumulative dose of 77 μg/ml. In isolated cardiomyocytes, the acetogenins-enriched extract induced apoptosis through the activation of the intrinsic pathway at 43 μg/ml. In isolated mitochondria, it inhibited complex I activity on NADH-linked respiration, as would be expected, but also induced permeability transition on succinate-linked respiration. Cyclosporine A, a known blocker of permeability transition, significantly prevented the permeability transition triggered by the acetogenins-enriched extract. In addition, our acetogenins-enriched extract inhibited ADP/ATP exchange, suggesting that an important element in phosphate or adenylate transport was affected. In this manner we suggest that acetogenins-enriched extract from Persea americana could directly modulate permeability transition, an entity not yet associated with the acetogenins' direct effects, resulting in cardiotoxicity.

Cyclooxygenase-2 (COX-2) is an inducible isoform of the enzyme responsible for the synthesis of several inflammatory mediators. In a search for phytochemicals with anti-inflammatory activity, the COX-2 inhibitory activity of 15 typical Annonaceous acetogenins was examined. Isodesacetyluvaricin (1), from the Formosan tropical fruit tree Annona glabra, exhibited the most potent activity. Reverse transcription PCR was used to test the effect of 1 on epidermal growth factor-stimulated expression of COX-2 in cultures of A431 human epidermoid carcinoma cells. Three hours after exposure to 1 (5 μM), A431 cells had barely detectable levels of COX-2 mRNA. A corresponding but smaller decline in the COX-2 protein appeared on using Western blots. Lipopolysaccharide-stimulated expression of COX-2 in Raw 264.7 mouse leukemic monocyte-macrophages showed a similar decrease. Luciferase assays revealed that cells exposed to 1 had reduced activities of two COX-2 promoter-transcription factors: cAMP response element-binding factor and nuclear factor of activated T-cells. Compound 1 did not affect cell proliferation, as measured by a colorimetric assay, or intracellular store-operated calcium influx, as determined by fluorescence imaging. Thus, 1 may serve as a lead compound for targeting inflammatory diseases as well as angiogenesis and cancer metastasis., (© 2012 American Chemical Society and American Society of Pharmacognosy)

Three new halogenated sesquiterpenes, 10-bromo-7α,8α-expoxychamigr-1-en-3-ol (1), 10-bromo-β-chamigren-8-ol (2), and 10-bromo-3-chlorocupar-5-en-2-ol (3), one new C₁₂-acetogenin, desepilaurallene (7), one new naturally occurring sesquiterpene, 7-hydroxylaurene acetate (4), two known sesquiterpenes, allolaurinterol acetate (5) and laurene (6), and one known C₁₅-acetogenin, epilaurallene (8), were isolated from the marine red alga Laurencia okamurai collected from the coast of Rongcheng, China. The structures of these compounds were unambiguously established by 1D, 2D NMR and mass spectroscopic techniques. The bioassay results showed that 4, 5 exhibited potent antibacterial activity, and 1, 4, 5 were toxic to brine shrimp., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Investigation of the endemic Madagascan plant Uvaria sp. for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new acetogenins. The structures of these two compounds were elucidated on the basis of analysis of their 1D and 2D NMR spectra, circular dichroism, and mass spectrometric data, together with chemical modification. The two acetogenins display weak antiproliferative activity against the A2780 ovarian cancer, the A2058 melanoma, and the H522 lung cancer cell lines.

Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.

Topical application of acetylenic acetogenins (AAG) from avocado (0.01-1.0mg/ear), was effective in inhibiting both 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema, and in decreasing tissue myeloperoxidase activity (indicative of polymorphonuclear leukocyte influx). Maximum edema inhibition of 72% was achieved by AAG at lower concentration (0.6 mg/ear) than that of the anti-inflammatory drug indomethacin (2mg/ear). The maximum myeloperoxidase inhibition of 60% was obtained at AAG concentration 0.1mg/ear. Chemical reduction of unsaturated bonds in aliphatic chain of AAG molecules almost abrogated inhibition effect of AAG at high concentration. In vitro AAG administration reduced secretion of PGE(2) in TPA-induced keratinocytes, and inhibited total PLA(2) and sPLA(2) activities in HaCaT cells. The results indicate a topical anti-inflammatory effect of acetylenic acetogenins which is associated with inhibition of PLA(2) activity in skin., (Copyright © 2011 Elsevier B.V. All rights reserved.)

