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Feature-based molecular networking allows the generation of molecular networks for mass spectrometry data that can recognize isomers, incorporate relative quantification and integrate ion mobility data.Molecular networking has become a key method to visualize and annotate the chemical space in non-targeted mass spectrometry data. We present feature-based molecular networking (FBMN) as an analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure that builds on chromatographic feature detection and alignment tools. FBMN enables quantitative analysis and resolution of isomers, including from ion mobility spectrometry.

"Chiniy-tref" (CT) is a traditional preparation used in folk medicine in Martinique Island (French West Indies) that is nowadays mainly taken orally to prevent or act against any "manifestation of evil". CT is easily prepared at home by macerating larvae of the endemic swallowtail Battus polydamas (ssp.) cebriones (Dalman, 1823), sometimes accompanied by a leaf of its host-plant Aristolochia trilobata L., in commercial rum. We have previously reported the detection of nephrotoxic and carcinogenic aristolochic acids (AAs) I and II in CT, leading the Regional Health Agency (ARS) of Martinique to issue an alert regarding the potential risks associated with its consumption in 2015. In order to complete the toxicity risk assessment for oral consumption of CT, a full qualitative analysis of AAs and their analogues (AAAs) was performed, as well as a quantitative determination of the major AAs, namely AAs I and II. The phytochemical profiling of AAAs present in CT, that also corresponds to that of B. polydamas cebriones larvae feeding on A. trilobata, has been established for the first time by ultra-high performance liquid chromatography/electrospray ionization quadrupole time of-flight tandem mass spectrometry. AAs I and II were quantified in a small panel of tinctures by using a validated UHPLC/UV method, allowing us to estimate the probable daily intakes of these toxins by CT consumers. The results proved the existence of a real risk of renal toxicity and carcinogenicity associated with the chronic oral consumption of CT in Martinique, and more generally of similar "snake bottles" throughout the Caribbean.

Latent HIV reservoirs are the main obstacle to eradicate HIV infection. One strategy proposes to eliminate these viral reservoirs by pharmacologically reactivating the latently infected T cells. We show here that a 4-deoxyphorbol ester derivative isolated from Euphorbia amygdaloides ssp. semiperfoliata, 4β-dPE A, reactivates HIV-1 from latency and could potentially contribute to decrease the viral reservoir. 4β-dPE A shows two effects in the HIV replication cycle, infection inhibition and HIV transactivation, similarly to other phorboids PKC agonists such PMA and prostratin and to other diterpene esters such SJ23B. Our data suggest 4β-dPE A is non-tumorigenic, unlike the related compound PMA. As the compounds are highly similar, the lack of tumorigenicity by 4β-dPE A could be due to the lack of a long side lipophilic chain that is present in PMA. 4β-dPE activates HIV transcription at nanomolar concentrations, lower than the concentration needed by other latency reversing agents (LRAs) such as prostratin and similar to bryostatin. PKCθ/MEK activation is required for the transcriptional activity, and thus, anti-latency activity of 4β-dPE A. However, CD4, CXCR4 and CCR5 receptors down-regulation effect seems to be independent of PCK/MEK, suggesting the existence of at least two different targets for 4β-dPE A. Furthermore, NF-κb transcription factor is involved in 4β-dPE HIV reactivation, as previously shown for other PKCs agonists. We also studied the effects of 4β-dPE A in combination with other LRAs. When 4β-dPE A was combined with another PKC agonists such as prostratin an antagonic effect was achieved, while, when combined with an HDAC inhibitor such as vorinostat, a strong synergistic effect was obtained. Interestingly, the latency reversing effect of the combination was synergistically diminishing the EC50 value but also increasing the efficacy showed by the drugs alone. In addition, combinations of 4β-dPE A with antiretroviral drugs as CCR5 antagonist, NRTIs, NNRTIs and PIs, showed a consistent synergistic effect, suggesting that the combination would not interefer with antiretroviral therapy (ART). Finally, 4β-dPE A induced latent HIV reactivation in CD4 + T cells of infected patients under ART at similar levels than the tumorigenic phorbol derivative PMA, showing a clear reactivation effect. In summary, we describe here the mechanism of action of a new potent deoxyphorbol derivative as a latency reversing agent candidate to decrease the size of HIV reservoirs. This work was supported by Ministry of Education of the Peruvian government (PRONABEC), the Universidad Complutense de Madrid (UCM-Santander PR87/19), the Instituto de Salud Carlos III (ISCIII-FIS PI16CIII/00034) and the Spanish AIDS Research Network RD12/0017/0015 that is included in the Spanish I D I Plan and is co-financed by ISCIII-Subdirección General de Evaluación and European Funding for Regional Development (FEDER). This work has also benefited from an “Investissement d’Avenir” grant managed by Agence Nationale de la Recherche (CEBA, ANR- 10-LABX-25-01). Sí

