Bioactive Acetogenins Research Articles

Anti‐Phytopathogenic and Phytotoxic Effects of Annona glabra Lin. and Annona muricata Lin. Seed Extracts: In vitro and In vivo Assessment, Bioactive Compound Quantification, and Mechanism Involved

AbstractBuilding upon prior research demonstrating the excellent antifungal and nematicidal efficacy of Annona squamosa Lin. seed extracts, this study extends its scope to investigate similar properties in seed extracts from two other Annonaceae species: Annona muricata Lin. and Annona glabra Lin. The focus is on assessing their effectiveness against tomato late blight (TLB) and wheat leaf rust (WLR) diseases, as well as their broader antifungal activity against Colletotrichum sp. and Fusarium sp. The A. glabra seed extract exerted a superior control efficacy against TLB (85 % at 62.5 μg/mL) and WLR (75 % at 125 μg/mL) in vivo. The two Annonaceous extracts also exhibited in vitro antifungal inhibition against Colletotrichum sp. and Fusarium sp., as well as toxicology against pine wilt nematodes and Artemia salina. Besides, they showed phytotoxicity against Raphanus sativus seed germination. Squamocin G, a potent bioactive acetogenin, was isolated from A. glabara, which was found to occur at high contents in the following ascending order in A. glabra, A. muricata and A. squamosa dichloromethane extracts. To investigate the antifungal mechanism, molecular docking and molecular dynamic of squamocin G ligand were also performed for the first time at the active site of succinate dehydrogenase and β‐tubulin.

Antifungal activity screening of fractions from Annona cherimola Mill. leaf extract against Fusarium oxysporum.

The antifungal effect of ethanolic extract fractions of Annona cherimola leaves against the mycelial growth of Fusarium oxysporum was studied. The ethanolic crude extract was solvent partitioned and the ethyl acetate phase was fractionated by column or preparative thin-layer chromatography. All fractions were developed on TLC and analyzed for acetogenins (ACG) with Kedde reagent. The antifungal effect assays were carried out in vitro by the diffusion method on PDA plates. The ethanolic extract of A. cherimola leaves was highly active against F. oxysporum growth; subfractions obtained from the antifungal screening had a significant effect (p < 0.05) on the F. oxysporum growth parameters. The screening showed that as the purification steps progressed, the inhibition of mycelial growth increased. Six bioactive ACG (Annomolon-B, 34-epi annomolon B, almunequin, cherimoline 1, cherimoline 2, and isocherimoline 1) were identified by LC-QTOF-MS/MS. These findings suggested that bioactive ACG from A. cherimola leaves could be an alternative resource of a promising botanical fungicide to control plant diseases caused by F. oxysporum.

Growth Inhibition, Residual Contact and Translaminar Toxicity of Annona-based Bioinsecticides on Tomato Leafminer: Laboratory and Greenhouse Assessments

This study aimed to evaluate the bioactivity of ethanolic extracts from different parts of some Annona species (A. montana, A. muricata and A. sylvatica) against T. absoluta. In the initial screening, the ethanolic extracts from leaves and seeds of A. muricata promoted pronounced lethality and growth inhibition of T. absoluta larvae by means of residual contact and translaminar action. However, these extracts did not affect its biology, oviposition in choice and no-choice tests, as well as egg viability. Afterwards, the crude ethanolic extracts of leaves and seeds from A. muricata were submitted to liquid-liquid partitioning, and their respective fractions were evaluated against T. absoluta larvae. These procedures disclosed the hydroalcoholic fraction from A. muricata seeds and both the ethyl acetate and dichloromethane fractions from its leaves as the most active against T. absoluta larvae. Then, proton nuclear magnetic resonance (1H NMR) experiments were performed aiming to identify the main constituents present in these fractions. The chemical analyses of each NMR spectrum revealed that A. muricata bioactive fractions presented acetogenins as major compounds. Moreover, a formulated ethanolic extract from A. muricata seeds presented similar bioactivity against T. absoluta larvae in both laboratory and greenhouse bioassays when compared with two commercial botanical insecticides (AnosomTM 1 EC and Azaamax 1.2 EC). Therefore, the seeds from A. muricata, discarded during the process of its fruit pulp extraction, are a potential source of bioactive acetogenins to formulate botanical insecticides to control populations of T. absoluta in tomato crops, mainly in organic production systems.

