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Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.

Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty-seven N,N′-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of the compounds, their ability to inhibit the expression of oncogenes related to telomerase activation and to the VEGF/VEGFR-2 autocrine process, such as c-MYC, hTERT and VEGF and their capability to downregulate c-MYC and VEGFR-2 proteins and the secretion of VEGF have been measured. In these biological evaluations, we have found that the change of the acetyl group in colchicines for an N-arylurea unit causes a great improvement in anticancer properties. The most promising derivatives were compounds 6 (o-Cl) and 14 (o,o-di-F) as they were able to downregulate all the tested targets at a concentration below their IC50 values. Thus, the arylurea unit enhances the potential of colchicine as an anticancer agent.

Several tricyclic compounds inspired by the structure of combretastatin A-4 and bearing group 14 elements have been synthesized by homocoupling lithiated aryl fragments followed by ring-closing metathesis. These tricyclic compounds and their diolefin precursors were evaluated for their antiproliferative action on the tumor cell lines HT-29, MCF-7, HeLa and A-549 and on the non-tumor cell line HEK-293. In addition, their effects on the cell cycle were also measured. The tricyclic compounds show antiproliferative activity similar to that of combretastatin A-4, even though they are not so active in arresting the cell cycle. However, some diolefin precursors are able to cause accumulation of cells in the G2/M phase in a higher percentage than combretastatin A-4 itself. Inhibition of endothelial tube formation and VEGFR-2 phosphorylation of some selected compounds is comparable to that of combretastatin A-4, particularly those of tin-containing compounds 23c and 26c, whose actions exceed those of sorafenib, a clinically used VEGFR-2 inhibitor.

As part of our medicinal chemistry program’s ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies. M.C., A.C.C., J.A.M., N.R. and J.F.S.-C. thank the Ministerio de Ciencia e Innovación of Spain (research grant CTQ2011-27560) and the Consellería d’Educació, Investigació, Cultura i Esport de la Generalitat Valenciana (research grant PROMETEO/2013/027) for financial support.

The asymmetric Mannich reaction between fluoroalkyl aldimines and aldehydes catalyzed by α,α-diphenylprolinol trimethylsilyl ether is reported. The corresponding Mannich adducts were reduced in situ to afford anti-β-alkyl-γ-fluoroalkyl-γ-amino alcohols in moderate yields and with very high diastereo- and enantioselectivities. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Pyrazole (Figure 1), a five-membered, two-nitrogen-containing heterocycle ring, is widely found as the core structure in a large variety of compounds that possess important agrochemical and pharmac...

The synthesis of enantiomerically pure, cyclic, gamma,gamma-difluorinated beta-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and diastereoselective chemical reduction of the resulting cyclic beta-enamino esters. The efficiency and scope of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also been studied in order to determine the optimal reaction conditions with regard to selectivity and reactivity.

A range of partially modified retro (PMR) psi[NHCH(2)] peptide mimetics containing a hydrolytically stable CH(2)CH(CF(3))CO unit have been synthesized. The first kind of peptidomimetics is obtained from the highly efficient aza-Michael addition of different amines to alpha-trifluoromethyl acrylamide acceptors. Subsequent deprotection of the amino group furnishes the key common intermediate for the synthesis of other families of peptidomimetics: dipeptides, tripeptides, peptidomimetics containing a urea moiety, and structures containing two units of alpha-trifluoromethyl-beta(2)-alanine. Finally, a conformational study of several of the newly synthesized peptidomimetics, performed with the aid of X-ray analysis and NMR techniques, shows a beta-turn-like conformation for the structures both in the solid state and in solution.

