Structure and Synthesis of Vindolicine and Derivatives.

This article describes the reaction of vindoline with formaldehyde and trimethyl orthoformate to prepare vindolicine, tris-vindolicinyl methane and higher molecular weight homologues. The synthesis of 10-formyl vindoline as an intermediate allowed further exploration of its chemistry, in particular the reaction with acetone which yielded a symmetrical dimer, which was further reacted with vindoline to give molecules containing three and four vindoline units. These molecules were characterized by NMR and for some of them (vindolicine, 10-formyl vindoline, 10-(1'-(but-1'-en-3'-one))-vindoline) by X-ray crystallography. Depending on the substitution and on the absence of axes of symmetry, the NMR spectra displayed non-equivalent spin systems for the vindoline moieties. The dimer formed from the double condensation of 10-formyl vindoline with acetone showed cytotoxic activity in the micromolar range.

Meroterpenoids? A historical and critical review of this biogenetic determinant.

In its original definition, meroterpenoids refer to substances of mixed biosynthesis including a terpenoid part. The number of compounds fulfilling this criterion is huge, and almost from the beginning, exclusions were made, more or less, explicitly stated. The concept is well accepted in the microorganism domain, where biosynthetic studies are advanced, while in the plant domain, meroterpenes and meroterpenoids randomly appear. The purpose of this article is to present and discuss miscellaneous categories of products that fulfill the definition and should be considered as meroterpenoids. Our proposal would be to retain the concept to characterize biosynthetic origins and not to consider it as a tool for classification.

Traditional Chinese medicine: saponins, critical micellar concentrations and partition coefficients.

INTRODUCTION: Traditional Chinese medicine (TCM) revolves around complex mixtures bound to specific roles within the formulation, among which saponin-containing plants with alleged properties of harmonising or detoxifying other compounds present in the preparations. OBJECTIVE: This article deals with the study of these interactions with, as a model, the interaction between saponins and selected active principles. METHODS: The measurement of the partition coefficient between water and octanol (logP) was used as an indicator and determined by nuclear magnetic resonance (NMR) for these active principles in the presence of saponins. For each compound, a graph was constructed showing the evolution of logP with increasing concentrations of saponins. RESULTS: Four distinct patterns of interactions were distinguished. Pattern A showed a constant decrease of logP, pattern B showed a decrease followed by a plateau, in pattern C the logP did not vary until the critical micellar concentration (CMC) and decreased afterwards, and pattern D exhibited an increase of logP. These properties were linked to the ability of saponins to form micelles in water once the CMC is reached. The interaction of aconitine and saponins followed pattern D, thus explaining the detoxification of herbal preparations using Aconitum with licorice. The licorice facilitated the extraction of the notoriously water-insoluble artemisinin from Artemisia annua. CONCLUSION: This investigation confirms that the physical properties of micelle forming saponins are intimately linked to a modification of behaviour of the other molecules in solution, as seen with the alteration of logP and the four types of interactions presented.

Addition of Vindoline to p-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations.

Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This "windshield wiper" effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 µM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.

Phenyl glycosides from the leaves of Flacourtia indica (Burm. f.) Merr (Salicaceae).

Thirteen phenolic glycosides, together with fourteen various known compounds, were isolated from the methanolic extract of leaves of Flacourtia indica. Twelve of these were composed of gentisyl or salicyl alcohols, glycosylated on the phenol and acylated on the primary alcohol with various more or less oxidized forms of pyrocatechuic acid. A number of positions on the glucose or on the acid were further acylated by benzoic or cinnamic acid. In addition to these, a glucoside of a phenyl propanoid was also isolated. The gross structures were elucidated by spectroscopic means including 1D and 2D NMR experiments and HR-ESI-MS analyses. Several of these structures, for example, xylosmin, were previously described but it proved extremely difficult to conclude on their exact identity with the absence of clear data on absolute configuration in the literature.

An easy-to-use and general nuclear magnetic resonance method for the determination of partition coefficients of drugs and natural products.

