Acyclic Terpenoids Research Articles

In Vivo, In Vitro and In Silico Anticancer Activity of Ilama Leaves: An Edible and Medicinal Plant in Mexico.

Ilama leaves are an important source of secondary metabolites with promising anticancer properties. Cancer is a disease that affects a great number of people worldwide. This work aimed to investigate the in vivo, in vitro and in silico anticancer properties of three acyclic terpenoids (geranylgeraniol, phytol and farnesyl acetate) isolated from petroleum ether extract of ilama leaves. Their cytotoxic activity against U-937 cells was assessed using flow cytometry to determine the type of cell death and production of reactive oxygen species (ROS). Also, a morphological analysis of the lymph nodes and a molecular docking study using three proteins related with cancer as targets, namely, Bcl-2, Mcl-1 and VEGFR-2, were performed. The flow cytometry and histomorphological analysis revealed that geranylgeraniol, phytol and farnesyl acetate induced the death of U-937 cells by late apoptosis and necrosis. Geranylgeraniol and phytol induced a significant increase in ROS production. The molecular docking studies showed that geranylgeraniol had more affinity for Bcl-2 and VEGFR-2. In the case of farnesyl acetate, it showed the best affinity for Mcl-1. This study provides information that supports the anticancer potential of geranylgeraniol, phytol and farnesyl acetate as compounds for the treatment of cancer, particularly with the potential to treat non-Hodgkin's lymphoma.

Anti-Microbial Activity of Aliphatic Alcohols from Chinese Black Cardamom (Amomum tsao-ko) against Mycobacterium tuberculosis H37Rv

The fruits of Amomun tsao-ko (Chinese black cardamom; Zingiberaceae) contain an abundance of essential oils, which have previously demonstrated significant antimicrobial activity. In our preliminary search for natural anti-tuberculosis agents, an acetone extract of A. tsao-ko (AAE) exhibited strong antibacterial activity against Mycobacterium tuberculosis H37Rv. Therefore, the aim of this study was to find the principal compounds in an AAE against M. tuberculosis. Nine aliphatic compounds (1−9) including a new compound (1, tsaokol B) and a new natural unsaturated aliphatic diester (6), together with three acyclic terpenoids (10−12), were isolated from an AAE by repetitive chromatography. The structures of the isolates were determined by spectroscopic data analysis. All isolates were evaluated for activity against M. tuberculosis H37Rv. Isolated compounds 1−6, and 11 had MICs ranging from 0.6−89 µg/mL. In contrast, compounds 7 to 10, and 12 had MICs that were >100 µg/mL. Tsaokol A (3) was the most active compound with MICs of 0.6 µg/mL and 1.4 µg/mL, respectively, against replicating and nonreplicating M. tuberculosis. These results are the first to illustrate the potency of tsaokol A (3) as a natural drug candidate with good selectivity for treating tuberculosis.

Understanding the Antilymphoma Activity of Annona macroprophyllata Donn and Its Acyclic Terpenoids: In Vivo, In Vitro, and In Silico Studies.