Fluorinated organic compounds, in particular those containingnitrogen atoms, are popular targets in medicinal chemistry. Theyare obtained through chemical synthesis, usually by employing small,fluorinated molecules as starting building blocks. This accountfocuses on the reactivity and synthetic applications of differenttypes of fluorinated building blocks. It summarizes recent methodologiesdeveloped in our and other laboratories for the synthesis of a varietyof nitrogen-containing organofluorine compounds. 1 Introduction 2 Fluorinated Imidoyl Halides 2.1 Reaction of Fluorinated Imidoyl Chlorides with Enolates: Synthesisof Fluorinated β-Amino Acids 2.2 Reaction of Fluorinated Imidoyl Chlorides with Sulfoxides 3 Fluorinated α-Imino Esters and Imines 3.1 Fluorinated α-Imino Esters 3.2 Fluorinated Aldimines and Ketimines 4 Fluorinated Acrylic Acid Derivatives 5 Fluorinated GEM-Difluoroalkynes 6 Fluorinated Nitriles 6.1 Synthesis of Fluorinated Uracils 6.2 Synthesis of Fluorinated Pyrimidin-2(1 H)-ones 7 Fluorinated β-Dicarbonylic Compounds 8 Miscellaneous 8.1 Tandem Ring-Closing Metathesis-Isomerization 8.2 β-Amino-α-trifluoromethyl Alcohols 9 Conclusion

An efficient and convenient synthesis of new fluorinated and non-fluorinated uracils is described herein. The condensation of nitriles with enolates generated from 2-alkyl-Δ 2 -oxazolines (I) affords fluorinated β-enamino acid derivatives, which react with triphosgene to give an isomeric mixture of oxazolopyrimidinones. These can then be easily transformed into a single C-6 pyrimidindione derivative through reaction with a suitable nucleophile.

The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of Tebufenpyrad with acaricide activity. Fil: Fustero, Santos. Universidad de Valencia; España Fil: Roman, Raquel. Universidad de Valencia; España Fil: Sanz Cervera, Juan F.. Universidad de Valencia; España. Centro de Investigaciones Principe Felipe; España Fil: Simon Fuentes, Antonio. Universidad de Valencia; España Fil: Cuñat, Ana. Universidad de Valencia; España Fil: Villanova, Salvador. Universidad de Valencia; España Fil: Murguia, Marcelo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentina

A new synthesis of fluorinated allylamines through the reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides (as vinyl anion equivalents) with imines and imino esters has been described. The process includes a TBAF-mediated fragmentation of 2-(trimethylsilyl)ethyl sulfones to afford the desired allylic amines. When the reaction is performed with the corresponding sulfoxides, the fragmentation takes place under the addition conditions, affording the final products in a single step. (C) 2007 Elsevier B.V. All rights reserved.

The combination of a proline-catalyzed Mannich-type reaction between protected fluorinated aldimines and 4-pentenal followed by reduction and regioselective 0-allylation gives '-amino ethers that can then be used as substrates for ring-closing metathesis (RCM) reactions to afford fluorinated β-aminoalkyl-oxepines in a highly stereo- and enantioselective fashion.

This paper describes a novel fluorous synthesis of fluorinated uracils 4. In this new protocol, fluorous alcohols 1, which are used as fluorous tags, are acetylated to yield acetates 2, which in turn are treated with a base to form their enolates. These are then reacted with fluorinated nitriles to furnish tagged β-enamino esters 3. Although this condensation step had been performed easily in previous solution and solid-phase syntheses, it proved to be very elusive in the fluorous version. Meticulous control of the reaction conditions was thus essential in order to achieve satisfactory yields of β-enamino esters 3. The final treatment of compounds 3 with isocyanates or isothiocyanates efficiently afforded uracils 4 with concomitant elimination of the fluorous tag, thereby facilitating the preparation of a small library of these derivatives.

The synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives 1 in which a ring-closing metathesis reaction (RCM) constitutes the key step is described. The approach employs imidoyl chlorides 3 as fluorinated building blocks, and the overall process involves the stereoselective creation of a quaternary stereocenter. Complete selectivity was achieved when (R)-phenylglycinol methyl ether was used as chiral auxiliary, allowing for the preparation of new six-membered cyclic fluorinated alpha-amino acids as single enantiomers.