The lipophilicity of a drug is an important parameter for its eventual development by the pharmaceutical industry. It is usually measured by HPLC following partition of the compound between water and 1-octanol. We present here an alternative, simple, sensitive and quantitative 1 H nuclear magnetic resonance (NMR) method for the experimental measurement of partition coefficients of natural compounds and pharmaceutical drugs. It is based on measuring concentrations in the water phase, before and after partitioning and equilibration between water and octanol, using the ERETIC (Electronic Reference To Access In Vivo Concentration) technique. The signal to noise ratio is improved by a Water Suppression by Excitation Sculpting sequence. Quantification is based on an electronic reference signal and does not need addition of a reference compound. The log P values of 22 natural metabolites and four pharmaceutical drugs were determined and the experimental results are in excellent agreement with literature data. The experiments were run on ~2 mg material. This technique proved to be robust, reproducible and suitable for log P values between -2 and +2.

Quinolizidine Alkaloids from Cylicomorpha solmsii.

Five new quinolizidine alkaloids were isolated from the leaves of Cylicomorpha solmstii (Urb.) Urb. (Caricaceae) and named cylicomorphins A-E (1-5). They all are ester derivatives of the same basic quinolizidine skeleton bearing hydroxy, methyl, and ethanoic acid substituents. Their structures were mainly established by NMR spectroscopy, and the absolute configuration is proposed on the basis of VCD data and Mosher ester derivatization. Compound 5 displayed cytotoxicity in the 10 µM range against an HCT-116 cell line.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide.

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27-C28 bond, and a Suzuki-Miyaura cross-coupling as the endgame to form the C15-C16 bond.

Intramolecular Diels-Alder Approaches to the Decalin Core of Verongidolide: The Origin of the exo-Selectivity, a DFT Analysis.

Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, Verongidolae. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the 1H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a cis-decalin core and we hypothesize that the relative configuration of the cis-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels-Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels-Alder reactions was exo and an in-depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity.

The Iboga Alkaloids.

Iboga alkaloids are a particular class of indolomonoterpenes most often characterized by an isoquinuclidine nucleus. Their first occurrence was detected in the roots of Tabernanthe iboga, a sacred plant to the people of Gabon, which made it cult object. Ibogaine is the main representative of this class of alkaloids and its psychoactive properties are well documented. It has been proposed as a drug cessation treatment and has a wide range of activities in targeting opioids, cocaine, and alcohol. The purpose of this chapter is to provide a background on this molecule and related compounds and to update knowledge on the most recent advances made. Difficulties linked to the status of ibogaine as a drug in several countries have hampered its development, but 18-methoxycoronaridine is currently under evaluation for the same purposes and for the treatment of leishmaniasis. The chapter is divided into six parts: an introduction aiming at defining what is called an iboga alkaloid, and this is followed by current knowledge on their biosynthesis, which unfortunately remains a "black box" as far as the key construction step is concerned. Many of these alkaloids are still being discovered and the third and fourth parts of the chapter discuss the analytical tools in use for this purpose and give lists of new monomeric and dimeric alkaloids belonging to this class. When necessary, the structures are discussed especially with regard to absolute configuration determinations, which remain a point of weakness in their assignments. Part V gives an account of progress made in the synthesis, partial and total, which the authors believe is key to providing solid solutions to the industrial development of the most promising molecules. The last part of the chapter is devoted to the biological properties of iboga alkaloids, with particular emphasis on ibogaine and 18-methoxycoronaridine.

Elaboration of Sterically Hindered δ-Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1-C27 Fragment of Hemicalide.

The synthesis of the C1-C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.

Synthetic Studies toward the C32-C46 Segment of Hemicalide. Assignment of the Relative Configuration of the C36-C42 Subunit.

The synthesis of five diastereomeric model compounds incorporating the C32-C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,ß-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia-Kocienski olefination. Comparison of the (1)H and (13)C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36-C42 subunit.

Constituents of Vigna angularis and their in vitro anti-inflammatory activity.

Nine non-phenolic compounds, including four furanylmethyl glycosides, angularides A-D, one ent-kaurane diterpene glycoside, angularin A, and four triterpenoid saponins, angulasaponins A-D, were isolated from seeds of Vigna angularis, together with eight known compounds. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic analysis as well as chemical methods. Angularin A, angulasaponins A-C, and azukisaponins III and VI showed inhibition of nitric oxide production in LPS-activated RAW264.7 macrophages, with IC50 values ranging from 13µM to 24µM.

Cytisine-like alkaloids from Ormosia hosiei Hemsl. & E.H. Wilson.