Annona macroprophyllata Donn (A. macroprophyllata) is used in traditional Mexican medicine for the treatment of cancer, diabetes, inflammation, and pain. In this work, we evaluated the antitumor activity of three acyclic terpenoids obtained from A. macroprophyllata to assess their potential as antilymphoma agents. We identified the terpenoids farnesyl acetate (FA), phytol (PT) and geranylgeraniol (Gg) using gas chromatography–mass spectroscopy (GC-MS) and spectroscopic (1H, and 13C NMR) methods applied to petroleum ether extract of leaves from A. macroprophyllata (PEAm). We investigated antitumor potential in Balb/c mice inoculated with U-937 cells by assessing brine shrimp lethality (BSL), and cytotoxic activity in these cells. In addition, to assess the potential toxicity of PEAm, FA, PT and Gg in humans, we tested their acute oral toxicity in mice. Our results showed that the three terpenoids exhibited considerable antilymphoma and cytotoxic activity. In terms of lethality, we determined a median lethal dose (LD50) for thirteen isolated products of PEAm. Gg, PT and AF all exhibited a higher lethality with values of 1.41 ± 0.42, 3.03 ± 0.33 and 5.82 ± 0.58 µg mL−1, respectively. To assess cytotoxic activity against U-937 cells, we calculated the mean cytotoxic concentration (CC50) and found that FA and PT were closer in respect to the control drug methotrexate (MTX, 0.243 ± 0.007 µM). In terms of antilymphoma activity, we found that FA, PT and Gg considerably inhibited lymph node growth, with median effective doses (ED50) of 5.89 ± 0.39, 6.71 ± 0.31 and 7.22 ± 0.51 mg kg−1 in females and 5.09 ± 0.66, 5.83 ± 0.50 and 6.98 ± 0.57mg kg −1 in males, respectively. Regarding acute oral toxicity, we classified all three terpenoids as category IV, indicating a high safety margin for human administration. Finally, in a molecular docking study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, we found binding of terpenoids to some amino acids of the catalytic site, suggesting an effect upon activity with a resulting decrease in the synthesis of intermediates involved in the prenylation of proteins involved in cancer progression. Our findings suggest that the acyclic terpenoids FA, PT, and Gg may serve as scaffolds for the development of new treatments for non-Hodgkin’s lymphoma.

Antihyperglycemic Effects of Annona diversifolia Safford and Its Acyclic Terpenoids: α-Glucosidase and Selective SGLT1 Inhibitiors.

Annona diversifolia Safford and two acyclic terpenoids were evaluated to determine their antihyperglycemic activity as potential α-glucosidase and selective SGLT-1 inhibitiors. Ethanolic extract (EEAd), chloroformic (CHCl3Fr), ethyl acetate (EtOAcFr), aqueous residual (AcRFr), secondary 5 (Fr5) fractions, farnesal (1), and farnesol (2) were evaluated on normoglycemic and streptozocin-induced diabetic mice. EEAd, CHCl3Fr, Fr5, (1) and (2) showed antihyperglycemic activity. The potential as α-glucosidase inhibitors of products was evaluated with oral sucrose and lactose tolerance (OSTT and OLTT, respectively) and intestinal sucrose hydrolysis (ISH) tests; the potential as SGLT-1 inhibitors was evaluated using oral glucose tolerance (OGTT), intestinal glucose absorption (IGA), and urinary glucose excretion (UGE) tests. In OSTT and OLTT, all treatments showed significant activity at two and four hours. In ISH, half maximal effective concentrations (CE50) of 565, 662 and 590 μg/mL, 682 and 802 μM were calculated, respectively. In OGTT, all treatments showed significant activity at two hours. In IGA, CE50 values of 1059, 783 and 539 μg/mL, 1211 and 327 μM were calculated, respectively. In UGE Fr5, (1) and (2) showed significant reduction of the glucose excreted compared with canagliflozin. These results suggest that the antihyperglycemic activity is mediated by α-glucosidase and selective SGLT-1 inhibition.

Acyclic diterpene and norsesquiterpene from the seed of Aphanamixis polystachya

Aphanamoxene A-D (1–4), three new acyclic diterpene derivatives and one new acyclic norsesquiterpene were isolated from the seed of Aphanamixis polystachya. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR and HRESIMS. And the absolute configuration of 1 was achieved by Mosher method. These acyclic terpenoids (1–4) showed obvious nitric oxide production inhibitory activity on lipopolysaccharide-Induced RAW264.7 macrophages with IC50 values of 17.6 ± 1.4, 9.8 ± 0.7, 16.6 ± 1.2, and 14.2 ± 0.9 μM, respectively.

Synthesis of Cembranoid Analogues through Ring-Closing Metathesis of Terpenoid Precursors: A Challenge Regarding Ring-Size Selectivity.