Starting with a fluorous analogue of 2-(trimethylsilyl)ethanol, we have designed an easy method for preparing a new fluorous tag ((F)TMSE) for the protection of carboxylic acids. Because mild conditions are employed in the tag cleavage (TBAF in the presence of 4 A molecular sieves, which prevent racemization), this tag can be advantageously used in the synthesis of peptides and modified peptides, as we have demonstrated with several examples, including the fluorous synthesis of short alpha- and beta-peptides as well as of modified fluorinated retropeptides.

Careful selection of the metathesis catalyst, solvent, and reaction conditions allows for the efficient and regioselective synthesis of isomeric fluorinated and nonfluorinated lactam derivatives II and III from precursor amides I through a ring-closing metathesis (RCM) reaction or a tandem RCM-isomerization protocol, respectively. The presence of the gem-difluoro moiety in the starting materials exerts a pivotal effect by directing the isomerization step, making the overall tandem transformation a regioselective process. The scope, limitations, and synthetic usefulness of this protocol are also discussed.

The aerial parts of two subspecies of Centaurea aspera L. (Asteraceae) yielded the germacranolides 1a – h , 2 , 3 , 4 and 5 , the elemane derivatives 6d and 6f , the lignan matairesinol, the degraded terpene loliolide, and the onopordopicrin–valine dimeric adduct 7 . From these, compounds 1e , 3 and 6d are natural products. The chemical composition of the two subspecies is very similar, a circumstance which does not support a taxonomic subdivision of the species.

Fluorinated carboxylic acids are valuable building blocks for several types of organofluorine nitrogenated derivatives. In this review paper, several strategies that use these compounds as starting materials are described. First, fluorinated seven-membered cyclic β-amino esters can be diastereoselectively synthesized from these compounds with a ring-closing metathesis (RCM) reaction as the key step. The use of the RCM reaction in a different approach enables the preparation of fluorinated cyclic α-amino acid derivatives. Fluorinated carboxylic acids also constitute the starting material for the asymmetric synthesis of fluorinated allylic amines. Finally, a solution and solid-phase synthesis of fluorinated uracils and thiouracils is described.

[reaction: see text] A simple, asymmetric synthesis of tetramic acid derivatives is described in this paper. The key step is a carbonyl transfer from carbonyldiimidazole (CDI) to alpha-diimines (I) to form N-alkyl-4-alkylamino-5-methylenepyrrol-2-ones (II). In turn, these compounds can be easily transformed into tetramic acid derivatives (III) in two additional steps.

It has been previously established in this laboratory that the β-methyl-β-hydroxyproline moiety of the potent anthelmintic agent paraherquamide A, is biosynthetically derived from l -isoleucine. The downstream events from l -Ile to paraherquamide A have now been investigated. The synthesis of [1- 13 C]-labeled l -β-methylproline is described by means of a Hoffman–Loeffler–Freytag reaction sequence from [1- 13 C]- l -Ile. This amino acid is shown to be a direct biosynthetic precursor to paraherquamide A by feeding and incorporation experiments in growing cultures of Penicillium fellutanum . Three tryptophan-containing dipeptides of l -β-methylproline have been constructed: [ 13 C 2 ]-2-(1,1-dimethyl-2-propenyl)- l -tryptophanyl-3( S )-methyl- l -proline; [ 13 C 2 ]-3( S )-methyl- l -prolyl-2-(1,1-dimethyl-2-propenyl)- l -tryptophan and [ 13 C 2 ]- cyclo -2-(1,1-dimethyl-2-propenyl)- l -tryptophan-3( S )-methyl- l -proline. [α- 15 N, 1- 13 C]-2-(1,1-Dimethyl-2-propenyl)- l -tryptophan was also prepared but none of these substances were found to serve as biosynthetic precursors to paraherquamide A.

The synthesis of three isoprenylated derivatives of cyclo-L-Trp-L-Pro is described. These substances have been evaluated for cytotoxic activity in rat normal fibroblast 3Y1 cells and have also been evaluated in vitro for the inhibition of microtubule assembly.

