Terpenoid Structures Research Articles

Further Investigation on the Anti‐inflammatory Mechanism of Action of Enoxolone

Enoxolone (18-β-glycyrrhetinic acid) has been widely used as a topical anti-inflammatory compound. Due to its terpenoid chemical structure related to steroids, it has never been excluded that it could act at least in part, as a glucocorticoid-like drug. In an animal model of inflammation, phorbol ester-induced mouse ear oedema, enoxolone effects were not inhibited by treatment with RU38486, a glucocorticoid-receptor antagonist whereas dexamethasone effects were inhibited by this agent. The results demonstrate that the enoxolone anti-inflammatory mechanism of action is not related to glucocorticoid receptor interaction.

Molecular modelling and QSAR analysis of the estrogenic activity of terpenoids isolated from Ferula plants

The relationship between chemical structure and estrogenic activity in a series of terpenoid esters with aromatic and aliphatic acid substituents isolated from Ferula plants, was studied. The fragments of the terpenoid structure that are potentially responsible for estrogenic activity were revealed. A quantitative structure-estrogenic activity study has been carried out using the QSAR approach with use of data derived from quantum-chemical calculations as well as data generated from three-dimensional structures of terpenoids. A number of molecular descriptors was obtained from the density functional theory (DFT) at the B3LYP/6-31G(d, p) level of calculation. Comparative analysis of the quantum-chemical computational data was also performed to confirm hypothesis concerning importance of the distance between the oxygen of alcohol hydroxyl group and the functional group in the para-position of the benzene ring (the hydroxyl or methoxy group). Use of the Genetic Algorithm in the QSAR analysis allowed the structural and physicochemical parameters of the terpenoids responsible for estrogenic activity to be determined. A significant QSAR model was obtained with an r 2 value of 0.892. The resulting model showed a reliable dependence of estrogenic activity of the terpenoids on such parameters as molecular shape, number of phenolic groups, surface polarity and the energy of the highest occupied molecular orbital.

Triosmium cluster with the bridging aminooxime derivative of pinane: Synthesis, crystal structure and conformational analysis

The reaction of 1R,2R,5R-2-dimethylamino-2,6,6-trimethylbicyclo[3.1.1]heptane-3-one oxime (pinaneoxime) with Os3(CO)10(NCMe)2 was used to synthesize the (μ-H)Os3(μ-κ1-O-N=C12H21N)(CO)10 cluster with coordination of the ligand through the oxime O atom and invariable terpenoid structure. The structure of the synthesized cluster was determined by X-ray diffraction analysis. The theoretical conformational analysis of the above cluster in a solution and in crystal state was performed by a combined MM3/MERA method. The rotation of a ligand about the O(1)-N(2) bond was found impossible due to a high energy barrier (E > 550 kJ/mol).

Structural determinants of odorant recognition by the human olfactory receptors OR1A1 and OR1A2

An interaction of odorants with olfactory receptors is thought to be the initial step in odorant detection. However, ligands have been reported for only 6 out of 380 human olfactory receptors, with their structural determinants of odorant recognition just beginning to emerge. Guided by the notion that amino acid positions that interact with specific odorants would be conserved in orthologs, but variable in paralogs, and based on the prediction of a set of 22 of such amino acid positions, we have combined site-directed mutagenesis, rhodopsin-based homology modelling, and functional expression in HeLa/Olf cells of receptors OR1A1 and OR1A2. We found that (i) their odorant profiles are centred around citronellic terpenoid structures, (ii) two evolutionary conserved amino acid residues in transmembrane domain 3 are necessary for the responsiveness of OR1A1 and the mouse ortholog Olfr43 to ( S)-(−)-citronellol, (iii) changes at these two positions are sufficient to account for the differential ( S)-(−)-citronellol responsiveness of the paralogs OR1A1 and OR1A2, and (iv) the interaction sites for ( S)-(−)-citronellal and ( S)-(−)-citronellol differ in both human receptors. Our results show that the orientation of odorants within a homology modelling-derived binding pocket of olfactory receptor orthologs is defined by evolutionary conserved amino acid positions.

Automatic identification of terpenoid skeletons by feed-forward neural networks

Feed-forward neural networks (FFNNs) were used to predict the skeletal type of molecules belonging to six classes of terpenoids. A database that contains the 13C NMR spectra of about 5000 compounds was used to train the FFNNs. An efficient representation of the spectra was designed and the constitution of the best FFNN input vector format resorted from an heuristic approach. The latter was derived from general considerations on terpenoid structures.