One new betaenone, theissenoic acid (1), together with three new acetogenins, theissenolactones A-C (2-4, resp.), were isolated from the fermented broth of Theissenia cinerea 89091602 isolated in Taiwan. The structures of 1-4 were elucidated by spectroscopic methods. Biological tests revealed that 3 and 4 exhibited moderate growth-inhibitory activities against A549 lung cancer cell line with GI(50) values of 14.9 and 47.9 μM, respectively., (Copyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich.)

Three new bistetrahydrofuran annonaceous acetogenins (1-3) were isolated from a 95% EtOH extract of Annona squamosa seeds. Four known annonaceous acetogenins, uvarigrandin A (4), bullatacin (5), squamostatin-A (6), and squamostatin-D (7), were also isolated. Their structures were elucidated by spectroscopic analyses, and the absolute configurations of the carbinol centers of 1-3 were defined by application of the Mosher method. These compounds all exhibited significant cytotoxic activity in vitro against five human tumor cell lines.

The methanol extract of Annona squamosa seeds was highly active against two phytoparasitic nematodes, Bursaphelenchus xylophilus and Meloidogyne incognita. It efficiently suppressed plant diseases, caused by Phytophthora infestans and Puccinia recondita. Ten annonaceous acetogenins (AAs) were isolated, and their chemical structures were identified by mass and nuclear magnetic resonance spectral data. Out of 10 substances, eight displayed strong in vitro nematicidal activity against B. xylophilus with LD(50) values ranging 0.006 to 0.048 μg/mL. Squamocin-G showed potent nematicidal activity against M. incognita. Squamocin, squamocin-G, and squamostatin-A also displayed potent in vitro and in vivo antifungal activities against P. infestans causing tomato late blight. In addition, squamostatin-A effectively controlled the development of wheat leaf rust caused by P. recondita. Our findings suggested that A. squamosa seeds and its bioactive AAs can be an alternative resource of a promising botanical nematicide and fungicide to control various plant diseases.

A unique procedure to effect a ring-expanding bromoetherification process is described, wherein tetrahydrofurans and tetrahydropyrans are smoothly transformed into 8- and 9-membered bromoethers in a regio- and stereocontrolled manner through the use of BDSB (bromodiethylsulfonium bromopentachloroantimonate). These products resemble the cores of the Laurencia C15 acetogenins. In light of the generality and effectiveness of the approach, this work provides a unique strategy for their laboratory preparation and may implicate a possible biosynthesis pathway.

The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Nine linear C23 and C21 acetogenins, named cananginones A-I (1-9), were isolated from stem bark of Miliusa velutina [corrected] . Their structures were established by spectroscopic methods. These compounds showed cytotoxicity against three cancer cell lines (KB, MCF7 and NCI-H187) with IC₅₀ values in the range 16.6-129.7 μM. Only 5 showed weak antimalarial activity against Plasmodium falciparum. In addition, 8 and 9 exhibited weak antifungal activity against Candida albicans., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Natural acetogenins are among the most potent inhibitors of bovine heart mitochondrial NADH-ubiquinone oxidoreductase (complex I). Our photoaffinity labeling study suggested that the hydroxylated bis-THF ring moiety of acetogenins binds at "site A" in the third matrix-side loop connecting the fifth and sixth transmembrane helices in the ND1 subunit [Kakutani et al. (2010) Biochemistry 49, 4794-4803]. Nevertheless, since this proposition was led using a photoreactive Δlac-acetogenin derivative, it needs to be directly verified using a natural acetogenin-type probe. We therefore conducted photoaffinity labeling using a photoreactive natural acetogenin mimic ([(125)I]diazinylated natural acetogenin, [(125)I]DANA), which has a small photolabile diazirine group, in place of a hydroxy group, attached to the bis-THF ring moiety. Analysis of the photocross-linked protein in bovine heart submitochondrial particles unambiguously revealed that [(125)I]DANA binds to the membrane subunit ND1 with high specificity. The photocross-linking was completely blocked in the presence of just a 5-fold excess of bullatacin, indicating that [(125)I]DANA is an excellent mimic of natural acetogenins and hence binds to the site that accommodates natural products. Careful examination of the fragmentation patterns of the cross-linked ND1 generated by different proteases and their combinations indicated that the cross-linked residue is predominantly located at the supposed site A in the third matrix-side loop., (2011 Elsevier B.V. All rights reserved.)