Tinospora crispa is a popular traditional herbal plant commonly used throughout the world for treatment of various diseases, in particular type 2 diabetes mellitus. We report here a new case of toxic hepatitis in a 57-year old male patient in the French West Indies following the consumption of two aqueous extracts of fresh Tinospora crispa stems. It thus differs from two previously reported cases that concerned the chronic intake of powdered dry stems delivered in solid oral dosage forms (i.e. pellets and tablets). Liquid Chromatography-Diode Array Detection-Mass Spectrometry (LC/DAD/MS) analyses were performed on an aqueous extract of the offending sample that mimics the swallowed preparation. They revealed the presence of species-specific molecular marker borapetoside C (1) and thus enabled an unambiguous phytochemical identification. The exploration of tandem MS/MS data obtained by ultra-high performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-HRMS) allowed the identification of 17 additional cis-clerodane-type furanoditerpenoid lactones, analogues of 1. These results support the hypothesis that the mechanisms underlying hepatotoxicity of Tinospora crispa are the same as those encountered with furanoditerpenoids-containing plants such as Teucrium chamaedrys or Dioscorea bulbifera. In the context of type 2 diabetes treatment, we recommend that Tinospora crispa intake should be more closely monitored for signs of hepatotoxicity.

International audience; In this retrospective series of 97 cases of manchineel fruit ingestion reported to French Poison Control Centers between 2009 and 2017, we investigated cases of poisoning due to manchineel fruit (from the Hippomane mancinella tree). This fruit is known to be responsible for oropharyngeal and gastrointestinal tract lesions and possibly hypotension and bradycardia (previously attributed to the presence of physostigmine). The most commonly observed clinical signs were oropharyngeal pain, abdominal pain, diarrhea and oropharyngeal irritation. No major gastrointestinal tract lesions were observed in the five cases in which upper gastrointestinal (GI) endoscopy was performed. One case of laryngeal edema and one case of bradycardia were observed, but analysis of the harvested fruits did not confirm the presence of physostigmine. Ingestion of manchineel fruit can cause mild abdominal pain and digestive irritation, requiring medical attention. Rarely, when several fruits have been ingested, severe oropharyngeal injury or hemodynamic disorders may require otorhinolaryngological consultation or cardiac monitoring for several hours, respectively.

International audience; The formation of calcium carbonate in water has important implications in industry. Chemical antiscalant is usually used to control scale depositions. Plant extracts have been recently used as new green antiscalant agents, as they can be easily prepared and are environmentally friendly. In this study, stock aqueous solutions of Spergularia rubra and Parietaria officinalis, two plants used in traditional medicine to treat or prevent urolithiasis, were obtained by infusion. The antiscaling properties of these extracts towards CaCO3 formation were tested by using chronoamperometry and Fast Controlled Precipitation methods. The aqueous solution of S. rubra was further fractionated to isolate compounds of lower polarity. Their efficiency towards CaCO3 precipitation was characterized by Fast Controlled Precipitation method. The inhibiting efficiency of this fractionated solution was greater than that of the stock aqueous solution.

A new 3,4-seco-cycloartane, identified as (24R,25S)-dihydroxy-26-O-nonadecylcarbonyloxy-3,4-secocycloarta-4(28)-en-3-oic acid (1), has been isolated from the leaves of Hopea odorata Roxb. (Dipterocarpaceae), together with the rare 3,4-seco-cycloart-4(28),24-diene-3,26-dioic acid (2 or abiesatrine J) and six other known compounds (3-8). Their structures were elucidated on the basis of both chemical and spectroscopic methods.