Terpenoids from Marine Organisms: Unique Structures and their Pharmacological Potential

Marine organisms produce a wide array of fascinating terpenoid structures distinguished by characteristic structural features. Certain structural classes, e.g. cembrane, chamigrene, amphilectane skeletons, and unusual functional groups such as isonitrile, isothiocyanate, isocyanate, dichloroimine and halogenated functionalities occur predominantly in marine metabolites. Especially striking is the frequent occurrence of sesterterpenes in marine organisms, and sponges must be considered as one of the prime sources of these C25 terpenoid compounds. In most cases however, these structural features are not strictly unique for marine natural products. The prominent biological activity of marine terpenes is evident in their ecological role in the marine environment, and makes them interesting as potential drugs. Several terpenoid compounds, e.g. eleutherobin, sarcodictyin, contignasterol derivatives, are in preclinical or clinical development. Despite the many structures known and their ecological and pharmacological importance, only a few biosynthetic studies on marine terpenoid compounds have been performed.

(2,3,4,4-Tetramethylcyclopentyl)Methyl Acetate, a Sex Pheromone from the Obscure Mealybug: First Example of a New Structural Class of Monoterpenes

The sex pheromone of the obscure mealybug, Pseudococcus viburni, consists of (1R*,2R*,3S*)-(2,3,4,4-tetramethylcyclopentyl)methyl acetate, the first example of a new monoterpenoid structural motif in which the two isoprene units forming the carbon skeleton are joined by 2'-2 and 3'-4 connections rather than the usual 1'-4, head-to-tail connections. This highly irregular terpenoid structure, and the irregular terpenoid structures of related mealybug species, suggest that these insects may have unique terpenoid biosynthetic pathways.

New Insights into the Acetylcholinesterase Inhibitory Activity ofLycopodium clavatum

Looking for acetylcholinesterase (AChE) inhibiting compounds within the plant kingdom, we came across the triterpene alpha-onocerin, which has recently been described as the active principle (IC(50) of 5.2 microM) of Lycopodium clavatum L. In order to discover related terpenoid structures with similar AChE inhibitory activity, we investigated the roots of Ononis spinosa L. using Ellman's reagent in a microplate assay. No inhibitory effect could be measured, not even with the isolated alpha-onocerin (1), which is in contrast to previous findings. Bioassay-guided fractionation of L. clavatum resulted in the isolation of lyclavatol (2), showing a weak, but dose-dependent inhibitory effect on AChE. (1)H- and (13)C NMR shift assignments for 1 and 2 are presented and discussed.

Direct-temperature mass spectrometric detection of volatile terpenoids and natural terpenoid polymersin fresh and artificially aged resins.

Electron impact (EI) ionization and ammonia chemical ionization (NH(3)/CI) direct-temperature mass spectrometry (DTMS) was used to characterize five natural terpenoid resins: dammar, mastic, colophony, Manila copal and sandarac. Compositional differences were highlighted by the identification of low molecular mass compounds, ranging from di- to triterpenoids, and polymeric components, based on polycadinene and polycommunic acid. Photo-ageing processes occurring under accelerated indoor and outdoor exposure conditions were also investigated. NH(3)/CI and tetramethylammonium hydroxide EI were applied to increase the sensitivity towards highly oxidized molecules. Oxidation and cross-linking reactions were found to affect mostly triterpenoid resins and diterpenoid abietane and pimarane molecules. Oxidation proceeds through a radical mechanism, generally starting from conjugated double bonds. Oxygen atoms are incorporated in the terpenoid structures in the form of alcohols, ketones and carboxylic acids. Oxidized cadinene oligomers released by pyrolytic degradation of the polycadinene fraction of dammar were detected even in unaged samples. Evidence is given indicating the occurrence of cleavages in the cross-linked polycommunic structure of aged sandarac and Manila copal. Bond scissions produce oligomeric fragments based on the communic acid structure and sufficiently volatile to be desorbed at low temperature in DTMS measurements.