A systematic study on ring-closing metathesis with Grubbs II catalyst to cembranoid macrocycles is described. Acyclic terpenoids with a functional group X in the homoallylic position relative to an RCM active terminus and substituents R, R(1) directly attached to the other terminal double bond were prepared from geraniol derived trienes and fragments that are based on bromoalkenes and dimethyl malonate. Such terpenoids were suitable precursors, despite the presence of competing double bonds in their framework. The size of R and R(1) is crucial for successful macrocyclization. Whereas small alkyl substituents at the double bond directed the RCM towards six-membered ring formation, cross metathesis leading to dimers dominated for bulkier alkyl groups. A similar result was obtained for precursors without functional group X. In the case of unsymmetrically substituted terpenoid precursor (R = Et, R(1) = Me) with homoallylic OTBS or OMe group, the RCM could be controlled towards formation of macrocyclic cembranoids, which were isolated with excellent E-selectivity. The role of the substituents was further studied by quantum chemical calculations of simplified model substrates. Based on these results a mechanistic rationale is proposed.

Comparative study on the free radical scavenging mechanism exerted by geraniol and geranylacetone using the combined experimental and theoretical approach

AbstractIn the current study the free radical scavenging mechanism of geraniol and geranylacetone has been investigated experimentally and theoretically. Two fragrant acyclic terpenoids were subjected to the ABTS and DPPH assay. Furthermore, the detailed quantum chemical calculations have been undertaken in order to evaluate the possible pathways underlying the radical scavenging activity of selected compounds in the non‐polar and polar media. The density functional theory (DFT) using the hybrid Becke three‐parameter exchange‐correlation functional (B3LYP) was applied. In general both investigated compounds possessed very weak anti‐radical activity at the applied experimental conditions but geranylacetone was significantly more effective as a ABTS•+ and DPPH• scavenger than geraniol. The comparison of DFT‐predicted reaction enthalpies associated with the hydrogen atom transfer mechanism (HAT), the single electron and proton transfer process (SET‐PT) and the sequential proton loss electron‐transfer (SPLET), revealed that the former mechanism should be favoured in geraniol solvated in both the non‐polar and polar media. On the contrary, an anti‐radical activity of geranylacetone in the non‐polar solvent was ascribed to the hydrogen donation mechanism while in the polar solvent it was assigned to the SPLET. According to the computational results the presence of allylic H‐atom (at the position 1C) close to the –OH group seemed to be essential for the observed anti‐radical activity of geraniol. The scavenging ability of geranylacetone was associated with the presence of both allylic and alkylic hydrogens in the close vicinity of the carbonyl functionality. Copyright © 2015 John Wiley & Sons, Ltd.

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX.

Allylic alcohols are valuable precursors in the synthesis of pharmaceutical intermediates, agrochemicals and natural products. Regioselective oxidation of parental alkenes is a challenging task for chemical catalysts and requires several steps including protection and deprotection. Many cytochrome P450 enzymes are known to catalyse selective allylic hydroxylation under mild conditions. Here, we describe CYP154E1 from Thermobifida fusca YX that enables this type of oxidation. Several acyclic terpenoids were tested as possible substrates for CYP154E1, and the regio- and chemoselectivity of their oxidation was investigated. Using a previously established bioinformatics approach we identified position 286 in the active site of CYP154E1 which is putatively involved in substrate binding and thereby might have an effect on enzyme selectivity. To tune regio- and chemoselectivity of the enzyme three mutants at position 286 were constructed and used for substrate oxidation. All formed products were analysed with GC–MS and identified using chemically synthesised authentic samples and known compounds as references. Best regioselectivity towards geraniol and nerol was observed with the wild type enzyme mainly leading to 8-hydroxy derivatives (8-hydroxygeraniol or 8-hydroxynerol) with high selectivity (100% and 96% respectively). Highest selectivities during the oxidation of geranylacetone and nerylacetone were observed with the following variants: V286F led mainly to 7-hydroxygeranylacetone (60% of the total product) and V286A produced predominantly 12-hydroxynerylacetone (75% of total product). Thus, CYP154E1 and its mutants expand the tool-box for allylic hydroxylation in synthetic chemistry.