Four alkaloids named hosieines A-D were isolated from the root and stem of Ormosia hosiei. Their flat structures were established by mass spectrometry and by a combination of NMR experiments. These molecules probably share a common biosynthetic origin with the lupin alkaloids but they differ in the formation of the last ring, being here part of a rare 2-azabicyclo[3.2.1]octane system. Their absolute configuration was determined by X-ray crystallography using CuKα radiation. As has been described for cytisine, they display a remarkable affinity towards neuronal nicotinic acetylcholine α4ß2 receptor.

Synthetic studies on hemicalide: development of a convergent approach toward the C1-C25 fragment.

Synthetic studies on hemicalide, a recently isolated marine natural product displaying highly potent antiproliferative activity and a unique mode of action, have highlighted a reliable Horner-Wadsworth-Emmons olefination to create the C6-C7 alkene and a remarkable efficient Suzuki-Miyaura coupling to form the C15-C16 bond, resulting in the development of a convergent approach toward the C1-C25 fragment.

Dichapetalins from Dichapetalum species and their cytotoxic properties.

Six dichapetalins named dichapetalins N-S were isolated from Dichapetalum mombuttense, Dichapetalum zenkeri and Dichapetalum leucosia. They were accompanied in the same plants by the known dichapetalins A, B, C, I, L and M. The structures of the compounds were elucidated by 1D and 2D NMR experiments and mass spectrometry. They all possessed the dammarane skeleton substituted at position C-3 by a C6-C2 unit forming a 2-phenylpyran moiety. All contained a lactone ring in the side chain except dichapetalins O, Q and R, in which this ring was replaced by a lactol. Dichapetalin Q and R were also the first dichapetalins bearing a tertiary methyl and a double bond instead of the cyclopropane of the dammaranes. All these compounds were assayed against cancer cell lines HCT116 and WM 266-4 and displayed cytotoxic and anti-proliferative activities in the 10(-6) to 10(-8)M range.

Relative stereochemical determination and synthesis of the C17-C25 δ-lactone fragment of hemicalide.

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined the relative stereochemistry of the C8-C13 hexad by synthesizing the C1-C13 fragment. Presently, we report the assignment of the C17-C25 δ-lactone fragment. NMR analysis of authentic hemicalide along with a computational conformation study allowed us to reduce the number of putative relative isomers from 16 to 4. Concise syntheses of the four candidate diastereomers were achieved using a common strategy based on a Dias aldehyde allylation reaction, an intramolecular Horner-Wadsworth-Emmons olefination, and a dihydroxylation reaction. Finally, thorough NMR comparisons enabled us to deduce the relative stereochemistry of the C1-C17 fragment with high certainty.

Nudicaulins, yellow flower pigments of Papaver nudicaule: revised constitution and assignment of absolute configuration.

The constitution of the aglycon of nudicaulin has been revised to be a pentacyclic indole alkaloid. The relative and absolute configurations of the two diastereomers, nudicaulins I (3a) and II (3b), have been assigned by NMR, conformational analyses, and interpretation of the experimental ECD spectra by quantum-chemical calculations.

Proteasome inhibitors from Neoboutonia melleri.

Thirty new cycloartane derivatives (1-3, 5-12, 14-32) have been isolated from the leaves of Neoboutonia melleri. Their novelty stems from the loss of one of the C-4 methyl groups (1-3, 5-12, 14-25, and 32) and from the presence of an "extra" carbon atom in the side chain (1-3, 5-12, 14-20, 26-29, and 30-32). Furthermore, compound 32 possesses a rare triterpene skeleton with the cyclopropane ring fused onto C-1 and C-10, instead of C-9 and C-10. The structures were determined by spectrometric means, chemical correlations, and X-ray crystallography of derivative 1c. The substitution pattern in ring A, with a cyclopropyl ring conjugated with an α,ß-unsaturated carbonyl moiety, confers to the molecule a particular reactivity, giving rise to a formal inversion of the stereochemistry of the cyclopropane ring under UV irradiation. These compounds showed an interesting level of activity on the proteasome pathway, thus motivating their evaluation as possible anticancer agents. The large number of isolated compounds permitted a structure-activity relationship analysis, which showed that the presence of the two enone functions was a requirement for the activity.