The mode of attachment of dimethylallyl pyrophosphate (DMAPP) in the biosynthesis of the indole alkaloids paraherquamide A, austamide, and brevianamide A has been studied. Feeding experiments on Penicillium fellutanum, Penicillium brevicompactum, and Aspergillus ustus using [13C2]-acetate showed isotopic scrambling of the geminal methyl groups originating from C-2 of the indole ring precursors in paraherquamide A, brevianamide A, and austamide biosynthesis. The labeling patterns suggest that the methyl groups of dimethylallyl pyrophosphate become equivalent during the biosyntheses; a non-face-selective SN‘ mechanism has been invoked to account for these observations.

The reactivity of model systems for the proposed [4+2] cycloaddition in the biosynthesis of the brevianamides, paraherquamides, and marcfortines is explored. The model for the intermolecular reaction reveals that the cycloaddition takes place under mild conditions only if activated, very reactive dienophiles are used. When relatively unreactive dienophiles such as cyclopentene and cyclohexene are used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the reaction. In contrast, the model for the intramolecular reaction demonstrates that the cycloaddition takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst. Conclusions drawn from these results are discussed in relation to the biosynthesis of the aforementioned metabolites.

The synthesis of [20-C2H3]-Taxa-4(5), 11(12)-diene (3b), [20-C2H2]-Taxa-4(20), 11(12)-diene (7b), [20-3H3]-Taxa-4(5), 11(12)-diene (3c), [20-3H2]-Taxa-4(20), 11(12)-diene, (7c), [20-C3H2]-Taxa-4(20), 11(12)-diene-5-α-ol (4b ), [20-13CH2]-Taxa-4(20), 11(12)-diene (7d) and [20-13CH3]-taxa-4(5), 11(12)-diene (3d) from the previously reported ketone 6 is described. Grignard addition to ketone provides the tertiary carbinols 8 which were dehydrated to a mixture of 3 and 7. Alternatively, 7 can be prepared directly from ketone 6 by Wittig olefination. Copyright © 2000 John Wiley & Sons, Ltd.

The total synthesis of VM55599, a natural metabolite of Penicillium sp. IMI332995, has been achieved via an intramolecular Diels−Alder cycloaddition of a reverse isoprene moiety across an azadiene system. The diastereoselectivity of the intramolecular Diels−Alder cycloaddition has biogenetic implications and is discussed in the context of the biogenetic relationship of VM55599 to the paraherquamides.

A photooxygenation reaction of 2′,2′,4′,4′-tetramethyl tetrahydroindole (9) followed by a pinacoltype rearrangement furnished 2′,2′,4′,4′-tetramethyl-3-spirocyclopentylsuccinimide (11). This transformation constitutes a model study for the synthesis of the spirosuccinimide ring system of asperparaline A.

Both a face-selective and a non-face-selective mode of formation of quaternary centers of isoprene-derived structural moieties of the natural alkaloid paraherquamide A (1) have been discovered by feeding experiments on Penicillium fellutanum with [U-13 C6 ]-glucose and [13 C2 ]-acetate. The labeling patterns suggest that the methyl groups (C22, C23) are introduced in a non-face-selective manner by a reverse prenyl transferase. The C5 unit comprising the dioxepin moiety retains stereochemical integrity indicative of a single, face-selective addition of the phenolic group to the dimethylallyl group.

Sowohl eine seitenspezifische als auch eine seitenunspezifische Bildung quartarer C-Zentren aus von Isopren abgeleiteten Strukturelementen im Alkaloid Paraherquamid A 1 wurden durch [U-13C6]Glucose- und [13C2]Acetat-Futterungsexperimente mit Penicilliumfellutanum entdeckt. Aus dem Markierungsmuster last sich ableiten, das die Methylgruppen (C22, C23) seitenunspezifisch durch eine Reverse Prenyltransferase eingefuhrt werden. In der C5-Einheit, die den Dioxepinrest umfast, bleibt die relative Konfiguration erhalten, was fur eine einzige, seitenspezifische Addition einer Phenoleinheit an die Dimethylallylgruppe spricht.