Identification of Components of Osage Orange Fruit (Maclura pomifera) and Their Repellency to German Cockroaches

The fruit of the Osage orange tree (Maclura pomifera (Raf.) Schnied.) was extracted by several methods: solid phase microextraction (SPME) volatile trapping of the headspace, solvent extraction with hexane, soxhlet extraction with hexane or methylene chloride and steam distillation. The isolates from each technique were subjected to GC/MS to compare extract components. Ripe and unripe fruits were compared using SPME. Several compounds of terpenoid structure, mostly sesquiterpenoids, were determined as present in the isolates. Among these were elemol/hedycaryol, α-copaene, α-cubebene, δ-cadinene, β-elemene, β-caryophyllene, α-ylangene/valencene, (Z,E)-farnesol and the green volatile hexyl hexanoate. The behavioral response of German cockroaches [Blattella germanica (L.)] to the oil and extracts was examined in a choice arena, and the extracts were found to be repellent. Individual compounds, including the isoflavones osajin and pomiferin, were purchased or isolated and tested directly, and several were found to be repellent to the cockroaches.

Polyene substrates with unusual methylation patterns to probe the active sites of three catalytic antibodies

The synthesis of two tetraenes that differ in their methylation pattern from the natural substrate in lanosterol biosynthesis, 2,3-oxidosqualene, and their examination with three catalytic antibodies is described. The design of these novel, linear terpenoid structures was governed by initial results obtained from the characterization of the three catalytic antibodies. These were generated by immunization with a steroidal hapten that mimics multicyclization without the necessity for anti-Markovnikov additions or ring expansions. Such a reaction cascade would represent a more ‘primitive’ version compared to the oxidosqualene cyclization observed in lanosterol, cycloartenol and β-amyrin biosynthesis and would not require a tail-to-tail connection of the third and fourth isoprene unit as seen in squalene. The first tetraene design (A) only contains trisubstituted double bonds and hence its synthesis starts from farnesol and tris-norgeraniol. The second tetraene design (B) is considered the more precise match to the inducing hapten that generated the antibody collections by exhibiting one disubstituted double bond and its synthesis utilizes a tris-norgeraniol derivative and a symmetrical bis-allylic alcohol as key building blocks. Chromatographic comparison studies lead to the conclusion that the currently studied antibodies also produce monocyclic products from the two substrates as has been formerly observed with a squalene-derived substrate. In contrast, 2,3-oxidosqualene is not accepted by these catalysts supporting the notion that the current substrates are fully bound by recognition of both terminal functional groups.

Juvenile hormone III-dependent conformational changes of the nuclear receptor ultraspiracle

The identification of potential endogenous or synthetic ligands for orphan receptors in the steroid receptor superfamily is important both for discerning endogenous regulatory pathways and for designing receptor inhibitors. The insect nuclear receptor Ultraspiracle (USP), an ortholog of vertebrate RXR, has long been treated as an orphan receptor. We have tested here the fit of terpenoid ligands to the JH III-binding site of monomeric and homo-oligomeric USP from Drosophila melanogaster (dUSP). dUSP specifically bound juvenile hormone III (JH III), but not control farnesol or JH III acid, and also specifically changed in conformation upon binding of JH III in a fluorescence binding assay. Juvenile hormone III binding caused intramolecular changes in receptor conformation, and stabilized the receptor's dimeric/oligomeric quaternary structure. In both a radiometric competition assay and the fluorescence binding assay the synthetic JH III agonist methoprene specifically competed with JH III for binding to dUSP, the first demonstration of specific binding of a biologically active JH III analog to an insect nuclear receptor. The recombinant dUSP bound with specificity to a DR12 hormone response element in a gel shift assay. The same DR12 element conferred enhanced transcriptional responsiveness of a transfected juvenile hormone esterase core promoter to treatment of transfected cells with JH III, but not to treatment with retinoic acid or T 3. The activity of JH III or JH III-like structures, but not structures without JH III biological activity, to bind specifically to dUSP and activate its conformational change, provide evidence of a terpenoid endogenous ligand for Ultraspiracle, and offer the prospect that synthetic, terpenoid structures may be discovered that can agonize or antagonize USP function in vivo.

The development of strategies for terpenoid structure determination.

The first page of this article is displayed as the abstract.

Two chromene derivatives from Calyptranthes tricona

Two α-monomethyl chromene derivatives were isolated from the leaf essential oil of Calyptranthes tricona from Brazil which were characterized by 1 H - and 13 C -NMR. Besides these components, which represent about half of the oil, classical terpenoid structures could be identified, among which cis-β-farnesene is the most abundant (26.6%). A biosynthetic pathway could be proposed to explain the formation of the chromene derivatives in the plant.