Chiral Pool/Henry/Enzymatic Routes to Acetogenin Synthons

Enantiospecific and enantioselective approaches to the natural (16R,19R)- and the unnatural (16S,19S)- THF core of the bioactive acetogenin annonacin are described which utilizes both a chiral pool synthesis and enzymatic transformations. In the antipodal (2S,5S) THF series derived from D- (+)-glucosamine, the semi-protected THF aldehyde synthon allows for two-directional synthetic elaboration through a Henry reaction with a lipid-like nitroalkane. The resulting nitroalcohol having the unnatural (2S,5S)-THF core was oxidized to the corresponding -nitroketone using a modified Collins oxidation. The intermediate -nitroketone has potential for the preparation of the C15-C32 core and analogues through subsequent removal of the nitro group and reduction of the carbonyl. Keywords: Acetogenins, angiogenesis, THF’s, lipases, chiral pool, Henry reaction.

Antimicrobial and cytotoxic acetogenin from Polyalthia debilis

ABSTRACT Objective: To isolate bioactive acetogenin compound and to investigate antimicrobial, antioxidant as well as cytotoxic activities of the isolate, fractions and extracts of Polyalthia debilis. Methods: The P. debilis (roots) extracts and isolated compound were tested for their antimicrobial (agar dilution method) against twenty-seven strains of microorganisms (gram positive and gram negative bacteria, and diploid fungus), antioxidant (DPPH assay) and cytotoxic activities. The plant extracts were isolated by column chromatography and structure of compound was confirmed by spectral data . Result: The plant extracts and isolated fractions exhibited antioxidant and cytotoxic activities. The isolated acetogenin 1 (debilisome E) displayed antimicrobial activity against Morexella catarrhalis with the MIC of 64 microgram/mL, Corynebacterium diphtheriae NCTC 10356 and Streptococcus pyogenes with partial inhibition (50-75%) at 128 microgram/mL. The compound 1 exerted cytotoxic activity against 5 cancer cells (HepG2, A549, HCC-S102,HL-60 and P388) with IC50 values 18.4 - 40.3 microgram/mL. Conclusion: The results demonstrate novel bioactivities of P. debilis as antimicrobials and anticancer agents.

Dietary Administration of Asimina triloba. (Paw Paw) Extract Increases Tumor Latency in N.-Methyl-N.-nitrosourea–Treated Rats

The paw paw tree, Asimina triloba. (L.) Dunal (Annonaceae), contains more than 50 bioactive components, primarily annonaceous acetogenins. Some therapeutic activities have been associated with this material, but the potential to mediate a cancer chemopreventive effect has not been reported. In this study, a standardized extract from the twigs, in which bullatacin, asimicin, and trilobacin represent the most potent and major bioactive acetogenins, was tested in the N.-methyl-N.-nitrosourea–induced mammary carcinogenesis model. With Sprague-Dawley rats given a diet containing paw paw extract (1250 and 2500 mg/kg diet; based on maximum tolerated dose studies), mammary tumor latency was increased from 55 to 66 days. However, mammary tumor incidence and multiplicity were not affected by extract consumption.

Molecular Simplification in Bioactive Molecules: Formal Synthesis of (+)-Muconin

The concept of molecular simplification as a drug design strategy to shorten synthetic routes, while keeping or enhancing the biological activity of the lead drug, has been applied to (+)-muconin, an acetogenin with remarkable cytotoxicity. A novel approach that enables the stereoselective synthesis of such a natural compound or its enantiomer from a common precursor is described. An additional advantage of the method is complete stereochemical control and the decrease in the number of chemical steps required, thus providing an enhancement of the overall yield. Antiproliferative studies against the human solid tumor cell lines showed that the aliphatic chain-THF/THP fragment of (+)-muconin has modest cytotoxic activity. The strategy opens the way to preparing novel bioactive acetogenin analogues by shorter synthetic routes.

Acetogenins as selective inhibitors of the human ovarian 1A9 tumor cell line.