A supercritical fluid chromatography-based targeted purification procedure using tandem mass spectrometry and molecular networking was developed to analyze, annotate, and isolate secondary metabolites from complex plant extract mixture. This approach was applied for the targeted isolation of new antiviral diterpene esters from Euphorbia semiperfoliata whole plant extract. The analysis of bioactive fractions revealed that unknown diterpene esters, including jatrophane esters and phorbol esters, were present in the samples. The purification procedure using semipreparative supercritical fluid chromatography led to the isolation and identification of two new jatrophane esters (13 and 14) and one known (15) and three new 4-deoxyphorbol esters (16–18). The structure and absolute configuration of compound 16 were confirmed by X-ray crystallography. This compound was found to display antiviral activity against Chikungunya virus (EC50 = 0.45 μM), while compound 15 proved to be a potent and selective inhibitor of H...

Made available in DSpace on 2018-12-11T17:31:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-03-01. Added 1 bitstream(s) on 2019-10-09T18:32:48Z : No. of bitstreams: 1 S0103-50532017000300475.pdf: 612042 bytes, checksum: 72fdf2c23c51d9f3984b194b81219854 (MD5) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC50 of 3.0 � 1.0 μM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC50 of 1.5 � 1 μM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4. N�cleo de Bioensaios Bioss�ntese e Ecofisiologia de Produtos Naturais (NuBBE) Departamento de Qu�mica Org�nica Instituto de Qu�mica Universidade Estadual Paulista (UNESP) Laborat�rio de Qu�mica Medicinal e Computacional Centro de Pesquisa e Inova��o em Biodiversidade e F�rmacos Instituto de F�sica de S�o Carlos Universidade de S�o Paulo (USP) Laborat�rio de Qu�mica Org�nica Sint�tica Instituto de Qu�mica Universidade Estadual de Campinas (UNICAMP) Instituto de Pesquisas de Produtos Naturais (IPPN) Centro de Ci�ncias da Sa�de Universidade Federal do Rio de Janeiro (UFRJ) Laboratoire de Pharmacognosie UMR 8638 COMETE CNRS Facult� de Pharmacie de Paris Universit� Paris Descartes, Sorbonne Paris Cit� N�cleo de Bioensaios Bioss�ntese e Ecofisiologia de Produtos Naturais (NuBBE) Departamento de Qu�mica Org�nica Instituto de Qu�mica Universidade Estadual Paulista (UNESP) FAPESP: 2013/07600-3

A supercritical fluid chromatography-based targeted purification workflow using tandem mass spectrometry and molecular networking was developed to analyze, annotate and isolate secondary metabolites from complex mixture. This approach was applied for targeted isolation of new antiviral diterpene esters from Euphorbia semiperfoliata whole plant extract. The analysis of bioactive fractions revealed that unknown diterpene esters, including jatrophane esters and phorboids esters, were present in the samples. The purification procedure using semi-preparative-supercritical fluid chromatography led to the isolation and identification of two jatrophane esters (13 and 14) and four 4-deoxyphorbol esters (15-18). Compound 16 was found to display antiviral activity against chikungunya virus (EC50 = 0.45 µM), while compound 15 was found to be a potent and selective inhibitor of HIV-1 replication in a recombinant virus assay (EC50 = 13 nM). This study showed that supercritical fluid chromatography-based workflow and molecular networking can facilitate and accelerate the discovery of bioactive small molecules by targeted molecules of interest, while minimizing the use of toxic solvents.

Natural products represent an inexhaustible source of novel therapeutic agents. Their complex and constrained three-dimensional structures endow these molecules with exceptional biological properties, thereby giving them a major role in drug discovery programs. However, the search for new bioactive metabolites is hampered by the chemical complexity of the biological matrices in which they are found. The purification of single constituents from such matrices requires such a significant amount of work that it should be ideally performed only on molecules of high potential value (i.e., chemical novelty and biological activity). Recent bioinformatics approaches based on mass spectrometry metabolite profiling methods are beginning to address the complex task of compound identification within complex mixtures. However, in parallel to these developments, methods providing information on the bioactivity potential of natural products prior to their isolation are still lacking and are of key interest to target the isolation of valuable natural products only. In the present investigation, we propose an integrated analysis strategy for bioactive natural products prioritization. Our approach uses massive molecular networks embedding various informational layers (bioactivity and taxonomical data) to highlight potentially bioactive scaffolds within the chemical diversity of crude extracts collections. We exemplify this workflow by targeting the isolation of predicted active and nonactive metabolites from two botanical sources (Bocquillonia nervosa and Neoguillauminia cleopatra) against two biological targets (Wnt signaling pathway and chikungunya virus replication). Eventually, the detection and isolation processes of a daphnane diterpene orthoester and four 12-deoxyphorbols inhibiting the Wnt signaling pathway and exhibiting potent antiviral activities against the CHIKV virus are detailed. Combined with efficient metabolite annotation tools, this bioactive natural products prioritization pipeline proves to be efficient. Implementation of this approach in drug discovery programs based on natural extract screening should speed up and rationalize the isolation of bioactive natural products. ispartof: ACS Chemical Biology vol:12 issue:10 pages:2644-2651 ispartof: location:United States status: published