The role of structure and molecular properties of terpenoids in determining their antimicrobial activity

The minimum inhibitory concentrations (MIC) of 60 terpenoids against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Candida albicans have been determined. Hierarchical cluster analysis was used to group the compounds into five groups according to their activity patterns against the four microorganisms. K-Means cluster analysis was then used to confirm these groupings and to show the differences in the activity patterns of the groups. Ten molecular properties of the terpenoids, either calculated via molecular modelling or determined by direct measurement, were then used as variables in a forward stepwise discriminant analysis to identify which variables discriminated between groups. Low water solubility of Group IV compounds, mainly hydrocarbons and acetates, was found to be associated with their relative inactivity. The remaining groups, all containing oxygenated terpenoids, showed characteristic but distinct activity patterns towards the four test organisms. Hydrogen bonding parameters were found to be associated with antimicrobial activity in all cases. Activity against Gram-negative E. coli and P. aeruginosa was associated with a combination of a hydrogen bonding and size parameters. This was not found to be the case for the Gram-positive S. aureus or the yeast C. albicans. Copyright © 1999 John Wiley & Sons, Ltd.

Phosphorus-Containing Fungicides: a Review of Current Research and Prospects

Two main types of phosphorus-containing compound are currently under investigation as potential fungicides: (a) esters of phosphoric, phosphorothioic, phosphorodithoic, or alkyl-phosphonic acids, including examples containing terpenoid or heterocyclic structures, and (b) aminophosphonic or aminophosphinic acids and their derivatives. The latter types are especially attractive environmentally but none has yet been commercialised.

Highlights in phytochemistry of hepaticae-biologically active terpenoids and aromatic compounds

Abstract

STRUCTURAL FEATURES OF ATHABASCA BITUMEN RELATED TO UPGRADING PERFORMANCE

ABSTRACT Using a combination of instrumental and chemical methods many new classes of compounds appearing as homologous series have been detected in Athabasca oil sand bitumen and in the chemical and thermal degradative products of asphaltene and the heavy ends of maltene. In general, the volatile portion of the maltene is rich in cyclic terpenoid structures and devoid in aliphatic compounds or normal alkane-derived cyclic molecules while the asphaltene fraction and heavy ends of maltene are abundant in normal alkyl-substituted aromatics, thianes, thiolanes, thiophenes, benzo- and dibenzothiophenes Ru(VM)-catalyzed oxidation permitted the quantitative estimation of the n-alkyl groups attached to aromatic carbons and of n-alkyl bridges between two aromatic units and their concentration distribution according to chain length. It also showed the presence of a large naphthenic core containing cyclic sulfides, which, during oxidation, were converted to their sulfones.

Synthesis of bibenzyl cannabinoids, hybrids of two biogenetic series found in Cannabis sativa

Syntheses of a series of compounds which merge a m-dihydroxybibenzyl with a terpenoid structure, giving a series of hybrid cannabinoids in which products of two major biogenetic routes of Cannabis are united, are described. The compounds made are the bibenzyl/o- and p-cannabigerols (19) and (18)/o- and p-cannabidiols (21) and (20),/Δ1-THC (22),/Δ6-THC (23),/o- and p-cannabichromenes (25) and (24),/o- and p-cannabicyclols (28) and (27) and/cannabicitran (26). Chromatographic and spectral data are listed in order to facilitate search for such ‘crossed’ types since only the bibenzyl cannabigerols and a chromene have as yet been found in natural sources.The bibenzyl/p-cannabigerol (18) has been reported in Helichrysum umbraculigerum(Compositae) and the liverwort Radula variabilis. Our synthetic work confirms the former observation, but the liverwort compound appears to be its o-isomer.

Structure of the coumarin glycoside reoselin from the roots ofFerula kirialovii

The structure of terpenoid and carbohydrate moieties of the molecule of reoselin have been confirmed by the use of13C NMR spectra, and the position of the carbohydrate moiety has been corrected. Reoselin is S-(−)-karatavikinol β-sophoroside at the tertiary hydroxy group (S-(−)-karativikinol tertiary-O-β-D-sophoroside) and not at the secondary hydroxy group, as was previously assumed. The absolute configuration of the single asymmetric center, the carbon atom to which the secondary hydroxy group is attached, has been assigned by analogy with S-(−)-epoxysqualene and S-(−)-epoxyfarnesol. S-(−)-Karatavikinol tertiary O-β-D-sophoroside has been isolated from giant fennels, a characteristic feature of which is the biosynthesis via direct antiparallel cyclization of bicyclic sesquiterpenoid derivatives of umbelliferone with the configuration of the ring linkage enantiometric to the linkage of rings A and B of triterpenoids.