Panama is a unique terrestrial bridge of extreme biological importance. It is one of the "hot spots" and occupies the fourth place among the 25 most plant-rich countries in the world, with 13.4 % endemic species. Panamanian plants have been screened for a wide range of biological activities: as cytotoxic, brine shrimp-toxic, antiplasmodial, antimicrobial, antiviral, antioxidant, immunosuppressive, and antihypertensive agents. This review concentrates on ethnopharmacological uses of medicinal plants employed by three Amerindian groups of Panama and on selected plants with novel structures and/or interesting bioactive compounds. During the last quarter century, a total of approximately 390 compounds from 86 plants have been isolated, of which 160 are new to the literature. Most of the work reported here has been the result of many international collaborative efforts with scientists worldwide. From the results presented, it is immediately obvious that the Panamanian flora is still an untapped source of new bioactive compounds., (© Georg Thieme Verlag KG Stuttgart · New York.)

A new series of linear dimeric compounds mimicking naturally occurring annonaceous acetogenins have been synthesized by bivalent analogue design, and their cytotoxicities have been evaluated against the growth of cancer cells by MTT method. Most of these compounds show selective action favored to human cancer cell lines over normal cell lines, and compound 9 with bis-terminal benzoquinone functionality exhibits an IC(50)=0.40 μM against MCF7 cell lines. This work mentions that appropriate conformational constraints might be a useful optimizing tool for this unique class of anticancer compounds., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Avocado (Persea americana) fruits are consumed as part of the human diet and extracts have shown growth inhibitory effects in various types of human cancer cells, although the effectiveness of individual components and their underlying mechanism are poorly understood. Using activity-guided fractionation of the flesh of avocado fruits, a chloroform-soluble extract (D003) was identified that exhibited high efficacy towards premalignant and malignant human oral cancer cell lines. From this extract, two aliphatic acetogenins of previously known structure were isolated, compounds 1 [(2S,4S)-2,4-dihydroxyheptadec-16-enyl acetate] and 2 [(2S,4S)-2,4-dihydroxyheptadec-16-ynyl acetate]. In this study, we show for the first time that the growth inhibitory efficacy of this chloroform extract is due to blocking the phosphorylation of EGFR (Tyr1173), c-RAF (Ser338), and ERK1/2 (Thr202/Tyr204) in the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway. Compounds 1 and 2 both inhibited phosphorylation of c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204). Compound 2, but not compound 1, prevented EGF-induced activation of the EGFR (Tyr1173). When compounds 1 and 2 were combined they synergistically inhibited c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204) phosphorylation, and human oral cancer cell proliferation. The present data suggest that the potential anticancer activity of avocado fruits is due to a combination of specific aliphatic acetogenins that target two key components of the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway., (Copyright © 2011 Elsevier Inc. All rights reserved.)

3-Hydroxy-3-methylglutaryl coenzyme A reductase (class II HMGR) could serve as a potential target to discover drugs fighting against the invasive diseases originated from Streptococcus pneumoniae, one of the major causes of bacterial disease in human. However, no strongly effective inhibitors of class II HMGR have been found so far. In the present study, for the first time, four annonaceous acetogenins (ACGs) were explored for the inhibition on S. pneumoniae HMGR. The results showed that the ACGs had higher inhibitory activities against S. pneumoniae HMGR with K(i) values in the range of 6.45-20.49 μM than the statin drug lovastatin (K(i)=116.25 μM), a classical inhibitor of class I HMGR. Then, three-dimensional modeling and docking simulations analyzed the possible binding mode of ACGs to S. pneumoniae HMGR and suggested a kind of novel structural and binding mode for designing promising inhibitor candidates of the targeted enzyme S. pneumoniae II HMGR., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Eight new halogenated C(15) acetogenins, 1-8, were isolated from the organic extract of the red alga Laurencia marilzae. The structure elucidation and the assignments of the relative configurations were established by extensive use of spectroscopic studies, particularly 1D and 2D NMR data, while the absolute configurations of compounds 1 and 5 were determined by single-crystal X-ray diffraction analysis. Compounds 1, 2, 4, 5, and 7, along with the previously reported related cyclic ether obtusallene IV (9), were evaluated against six human solid tumor cell lines. All compounds were found to be essentially inactive (GI(50) > 10 μg/mL).