International audience; Chemical antiscalants are usually used to control scale depositions, a major concern in industry. Some of these products may be harmful towards environment or toxic for humans, so environmentally friendly antiscalant are needed. In this respect, plant extracts can be used as new green antiscalant agents. In this work, stock aqueous solution of Herniaria glabra (H. glabra) was obtained by infusion. H. glabra is used in traditional medicine to treat or prevent urolithiasis; it could be an interesting candidate as a green antiscaling agent. The properties of H. glabra towards CaCO3 formation were tested by using chronoamperometry and Fast Controlled Precipitation methods. An n-butanol solution was used to partition the aqueous solution of H. glabra, yielding a polar compounds-free fraction. This fraction was also studied by chronoamperometry and Fast Controlled Precipitation methods. The results showed a better inhibition efficiency towards CaCO3 precipitation for the n-butanol fraction compared to the crude H. glabra solution.

In this paper, the inhibiting properties of an aqueous solution containing Hylocereus undatus towards CaCO 3 formation were studied by using fast controlled precipitation and chronoamperometric methods, in order to study the calcium carbonate formation in solution and on a metallic surface, respectively. As a purpose of comparison, the antiscaling properties of citric acid were studied in the same experimental conditions. The results obtained by fast controlled precipitation method showed that Hylocereus undatus solution was more efficient than citric acid to inhibit CaCO 3 formation in solution (optimal concentrations of 20 and 24 mg.L –1 , respectively). By using the chronoamperometric method, a concentration of citric acid at 160 mg.L -1 was required to totally prevent the precipitation of CaCO 3 whereas it was 180 mg.L -1 for Hylocereus undatus solution. The morphology analysis by scanning electronic microscopy and X-ray diffraction revealed that vaterite was favored in the presence of Hylocereus undatus solution, whereas a mixture of calcite and vaterite was obtained with citric acid.

“Chiniy-tref” is a traditional medicinal preparation used in Martinique, French West Indies, for the prevention of all kinds of attempted poisoning and hex. It is produced by the maceration in alcohol (mostly rum) of larvae (caterpillars) of the butterfly Battus polydamas ssp. cebriones, feeding on the leaves of Aristolochia trilobata. Aristolochic acids I and II that are well-known nephrotoxic and carcinogenic substances were identified on two samples of “chiniy-trefl” by chromatographic methods.

Chromatographic fractionation of the cytotoxic n -hexane extract of Hopea odorata Roxb. leaves led to the isolation of eight lupane triterpenes, which constitutes the first report of lupane-type triterpenes from this plant source. Furthermore, 3,30-dioxolup-20(29)-en-28-oic acid ( 6 ) was isolated for the first time from a natural source. Their structures were determined on the basis of spectroscopic methods, including 2D NMR analysis, and by comparison of their spectral data with literature values. Complete NMR assignments of the 1 H and 13 C NMR data were achieved for all compounds. Finally, the cytotoxic activities of the isolated compounds against four human cell lines (PC3, MDA-MB-231, HT-29 and HCT116) was also reported.

Tumor blood vessels are an important emerging target for anti-cancer therapy. The antimitotic agent combretastatin A-4 (CA- 4), a cis-stilbene natural product isolated from the South African tree Combretum caffrum Kuntze, is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. CA-4 inhibits tubulin polymerization by interacting at the colchicine binding site on tubulin. This alters the morphology of endothelial cells and causes vascular shutdown and regression of tumor vasculature. Some tubulin-binding vascular-disrupting agents (VDAs) are currently in clinical trials for cancer therapy. As a consequence of the potential favorable applications of these compounds, several analogs projected to induce rapid and selective vascular shutdown in tumors have been synthesized during the last few years. Many of these molecules have already been tested for their effects on tubulin polymerization as well as for their antiproliferative activity and other biological properties, and possible mechanisms of action have been investigated. The aim of the present review is to offer an overview of most recently developed combretastatin derivatives, focusing on biological effects exerted by these compounds. The published data about new analogs are presented and compared, and a detailed investigation of structure-activity relationships is described.