Several bioactive acetogenins were selective against 1A9 (ovarian cancer) cell replication but did not show a corresponding hyperactivity against other cell lines. The most active compound (26, molvizarin) was a selective inhibitor of 1A9 cell replication with a potency (ED(50) = 5 pg/mL) of over 1 million times more than that for other cell lines.

Bioactive acetogenins from the seeds of Annona atemoya

Six new annonaceous acetogenins, 12,15-cis-squamostatin-D (1), 12,15-cis-squamostatin-A (2), artemoin-A (3), artemoin-B (4), artemoin-C (5) and artemoin-D (6), along with eleven known ones, were isolated from the seeds of Formosan Annona atemoya. The structures of these isolates were established on the basis of mass and related spectral evidence. All of them, except for four linear annonaceous acetogenins, exhibited potent cytotoxicity against Hep G2, Hep 2,2,15, KB, CCM2 and CEM cancer cell lines.

Muridienin-1 and -2: The missing links in the biogenetic precursors of acetogenins of annonaceae

Isolation of Δ n,n+4 diunsaturated γ-lactone derivatives of lacceroic and ghedoic acids, allows us to confirm the biogenetic pathway of the bioactive acetogenins of Annonaceae.

Cis-Gigantrionenin and 4-acetyl gigantetrocin A, two new bioactive annonaceous acetogenins from Goniothalamus giganteus, and the stereochemistries of acetogenin 1,2,5-triols

Using activity-directed fractionation, two new bioactive acetogenins, cis-gigantrionenin (1) and 4-acetyl gigantetrocin A (2), have been isolated from the bark of Goniothalamus giganteus (Annonaceae). Compound 1 has a cis-mono-THF ring with one flanking hydroxyl and possesses a cis-double bond at C-21/22 of the aliphatic chain; it represents only the second example of the cis-mono-THF ring annonaceous acetogenins having one flanking hydroxyl. Compound 2 has a trans-mono-THF ring with one flanking hydroxyl, but it possesses a mono-acetyl group at the 4-OH position; it represents only the second natural example of the acetylated annonaceous acetogenins; the first acetogenin reported, uvaricin, was mono-acetylated at the 24-OH. The stereochemistries of 1 and 2 were determined by the advanced Mosher ester method. In addition, the absolute stereochemistries of gigantriocin (3), gigantrionenin (4), and giganenin (5) were determined by the advanced Mosher ester method and by circular dichroism (CD). The stereochemistries of the 7,8-diols in murihexocins A (6) and B (7) were determined to have the S,S-configurations, respectively.

4-Acetyl Annonacin and 4-Acetyl Xylomaticin: Two Novel Bioactive Mono-Tetrahydrofuran Annonaceous Acetogenins fromAsimina Longifolia(Annonaceae)

Abstract Two novel bioactive acetogenins, 4-acetyl annonacin (1) and 4-acetyl xylomaticin (2), were isolated from the leaves and twigs of Asimina longifolia K. (Annonaceae) by directing the fractionation with the brine shrimp lethality test. 1 and 2 each has a mono-tetrahydrofuran (THF) ring with two flanking hydroxyl groups and an α, β-unsaturated γ-lactone with a 4-acetoxyl. The presence of acetoxyl groups is a feature rarely found in the Annonaceous acetogenins. 1 and 2 showed potent and selective cytotoxicities among six human tumor cell lines.

Applying Mosher's method to acetogenins bearing vicinal diols. The absolute configurations of muricatetrocin C and rollidecins A and B, new bioactive acetogenins from Rollinia mucosa

Muricatetrocin C (1), rollidecin A (2), and rollidecin B (3), three new bioactive annonaceous acetogenins bearing vicinal diols, were isolated from the leaves of Rollinia mucosa (Annonaceae) using activity-directed fractionation. The total structural elucidations of 1–3, including the absolute stereochemistries of the vicinal diols, were achieved by analyzing their per-Mosher ester derivatives. All three compounds showed potent and selective inhibitory effects against several human cancer cell lines.

Squamotacin: an annonaceous acetogenin with cytotoxic selectivity for the human prostate tumor cell line (PC-3).