Unlabelled: The antiproliferative effects of three synthetic analogs of aliphatic acetogenins selected from a previous screening were compared to those of the drugs used for the treatment of malignant pleural mesothelioma (MPM) and pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: Four PDAC and three MPM cell lines were used in the study. Cell growth inhibition was determined after 48 h exposure to the drugs. Cell-cycle disruption and apoptosis induction were studied by flow cytometry. The modulation of Akt phosphorylation was studied using a specific ELISA for P-Ser473 Akt., Results: The new compounds inhibited cell growth, induced apoptosis and cell-cycle abrogation in all cell lines. Phosphorylated Akt levels rose after treatment., Conclusion: The results demonstrated better performance of aliphatic acetogenin analogs against PDAC cells when compared to standard anticancer drugs. For MPM cells, the application of the new compounds may play an important role in overcoming the resistance to conventional treatments.

A stereocontrolled total synthesis of (+)-chamuvarinin, isolated from the root extract of Uvaria Chamae, utilizes a convergent modular strategy to construct the adjacently linked C15-C28 ether array, followed by a late-stage Julia-Kocienski olefination to append the butenolide motif. This constitutes the first total synthesis of (+)-chamuvarinin, defining the relative and absolute configuration of this unique annonaceous acetogenin.

Annonaceous acetogenins are a large family of naturally occurring polyketides exhibiting remarkable anticancer activities. The first generation of annonaceous acetogenin mimetic (1, AA005) exhibits comparable activity as that of natural products and presents much higher selectivity between cancer and normal cells. In this work, we report the design, synthesis, and evaluation of a new series of compound 1 analogues in which a variety of conformation-constrained fragments were embedded in the left hydrocarbon chain part. Compound 7 bearing a biphenyl moiety was identified to exhibit more potent antiproliferative activity and preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.

The petroleum ether extract of the red alga Laurencia obtusa afforded three new C(15) acetogenins (cyclic ether enyne): (12Z)-cis-maneonene-D (1), (12E)-cis-maneonene-E (2), and (12Z)-trans-maneonene-C (3), along with one known cis-maneonene-A (4). Blood neutrophils were prepared, cultured, and incubated for 24, 48, and 72 h in medium with and without isolated compounds. Blood neutrophils were prepared, cultured, and incubated for 24, 48 and 72 h in medium with and without the isolated compounds. Both morphology and DNA fragmentation methods assessed the percentage of neutrophils apoptosis in each culture. In the present study, several observations have been made concerning the apoptosis-inducing or inhibiting effect of 1 and 2. Both compounds had no inhibition of apoptosis but apoptosis was enhanced significantly by aging. However, 1 stimulated apoptosis of normal only at the initial 24 h. After that there was no significant difference in apoptosis with or without compound 1, while 2 stimulated apoptosis at all the times. The apoptosis induced by these two compounds was demonstrated by DNA fragmentation assay and microscopic observation. These observations suggest that compounds 1 and 2 may be involved in regulation of programmed death in the initiation and propagation of inflammatory responses.

Collision-induced dissociation experiments of seven annonaceous acetogenins were carried out under high and low collision energy conditions. Each compound was studied as protonated or deprotonated and lithium- or sodium- cationized molecules, using ElectroSpray Ionisation (ESI) with a hybrid linear trap/orbitrap mass spectrometer (LTQ-Orbitrap®). The same ion species were studied with a Matrix-Assisted Laser Desorption Ionisation (MALDI) tandem mass spectrometer in a high collision energy regime (1 or 2 keV). Although each of the techniques showed some limitations in the detection of functional groups, unambiguous structural identification of the acetogenins was obtained. MALDI ToF-ToF has the advantage over ESI-based methods to provide mass spectra rich in informative fragments which allows the confirmation of some functional groups position. By contrast, ESI-LTQ-Orbitrap® analysis has the advantage over MALDI that the mass spectra are relatively simple with only fragments close to the functional groups. However, this technique needs to carry out experiments both in negative and positive ionization modes. Copyri, (Copyright © 2010 John Wiley & Sons, Ltd.)

From Mitrephora maingayi, a new C21-type Annonaceous acetogenin (1) has been isolated, along with a biogenetically related known compound, oropheic acid (2). Their structures were elucidated on the basis of extensive spectroscopic analysis. The insecticidal activity of 1 was also assessed.