A large-scale in vitro screening of tropical plants using an antibacterial assay permitted the selection of several species with significant antibacterial activities. Bioassay-guided purification of the dichloromethane extract of the leaves of the Malaysian species Vitex vestita, led to the isolation of six new labdane-type diterpenoids, namely, 12-epivitexolide A (2), vitexolides B and C (3 and 4), vitexolide E (8), and vitexolins A and B (5 and 6), along with six known compounds, vitexolides A (1) and D (7), acuminolide (9), 3β-hydroxyanticopalic acid (10), 8α-hydroxyanticopalic acid (11), and 6α-hydroxyanticopalic acid (12). Their structures were elucidated on the basis of 1D and 2D NMR analyses and HRMS experiments. Both variable-temperature NMR spectroscopic studies and chemical modifications were performed to investigate the dynamic epimerization of the γ-hydroxybutenolide moiety of compounds 1-4. Compounds were assayed against a panel of 46 Gram-positive strains. Vitexolide A (1) exhibited the most potent antibacterial activity with minimal inhibitory concentration values ranging from 6 to 96 μM, whereas compounds 2 and 6-9 showed moderate antibacterial activity. The presence of a β-hydroxyalkyl-γ-hydroxybutenolide subunit contributed significantly to antibacterial activity. Compounds 1-4 and 6-9 showed cytotoxic activities against the HCT-116 cancer cell line (1IC50s10 μM) and human fetal lung fibroblast MRC5 cell line (1IC50s10 μM for compounds 1, 2, 7, 8, and 9).

Two series of combretastatin A4 derivatives (acrylamide = carboxamide and carbamate) were synthesized in order to improve the water solubility and stabilize the cis -configuration of the double bond. Their cytotoxic effects were evaluated against MCF-7, KB-3-1 and IGROV human cancer cell lines, as well as their inhibitory activity on tubulin polymerization. Results were compared to those of carboxamide 1 , chosen as reference. Potent inhibitions were observed on both tests in the carboxamide series, particularly for compound 4d bearing a fluorine group in replacement of the 3-hydroxyl of CA4 . In contrast, most of the carbamates were either inactive or displayed only moderate cytotoxicities. Interestingly, a submicromolar IC 50 was measured on MCF-7 cells for 6g , although this compound was totally devoid of antitubulin activity.

Herbal remedies are becoming increasingly popular in many countries. Tinospora species (Menispermaceae) is commonly used as a herbal medicine in South Asia, but very few toxic effects have been described. We report a case of acute hepatitis associated with chronic use of high doses of Tinospora crispa. A 49-year-old male with chronic low back pain bought a herbal medicine at a market in Vietnam that was supposed to be Tinospora crispa, and started to take 10 pellets per day. He had no medical history and did not take any other drugs or toxins. Four weeks later; he developed dark urine and pale stools, associated with asthenia and right hypochondrial pain. Two months after starting treatment, he was referred to the hepatology department with jaundice. Blood tests showed aspartate aminotransferase: 1.169 IU/l, alanine aminotransferase: 2.029 IU/l, total bilirubin: 20.47 mg/dl, direct bilirubin: 13.29 mg/dl, and γ-glutamyltransferase: 243 IU/l. Viral and autoimmune hepatitis were eliminated. Upper abdominal ultrasound was normal. Histopathological findings were consistent with a toxic reaction. The herbal medicine was stopped on admission and the patient fully recovered without treatment, with normal liver function 2 months after the acute episode. Tinospora crispa was clearly identified in the pellets by microscopic analysis of the botanical characters combined with chromatographic fingerprints. The use of herbal medicines containing Tinospora crispa can induce toxic hepatitis. Recovery can be complete after discontinuation. This case highlights the risk associated with traditional herbal remedies.

Treatment of iodolactone 8a, having a cyclopentano[c]pyran skeleton and deriving from aucubin (1) (Scheme 1), with sodium trimethylsilanolate permitted a straightforward rearrangement to bicyclo[3.1.0]hexenes 10a and 10b (Schemes 3 and 4). Introduction of an N-atom via a modified Curtius reaction provided an easy entry to fused aminocyclopentitols (Schemes 4 and 5). Target 4 is a conformationally restricted cyclopropane-fused analogue of the glycosidase inhibitors mannostatins A (2) and B (3).