Insect hormones: more than 50-years after the discovery of insect juvenile hormone analogues (JHA, juvenoids)

Insect hormones: more than 50-years after the discovery of insect juvenile hormone analogues (JHA, juvenoids)

Phytochemical and antimicrobial screening of Capparis decidua stems

Background: The chromatographic separation of aerial parts of Capparis decidua , a woody medicinal plant, afforded one shikimate derivative, two acyclic terpenoids, four fatty acids, two sterols and two lupare triterpenoids Methods: in the present study, qualitative chemical screening of ethyle ether, methanol and water extracts of Capparis decidua stems (family Cappariaceae ) showed the presence of triterpenes, fatty acids, carotenoids, coumarins and basic alkaloids. The methanol extract revealed the presence of condensed tannins, alkaloids, cardiac glycosides and anthocyanins while the aqueous extract revealed the presence of saponins, polyurenoids, condensed tannins, alkaloids and anthocyanine. All extracts were devoid of anthracene glycosides, flavanoids and reducing compounds. The antimicrobial activity of chloroform, methanol and water extract were studied in vitro against two standard gram positive bacteria ( Bacillus subtilis and Staphylococcus aureus ), two standard gram negative bacteria ( Escherichia coli and Pseudomonas aeruginosa ) and two standard fungal organisms ( Aspergillus niger and Candida albicans ) using the cup-plate agar diffusion method. Results: The results showed that the extracts had antimicrobial activity against at least two of the tested standard organisms; methanol extract was found to be highly active against the standard gram positive bacteria and Candida albicans , followed by the chloroform extract. The least antimicrobial activity was associated with the aqueous extract. Ten fractions were obtained when the chloroform extract was fractionated by the Preparative Thin Layer Chromatography (PTLC), their antimicrobial activity was studied in vitro against two standard gram positive bacteria ( Bacillus subtilis and Staphylococcus aureus ). Conclusion: The methanol extract fractionation gave five fractions and their antimicrobial activity was studied against Staphylococcus aureus and Candida albicans .

Identification and Characterization of the Linalool/Nerolidol Synthase from Streptomyces clavuligerus

No cyclization: To produce the parent skeletons of diverse terpenoids, linear isoprenyl diphosphate precursors are usually cyclized by terpenoid cyclases. However, some terpenoid synthases produce acyclic terpenoids from the linear substrates. The linalool/nerolidol synthase reported here is the first example of a bacterial acyclic terpenoid synthase that shows significant homology to bacterial terpenoid cyclases.

Catabolism of citronellol and related acyclic terpenoids in pseudomonads

Terpenes are a huge group of natural compounds characterised by their predominantly pleasant smell. They are built up by isoprene units in cyclic or acyclic form and can be functionalised by carbonyl, hydroxyl or carboxyl groups and by presence of additional carbon-carbon double bonds (terpenoids). Currently, much more than 10,000 terpenoid compounds are known, and many thereof are present in different iso- and stereoforms. Terpenoids are secondary metabolites and can have important biological functions in living organisms. In many cases, the biological functions of terpenoids are not known at all. Nevertheless, terpenoids are used in large quantities as perfumes and aroma compounds for food additives. Terpenoids can be also precursors and building blocks for synthesis of complex chiral compounds in chemical and pharmaceutical industry. Unfortunately, only few terpenoids are available in large quantities at reasonable costs. Therefore, characterisation of suited biocatalysts specific for terpenoid compounds and development of biotransformation processes of abundant terpenoids to commercially interesting derivates becomes more and more important. This minireview summarises knowledge on catabolic pathways and biotransformations of acyclic monoterpenes that have received only little attention. Terpenoids with 20 or more carbon atoms are not a subject of this study.