The bark extracts of Annona squamosa yielded a new bioactive acetogenin, squamotacin (1), and the known compound, molvizarin (2), which is new to this species. Compound 1 is identical to the potent acetogenin, bullatacin (3), except that the adjacent bistetrahydrofuran (THF) rings and their flanking hydroxyls are shifted two carbons toward the gamma-lactone ring. Compound 1 showed cytotoxic selectively for the human prostate tumor cell line (PC-3), with a potency of over 100 million times that of Adriamycin.

Additional bioactive acetogenins, annomutacin and (2,4-trans and cis)-10R-annonacin-A-ones, from the leaves of Annona muricata.

In a continuation of our research on bioactive components from the leaves of Annona muricata, three novel monotetrahydrofuran Annonaceous acetogenins, namely, annomutacin [1], (2,4-trans)-10R-annonacin-A-one [2], and (2,4-cis)-10R- annonacin-A-one [3], have been identified. Their structures were deduced by ms, nmr, ir, and uv spectral and chemical methods, and the absolute configurations were determined by Mosher ester methodology. A known bioactive amide, N-p-coumaroyl tyramine, was also found. Compound 1 and the mixture of compounds 2 and 3 showed selective cytotoxicities against the human A-549 lung tumor cell line.

Aplyparvunin, a bioactive acetogenin from the sea hare Aplysia parvula

A novel bioactive acetogenin, aplyparvunin ( 1) was isolated from the Japanese marine mollusk Aplysia parvula (Aplysiidae). Its structure has been elucidated by spectroscopic evidence and a single crystal X-ray analysis.

Annohexocin, a novel mono-THF acetogenin with six hydroxyls, from Annona muricata (Annonaceae)

A novel bioactive acetogenin, annohexocin ( 1), was isolated from the leaves of the sour sop (or guanabana) tree, Annona muricata (Annonaceae). Compound 1 is a C-35 mono-tetrahydrofuran (THF) acetogenin having six OH groups, and its structure has been elucidated by spectroscopic analyses. Compound 1 is the first Annonaceous acetogenin to be reported in which six OH groups include a 1,3,5 triol. Compound 1 was isolated by following brine shrimp lethality, and it showed significant inhibitory effects among six human tumor cell lines.

Murihexocins A and B, two novel mono-THF acetogenins with six hydroxyls, from Annona muricata (Annonaceae)

Two novel bioactive acetogenins, murihexocins A (1) and B (2), were isolated from the leaves of the sour sop tree, Annona muricata (Annonaceae). 1 and 2 are C-35 mono-tetrahydrofuran (THF) acetogenins having six hydroxyls, and their structures have been elucidated by spectroscopic analyses and derivations. No Annonaceous acetogenins having six hydroxyls or with two vicinal diol groups have been reported previously. 1 and 2 showed significant inhibitory effects among six human tumor cell lines with interesting selectivities to the prostate (PC-3) and pancreatic (PACA-2) cell lines.

Murihexocins A and B, two novel mono-THF acetogenins with six hydroxyls, from Annona muricata (Annonaceae)

Two novel bioactive acetogenins, murihexocins A ( 1) and B ( 2), were isolated from the leaves of the sour sop tree, Annona muricata (Annonaceae). 1 and 2 are C-35 mono-tetrahydrofuran (THF) acetogenins having six hydroxyls, and their structures have been elucidated by spectroscopic analyses and derivations. No Annonaceous acetogenins having six hydroxyls or with two vicinal diol groups have been reported previously. 1 and 2 showed significant inhibitory effects among six human tumor cell lines with interesting selectivities to the prostate (PC-3) and pancreatic (PACA-2) cell lines.

Rioclarine et Membranacine, Deux Nouvelles Acetogenines Bis-tetrahydrofuraniques des Graines de Rollinia membranacea

The fractionation of the cytotoxic MeOH extract of the seeds of Rollinia membranarea (Annonaceae) led to the isolation of two new adjacent bis-tetrahydrofuran acetogenins, rioclarin [1] and membranacin [2], and two other known acetogenins, squamocin [3] and rolliniastarin 1 [4]. In addition to these bioactive acetogenins, a new furofuranic lignan (membrin [5]) and a known one (magnolin [6]), have been obtained. Rioclarin [1] is an original terrahydroxylared bis-tetrahydrofuran acetogenin. Its structure was established on the basis of ms and 1D and 2D nmr experiments