Dysiherbaine and neodysiherbaine are two functionalized glutamate amino acids of marine origin presenting an original bicyclic pyranofuran core. Moreover, they display powerful neuropharmacological activities as CNS agents. Combination of their unique chemical structures with their pharmacological profiles makes these compounds attractive targets both for the ‘synthetic' and the ‘biological' communities. This review describes the different synthetic approaches published during the period 2000–2012.

In the title compound, C21H24N2O3 [systematic name: methyl (20α)-16,17-didehydro-19α-methyl-18-oxayohimban-16-carboxylate], the molecule adopts an L-type conformation. The crystal packing is governed by one N—H...π and one C—H...π interactions. The crystal cohesion is ensured by intermolecular van der Waals contacts [shortest O...O contact = 3.199 (2) Å].

The synthesis and the antiproliferative activity against the human breast MCF-7, SkBr3 and the prostate LNCaP cancer cell lines of a series of bis(indolyl)methane derivatives are reported. The synthesis of new compounds was first accomplished by the reaction of different indoles with trimethoxyacetophenone in the presence of catalytic amounts of hydrochloric acid. A second procedure involving the use of oxalic acid dihydrate [(CO2H)2·2H2O] and N-cetyl-N,N,N-trimethylammonium bromide in water was carried out and led to better yields. Compound 5b significantly reduced LNCaP prostate cancer cell viability in a dose-dependent manner, with an IC50 of 0.64 ± 0.09 μM. To determine whether the growth inhibition was associated with the induction of apoptosis, treated cells were stained using DAPI. LNCaP cells treated with 1 μM of 5b showed the morphological changes characteristic of apoptosis after 24 h of incubation.

A six-step one-pot reaction was designed for synthesizing homodimeric 7-phenylindolo[3,2-a]carbazoles from 1H-indoles and β-nitrostyrenes, in the presence of SnCl2·2H2O. The reactions proceeded under very mild conditions and the desired heterocycles were obtained in moderate to good yields. An unprecedented mechanism involving sequential indole dimerization, regioselective nucleophilic conjugate addition of the resulting 2,3′-biindole to β-nitrostyrene and formal intramolecular [4 + 2]-cycloaddition is proposed.

International audience; A series of 5-(3',4',5'-trimethoxyphenyl)pyrrolo[3,4-a]carbazole-1,3(2H,10H)-diones was designed as cis-restricted analogues of 3-aroylindoles, arylthioindoles and 3-benzylidoneindolin-2-ones derived from combretastatin A4 (CA-4). Starting from various indoles, compounds were synthesized by means of a convenient two-step procedure involving a one-pot multicomponent reaction as key step. Intermediate tetrahydro[3,4-a]carbazoles and their corresponding carbazoles were submitted to biological screening tests involved in antivascular action, including the cytotoxicity against murine B16 melanoma cells, the rounding up of endothelial cells (EA.hy 926) and the inhibition of tubulin polymerization. Of the 31 compounds screened, those bearing a methoxy group at the 8-position endowed significant biological activities. A carbazole compound 30 was identified as a promising candidate for further development of novel vascular targeting agents.

Five new unsaturated iridolactones 3-7 related to natural cytotoxic oxylipins, Tei 9826, and iridolactone 2, were prepared by parallel synthesis from natural aucubin. It was found that perpivaloyl iridoid glucosides 2, 3, and 4 were markedly cytotoxic against both L1210 and KB-3-1 cell lines.

6-Methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole (BPR0L075) (1) is a potent inhibitor of tubulin polymerization which exhibits both in vitro and in vivo activities against a broad spectrum of solid tumors. This compound was designed as a heterocyclic analogue of combretastatin A4 (CA-4), a natural stilbene derivative that disrupts the tumor vasculature and causes tumor regression. In the present work, we describe the design and synthesis of several new disubstituted analogues of 1, along with their biological evaluation as potential antivascular agents. Compound 13, bearing a hydroxyl group at the 7-position of the indole nucleus that mimics the hydroxyl group at the 3-position of the B-ring of CA-4, was identified as a potent inhibitor of tubulin polymerization and also as a cytotoxic agent against B16 melanoma cells at sub-micromolar concentration. In addition, compound 13 displayed marked morphological activity (rounding up) at nanomolar concentrations on endothelial cells (EA.hy 926 cells), which is indicative of potential antivascular activity. Interestingly, the corresponding 7-O-mesylate derivative 28 (an intermediate in the synthesis of 13), was also found active in cellular assays, although it was moderately active in the tubulin polymerization inhibition test. Finally, in order to better understand the SAR of disubstituted analogues of 1, two other position isomers (10 and 14), were synthesized and evaluated for their biological activities. It was noted that the 7-hydroxysubstituted analogue 13 was more potent than the 5-hydroxysubstituted analogue 10. In conclusion, this work has allowed the identification of biologically potent CA-4 analogues (13 and 28) and also contributes to a better understanding of the SAR of 1.