Studies on the Annonaceous acetogenins began after the first cytotoxic acetogenin, uvaricin, was isolated in 1982. This attractive finding made many medicinal and natural product chemists direct their efforts on the isolation and identification of these classes of compounds. As more Annonaceous acetogenins were isolated, more information about them was uncovered. From their structural identification to the total synthesis of natural product analogues and from cell-based screening and molecular-based targeting to animal testing, the mechanisms of action of the Annonaceous acetogenins became clearer. The purpose of this review is to give an account of recent studies on this class of compounds and their analogues, which will aid us not only in clarifying how the Annonaceous acetogenins act but also in establishing principles for the further development of this class of compounds., (© Georg Thieme Verlag KG Stuttgart-New York.)

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.

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.

Products that contain twig extracts of pawpaw (Asimina triloba) are widely consumed anticancer alternative medicines. Pawpaw crude extract (CE) and purified acetogenins inhibited hypoxia-inducible factor-1 (HIF-1)-mediated hypoxic signaling pathways in tumor cells. In T47D cells, pawpaw CE and the acetogenins 10-hydroxyglaucanetin (1), annonacin (2), and annonacin A (3) inhibited hypoxia-induced HIF-1 activation with IC(50) values of 0.02 microg/mL, 12 nM, 13 nM, and 31 nM, respectively. This inhibition correlates with the suppression of the hypoxic induction of HIF-1 target genes VEGF and GLUT-1. The induction of secreted VEGF protein represents a key event in hypoxia-induced tumor angiogenesis. Both the extract and the purified acetogenins blocked the angiogenesis-stimulating activity of hypoxic T47D cells in vitro. Pawpaw extract and acetogenins inhibited HIF-1 activation by blocking the hypoxic induction of nuclear HIF-1alpha protein. The inhibition of HIF-1 activation was associated with the suppression of mitochondrial respiration at complex I. Thus, the inhibition of HIF-1 activation and hypoxic tumor angiogenesis constitutes a novel mechanism of action for these anticancer alternative medicines.

One new acetogenin, 6-hydroxy-8-pentadecyloxocane-2,7-dione ( 1), and four new prenylated flavonoids, 4''a,5'',6'',7'',8'',8''a-hexahydro-5,3',4'-trihydroxy-5'',5'',8''a-trimethyl-4 H-chromeno[2'',3'':7,6]flavone ( 2), 4''a,5'',6'',7'',8'',8''a-hexahydro-5,3',4',-trihydroxy-5'',5'',8''a-trimethyl-4 H-chromeno[2'',3'':7,8]flavone ( 3), 2-(3,4-dihydroxyphenyl)-6-((2,2-dimethyl-6-methylenecyclohexyl)methyl)-5,7-dihydroxy-chroman-4-one ( 4), and 2-(3,4-dihydroxy-2-[(2,6,6-trimethylcyclohex-2-enyl)methyl]phenyl)-3,5,7-trihydroxy-4 H-chromen-4-one ( 5), together with six known compounds, were isolated and purified from the rhizomes of Helminthostachys zeylanica by column chromatography and high performance liquid chromatography (HPLC) via bioactivity-guided fractionation isolation. The structures of the new isolates were elucidated by spectroscopic methods. Compounds 1, 3, and 5 showed inhibitory activities on either superoxide anion generation or elastase release by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (FMLP/CB)., ((c) Georg Thieme Verlag KG Stuttgart . New York.)

Annonaceous acetogenins represent a class of bioactive compounds whose primary mode of action is the inhibition of NADH-ubiquinone oxidoreductase (Mitochondrial Complex I). Given the potential pesticidal use of these compounds, we evaluated the effects of seven acetogenins: squamocin (1), molvizarin (2), itrabin (3), almuñequin (4), cherimolin-1 (5), cherimolin-2 (6), and tucumanin (7) isolated from Annona cherimolia Mill. against Ceratitis capitata Wiedemann (Tephritidae). These acetogenins did not display insecticidal action at 250 microg of treatment per g of adult diet. However, the oviposition capacity of C. capitata females was significantly altered by some of the acetogenins at this concentration. The most potent compounds were itrabin, molvizarin and squamocin. Moreover, significant differences were detected in the preference of oviposition sites when itrabin and squamocin were spread on the surface of artificial fruits at doses of 30 microg/cm2. Additionally, we investigated the mutagenic effects displayed by itrabin, as well as the phytotoxic and genotoxic action of squamocin and itrabin. Both compounds displayed slight phytotoxic and genotoxic effects on roots of Allium cepa at 2.5 microg/mL though no mutagenic effects were detected at 0.25, 0.5 and 2.5 microg/mL on Salmonella typhimurium strains TA98 and TA100.