General Preparation and Controlled Cyclization of Acyclic Terpenoids

A general preparation method of the all-(E)-polyprenols 12 has been developed from readily available geranyl sulfone by the chain-extension process utilizing the C5 unit 5 and the chain-termination process utilizing the C5 unit 10 together with the chemoselective reductive desulfonylation. The polyprenols 12 were converted to compounds 3 containing two consecutive prenyl sulfone moieties at the tail end, which underwent the controlled electrophilic cyclization only at the carbon-carbon double bonds that were remote from the flat and rigid benzenesulfonyl groups.

Synthesis of moenocinol and its analogs using BT-sulfone in Julia-Kocienski olefination

Moenocinol (C 25H 42O), the acyclic terpenoid unsaturated lipid part of moenomycin antibiotics, was prepared by an expedient method, which comprised organometallic reaction, Julia-Kocienski olefination, and enolate carbon bond formation as the key steps. The starting materials, nerol and 3-butyn-1-ol, were elaborated to the benzothiazole sulfone 2 and aldehyde 3, and the subsequent Julia-Kocienski olefination occurred in a stereospecific manner to give the desired 6 E-configuration of moenocinol. Moenocinol ( 1) was thus synthesized by 10 linear steps in 12% overall yield, and its analogs 23, 24, and 28 with different chain lengths and unsaturation degrees were also realized by the similar reaction sequences.

An Effective and Highly Stereoselective Julia Olefination of Cyclopropyl Carbinol Mediated by CeCl3×7H2O/NaI.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Effective and Highly Stereoselective Julia Olefination of Cyclopropyl Carbinol Mediated by CeCl3·7H2O/NaI

[reaction: see text] An efficient and highly stereoselective synthesis of functionalized trisubstituted E-olefins from cyclopropyl carbinol derivatives via a Julia-type olefination mediated by an intriguing Lewis acidic system consisting of CeCl(3).7H(2)O and NaI in refluxing acetonitrile is reported. This facile olefination allows for the iterative incorporation of methylcyclopropyl ketone as a C(5) prenylation synthon in the synthesis of acyclic terpenoids, as demonstrated in the facile synthesis of plaunotol 6E-isomer 12, a biologically significant diterpene diol, and naturally occurring diterpene 17.

Comparison of three diacetyl-cyclodextrin gas chromatographic stationary phases: Possible indicators of the chemical nature of constituents of volatile oils

Relative retention times (RR) versusn-undecane for thirty solutes from volatile oils are determined for Alpha-, Beta- and Gamma-Dex 225 capillaries. These are diacetyl-cyclodextrin phases to which some solutes respond as though they were conventional phases. However, lowest RR of the three on Beta-Dex 225 indicates a bicyclic terpenoid. Highest RR on this phase can be by an aromatic, or an acyclic terpenoid. Lowest values of correlation coefficients between pairs of variously modified-cyclodextrins for RR of ten selected diverse solutes occur with combinations of any one-Dex 225 phase, indicating that these are desirably different to many other modified-CDs, although not to each other.

Stereocontrolled Synthesis of Acyclic Terpenoids via N‐Ylide [2,3]Rearrangement of Ammonium Salts with the Stereodefined Isoprene Unit.

Stereocontrolled Synthesis of Acyclic Terpenoids via N‐Ylide [2,3]Rearrangement of Ammonium Salts with the Stereodefined Isoprene Unit.

Endo‐Oxacyclizations of Polyepoxides: Biomimetic Synthesis of Fused Polycyclic Ethers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereocontrolled synthesis of acyclic terpenoids via N-ylide [2,3]rearrangement of ammonium salts with the stereodefined isoprene unit

Stereocontrolled elongation of a functionalized isoprene unit on the E or Z terminal methyl of terpenoids was achieved by N-ylide rearrangement of the common ammonium salts under selected reaction conditions. A 1,5-diene or conjugated triene skeleton can be furnished by reductive or oxidative removal of the amino group of the rearrangement product, respectively. As an application to natural-product synthesis, all-(E)-terpenoid (E)-11d and (E,Z)-terpenoid (Z)-11c were converted into β-sinensal and (13Z)-retinol, respectively. General aspects of these transformations and a plausible transition state for the N-ylide rearrangement are discussed.