International audience; Combretastatin A-4 (CSA-4), a stilbene derivative, is a potent vascular disrupting agent (VDA) with the structural requirement of a cis-configuration to maintain a molecular geometry and a correct orientation of both phenyl groups. A series of indolic analogues of CSA-4 was synthesized by means of an efficient strategy. Six compounds (20b, 25b-27b, 32b, and 35b) were identified as potent inhibitors of tubulin polymerization and also displayed cytotoxic activities on B16 melanoma cells at a nanomolar level. Both activities were well correlated with the ability to induce morphological changes of EA.hy 926 endothelial cells. In conclusion, the cis-stilbene skeleton of CSA-4 could conveniently be replaced by the 3-aroylindolic moiety, thus avoiding any isomerization leading to inactive trans compounds.

Treatment of iodolactone 8a, having a cyclopentano[c]pyran skeleton and deriving from aucubin (1) (Scheme 1), with sodium trimethylsilanolate permitted a straightforward rearrangement to bicyclo[3.1.0]hexenes 10a and 10b (Schemes 3 and 4). Introduction of an N-atom via a modified Curtius reaction provided an easy entry to fused aminocyclopentitols (Schemes 4 and 5). Target 4 is a conformationally restricted cyclopropane-fused analogue of the glycosidase inhibitors mannostatins A (2) and B (3).

The stereochemistry of the title compound, C20H28O8, a key step in the preparation of analogues of mannostatins, potent inhibitors of α-mannosidase, has been established. The carboxyl­ic acid group at C1 unexpectedly eclipses the C1—C2 bond. The cyclo­propane ring makes a dihedral angle of 109.4 (2)° with the cyclo­pentene ring.

Selective deprotection of peracetylaucubin (3) by use of KCN led to 6-O-acetylaucubin (4), which was readily converted into 2',3',4',6', 10-penta-O-benzoylaucubin (7). Configuration inversion performed on 7, using a modified Mitsunobu reaction, followed by deprotection, afforded 6-epi-aucubin (2).

Dysiherbaine and neodysiherbaine are two functionalized glutamate amino acids of marine origin presenting an original bicyclic pyranofuran core. Moreover, they display powerful neuropharmacological activities as CNS agents. Combination of their unique chemical structures with their pharmacological profiles makes these compounds attractive targets both for the ‘synthetic' and the ‘biological' communities. This review describes the different synthetic approaches published during the period 2000–2012.

A six-step one-pot reaction was designed for synthesizing homodimeric 7-phenylindolo[3,2-a]carbazoles from 1H-indoles and β-nitrostyrenes, in the presence of SnCl(2)·2H(2)O. The reactions proceeded under very mild conditions and the desired heterocycles were obtained in moderate to good yields. An unprecedented mechanism involving sequential indole dimerization, regioselective nucleophilic conjugate addition of the resulting 2,3'-biindole to β-nitrostyrene and formal intramolecular [4 + 2]-cycloaddition is proposed.

Reaction of hydrazine hydrate with the dipivaloyl ester of (1S, 4R, 5R, 6R)-4-hydroxy-2-hydroxymethyl-1-formylbicyclo[3.1.0]hex-2-ene-6-carboxylic acid (2) afforded (1S, 2R, 4R, 5R, 6R)-8,9-diaza-2-[(2,2-dimethylpropanoyloxy)methyl]-7-oxotricyclo[4.4.0.0 1 , 5 ]dec-9-en-4-yl 2,2-dimethylpropanoate (3). The structure and conformation of the new 8,9-diazatricyclo[4.4.0.0 1 , 5 ]dec-9-ene system were determined by X-Ray cristallography and 2D NMR experiments.