The synthesis of the subgroups of acetogenins containing non-adjacent bis-THF and non-adjacent THF-THP core units is reviewed. Specifically, total syntheses of gigantecin, 4-deoxygigantecin, cis-sylvaticin, squamostatin-C, squamostatin-D, sylvaticin and mucocin are discussed.

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

A methylene chloride extract of the pulp of Annona muricata L. was fractionated in search for scarcely functionalized Annonaceous acetogenins (type E). Previously known C-35 and C-37 mono-epoxy unsaturated compounds, epomuricenins-A and -B (1+2) and epomusenins-A and -B (3+4), were obtained. Two new mono-epoxy saturated C-35 representatives, epomurinins-A and -B (5+6) were also isolated.

Most Annonaceous acetogenins are characterized by between one and three THF ring(s) with one or two flanking hydroxyl group(s) in the center of a C32/34 fatty acid, and the terminal carboxylic acid is combined with a 2-propanol unit to form an alpha,beta-unsaturated gamma-lactone. While many studies have addressed the properties and synthesis of natural acetogenins due to their attractive biological activities and unique structural features, a number of analogues have also been described. This review covers the design, synthesis, and biological evaluation of acetogenin analogues.

Three new C-methylated acetogenins, (2E,6Z)-9,10-dihydroxy-4-hydroxymethyl-2,6-decadiene (1), (2E,6Z)-8,9,10-trihydroxy-4-hydroxymethyl-2,6-decadiene (2), and (2E,6Z)-9-hydroxy-4-hydroxymethyl-2,6-nonadiene (3), together with two known compounds, p-hydroxybenzyl alcohol (4) and indolyl-3-carboxylic acid (5), were isolated from endophytic fungus S20 of Cephalotaxus hainanensis Li. Their structures were determined based on HR-ESI-MS and spectroscopic techniques (IR, UV, 1D, and 2D NMR). Compound 5 showed inhibitory effects on Staphylococcus aureus and methicillin-resistant S. aureus by the filter paper disc agar diffusion method.

Twelve annonaceous acetogenins (ACGs) with different stereochemical structures and configuration were selected to test for their inhibitions on the growth of Hela, SMMC-7541, SGC-7901, MCF-7 and A-5408 tumor cell lines using MTT method. This was the first to simultaneously investigate effects of structural factors of stereochemical structures and configuration on cytotoxicities with structure-activity relationship. The present study showed that cytotoxic selectivities of ACGs with threo/trans/threo/trans/erythro stereochemical arrangement were gently more active than those with threo/trans/threo/trans/threo stereochemical arrangement, and ACGs with cis THF ring partly produced notable cytotoxic selectivities. Furthermore, ACGs with S configuration at C-24 exhibited gently more cytotoxic selectivities potency than those with R configuration at C-24.

Two new annonaceous acetogenins named as squamostanin-C and squamostanin-D were isolated from 95% EtOH extract of the seeds of Annona squamosa. Their structures were determined by spectroscopic method, and their cytotoxicities were evaluated by using MTT method.

Four Deltalac-acetogenins have been prepared and characterized as inhibitors of the mitochondrial respiratory chain, to define the effects of unsaturation within the alkyl substituents. In keeping with earlier reports, the presence of acetylenic functionalities within the alkyl substituents slightly diminished their potency of inhibition of NADH oxidase activity, which measures the overall transfer of electrons from NADH to oxygen through mitochondrial complexes I, III, and IV. In contrast, both of the acetylenic Deltalac-acetogenins were far more active in a NADH-ubiquinone Q(1) oxidoreductase assay that measures complex I function per se.

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.

Two new annonaceous acetogenins named as squamostanin-A and squamostanin-B were isolated from 95% EtOH extract of the seeds of Annona squamosa. Their structures were determined by spectroscopic method, and their cytotoxicities were evaluated using MTT method.