A potentially bio-mimetic Diels–Alder cyclization to construct the bicyclo[2.2.2] ring system common to the paraherquamides, marcfortines, sclerotamides, brevianamides, VM55599, and asperparaline is reported. Epi-deoxybrevianamide E (22) is converted into the corresponding lactim ether (23) and then oxidized with DDQ to provide an azadiene (24) which is tautomerized in the presence of base to azadiene 25 which, spontaneously cyclizes to give a 2:1 mixture of cycloadducts 26 and 27. These cycloadducts are each in turn, converted into d , l -C-19-epi-brevianamide A (20) and d , l -brevianamide B (6). The stereochemical implications of the [4+2] cycloaddition is discussed in the context of a working hypothesis on the biosynthesis of this family, particularly VM55599.

The aerial parts of Euphorbia terracina yielded 11 new jatrophane derivatives as well as a further diterpene displaying the novel 1(15 → 14) abeo -jatrophane framework.

The latex of Euphorbia canariensis yielded, in addition to five known ingenol esters, the ingenane derivatives ingenol 3-angelate 5,20-diacetate and 5-deoxyingenol 3-angelate 20-acetate, and the lathyrane derivatives 2,3-diepiingol 7,12-diacetate 8-benzoate, 2,3-diepiingol 7,12-diacetate 8-isobutyrate and 2-epiingol 3,7,12-triacetate 8-benzoate. The structures were established with the aid of spectroscopic methods, mainly NMR, and molecular mechanics calculations. They were also supported by the results of some chemical transformations.

The aerial parts of Artemisia inculta collected in three different locations in Egypt have been chemically investigated. As a result, a new eudesmanolide and a new tetranorsesquiterpene lactone have been isolated, together with several known compounds. The chemical data available suggest the existence of distinct chemotypes for this species, but do not support its identity with other North African members of the genus.

The aerial parts of Artemisia lucentica yielded, in addition to several known compounds, a bicyclic monoterpene ketone, two germacranolides, an eudesmanolide, a 10- epi neudesmanolide, a 2-norelemanolide and three bisabolene derivatives. The stereochemistry of a germacranolide, described as 2α-hydroxyartemorin in a previous investigation of the species, has now been corrected and the compound has been renamed lucentolide.

We have analysed the effects of 7,12-O-diacetyl-8-O-benzoil-2,3-diepiingol (DBI), an ingol derivative isolated from E. canariensis, on isometric tension developed by isolated rabbit basilar and carotid arteries. Concentration-response curves to DBI (10−8 - 3 × 10−5 m) were obtained cumulatively in both arteries at resting tension and active tone (KC1, 50 mm). At resting tension, DBI induced a concentration-dependent contraction, which was not inhibited in Ca2+-free medium. H7 (1-(5-isoquinoline sulphonyl)-2-methylpiperazine dichloride) (10−4 m) inhibited the DBI-induced contraction both in basilar and in carotid arteries. Calmidazolium (10−4 m) inhibited the maximum contraction of the carotid artery to DBI, and completely abolished the response in the basilar artery. In pre-contracted basilar arteries DBI induced a concentration-dependent relaxation that was not modified by incubation with NG-nitro-l-arginine (l-NOARG; 10−5 m) or indomethacin (10−5 m). In the carotid artery with active tone DBI induced further contractions, which were not significantly modified by l-NOARG (10−5 m) and were potentiated by indomethacin (10−5 m). These results suggest that DBI contracts rabbit basilar and carotid arteries by a mechanism that is independent of extracellular Ca2+ and involves the participation both of protein kinase C and of calmodulin. DBI relaxes basilar but not carotid arteries by a mechanism independent of the liberation of nitric oxide and prostacyclin. In the carotid artery prostacyclin but not nitric oxide partially counteracts the contractile action of DBI.

The aerial parts of Euphorbia terracina yielded five new bishomoditerpene lactones, named terracinolides C-G, which display the novel C 22 17-ethyljatrophane framework.

An ab initio study of the transition structures for the intramolecular Diels−Alder cycloaddition of the aza diene 6 to give brevianamides A, 1, and B, 2, has been carried out with analytical gradients at ab initio 3-21G and 6-31G* basis sets within Hartree−Fock procedures. The correlation effects have been estimated by using the perturbational approach at MP2 and MP3 levels. The geometry, electronic structure, and transition vector component are qualitatively model independent in this study. An analysis of the geometries and energies of the corresponding transition structures provides an explanation for the fact that brevianamide A, 1, is biosynthesized in larger quantities than brevianamide B, 2, while their respective epimers at C7 are not formed.

The aerial parts of Artemisia chamaemelifolia ssp. chamaemelifolia yielded, in addition to known compounds, four acids with the silphiperfolane framework, a presilphiperfolane derivative, a bicyclic sesquiterpene formed therefrom by oxidative cleavage, a diacetylated monoterpene diol, a cadinane derivative, three acyclic sesquiterpenes and two tetrahydrofurane lignans.

Acid-catalyzed cyclization of the natural germacranolide gallicin (8) yielded, among other products, the 1,4-epoxyeudes-manolide 9, which has a trans-fused decaline system. Under the same conditions the closely related germacranolide shonachalin A (8α-hydroxygallicin) (3) cyclized to the eudesmanolide 4 with a cis fused decaline system. The structures of these cyclization products were secured by means of chemical correlations and X-ray diffraction analyses.

The aerial parts of five Cheirolophus species yielded three new guaianolides, a new lignan and three new aromatic esters, together with other known compounds of the same type.

The aerial parts of Artemisia reptans yielded a new thiophene acetylene, four new guaianolides, a new acyclic sesquiterpene related to davanone and several known compounds.

The aerial parts of two Andryala species yielded several guaianolides and guaianolide glycosides, three of them being new. The aerial parts of Urospermum dalechampii yielded several known germacranolides and the new dihydroflavonol 3- O -methyltaxifolin.

The aerial parts of Artemisia hugueti and A. ifranensis yielded several known compounds and 15 new ones, among these were 13 eudesmanolides, a 1,10-secoeudesmanolide, and a dialcohol with a menthane framework. The stereochemistry of a previously described epimer of the eudesmanolide artemin has been corrected.

Three new xanthanolides have been isolated from Xanthium spinosum and X. strumarium subsp. italicum , together with other known compounds. The absolute configurations of xanthanol, isoxanthanol and their C-4 epimers have been established.

The aerial parts of Artemisia turcomanica and A. deserti yielded two new germacranolides, a new guaianolide, and several known mono- and sesquiterpenes.

The aerial parts of Artemisia sieberi yielded three new oplopanone derivatives, three new monoterpene glycosides, a new germacrane alcohol and a monoterpene acid related to nerolidol.

A [13C]labeled hypothetical intermediate metabolite that was invoked by Birch in the biogenesis of brevianamides A and B has been synthesized and used in a biosynthetic feeding experiment. No incorporation of this substance was evident nor could it be detected in culture extracts of the producing organism Penicillium brevicompactum. In contrast with this, [3H]labeled deoxybrevianamide E was shown to be efficiently incorporated in brevianamides A, B, and E, while [3H]labeled brevianamide E was not incorporated at all in these substances. Moreover, brevianamide E has been found not to be an artifact, in contrast with an earlier suggestion found in the literature. These results are discussed in terms of an alternative biosynthetic pathway for the brevianamides.

The aerial parts of Imula crithmoides yielded a known bisnorlabdane and six thymol derivatives, five of which were new. Two of these are the first chlorinated thymol derivatives reported in natural sources.