Heliangolides and other constituents from Bejaranoa semistriata

The investigation of Bejaranoa semistriata, a new genus in the tribe Eupatorieae, afforded in addition to known compounds a new furanoheliangolide, two epimeric 1-keto-heliangolides, two germacranolides, two nerolidol derivatives and a geranylnerol derivative. The structures were elucidated by spectroscopic methods and a few chemical transformations.     

Labdane derivatives from hemizonia species

The investigation of three Hemizonia species afforded in addition to known compounds seven new labdane derivatives, all derived from labd-13-en-15-ol. The absolute configuration of these diterpenes was determined by degradation of the triol by periodate cleavage, which afforded a known norditerpene ketone. From H. fitchii two new chromene esters and the cis-isomer of a known coumarate were isolated. H. congesta afforded in addition to labdane derivatives a hydroxycubebol.     

Chemical variation and defense of Encelia farinosa

Chemical analysis of leaves from 12 different localities of Encelia farinosa (including var. phenicodonta and var. radians) collected on the peninsula of Baja California (Mexico) revealed the presence of various chemotypes that differed with regard to the concentrations of chromenes and sesquiterpene lactones. Localities of E. farinosa collected in the northern part of Baja California were characterized by high concentrations of the chromene encecalin (up to 252 μmol g⁻¹ dry wt.), whereas the sesquiterpene lactone farinosin was not detected. Localities of E. farinosa collected at the southern tip of the peninsula lacked encecalin, but were shown to accumulate farinosin (up to 85 μmol g⁻¹ dry wt.) instead. On the mainland of Mexico, as well as in Arizona (U.S.A.), farinosin concentrations varied from 18 to 44 μmol g⁻¹ dry wt. for 10 different localities analyzed. Chromenes were not detected or present only in minor amounts (up to 13 μmol g⁻¹ dry wt.), when compared to the samples from northern Baja California. Chemical variation within localities was small when compared to variation between different localities. Accumulation of encecalin and aridity seem to coincide at least on the peninsula of Baja California, as localities of E. farinosa that receive the least amount of rainfall contained the largest amounts of encecalin in their leaves. Leaves of E. farinosa that contained sufficiently large amounts of either encecalin or farinosin were both detrimental to neonate larvae of the polyphagous pest insect Spodoptera littoralis as shown by addition of the respective crude leaf extracts to artificial diet. Possible advantages of the observed intraspecific chemical variability of E. farinosa with regard to adaptation by generalist insect herbivores are discussed.     

Detoxification of naturally occurring chromenes in larvae of the generalist herbivore Spodoptera littoralis (Noctuidae)

Five naturally occurring chromenes from the Asteraceae including the insecticidal compounds precocene II (1) and encecalin (2) were administered to last instar larvae of Spodoptera littoralis via the food or by topical contact. Metabolites formed and excreted via the frass were analysed by GC-MS and by direct comparison with reference compounds obtained by partial synthesis. In total 28 different metabolites were identified, many of them reported here for the first time. All metabolites detected originated from phase I reactions (most probably catalysed by Cytochrom P-450-dependent monooxygenases) by hydroxylation, demethylation or reduction of the parent chromenes. The resulting metabolites can be regarded as detoxification products based on previous structure-activity studies. The increased polarity of the metabolites will furthermore facilitate their excretion by the larvae compared to the more apolar parent chromenes. The largest number of metabolites (eight for each compound) was detected following oral treatment with precocene II and encecalin respectively. 3-Monool as well as 3,4-trans-diol derivatives predominated in the frass of larvae treated with the latter compounds whereas the 6-hydroxyethyl derivatives were the major metabolites of the other chromenes investigated. The patterns of metabolites originating from precocene II or encecalin were the same following oral application or topical treatment.     

Deterrent and insecticidal chromenes and benzofurans from Encelia (asteraceae)

Four analogous chromenes and benzofurans that are among the major natural products of the genus Encelia were bioassayed for deterrency and toxicity against pest insects. The chromene encecalin has both antifeedant and insecticidal properties towards larvae of the noctuid pests Peridroma saucia and Plusia gamma. In addition to reducing larval growth and decreasing survivorship of neonate larvae fed artificial diets containing encecalin, this chromene was directly insecticidal to neonate larvae after 4 hr using a residue contact bioassay. Topical application of encecalin to third instar larvae of Peridroma led to a reduction in dietary utilization, indicative of a metabolic cost of handling the compound. The demethyl analogue of encecalin is considerably less active, and the benzofurans euparin and methyleuparin, all common constituents of Encelia, were essentially inactive or only weakly active in all bioassays against the insects.     

2-Oxo-labda-8(17),13-dien-15-OL from Ophryosporus chilca

The aerial parts of Ophryosporus chilca afforded several prenylated p-hydroxyacetophenones, two labdane derivatives and a cinnamyl ester. Ophryosporus peruvianus also contains prenylated p-hydroxyacetophenones. Three compounds were isolated for the first time; their structures were established by ¹H NMR spectroscopy.     

Labdane derivatives from Planaltoa lychnophoroides

The investigation of a representative of the small Brazilian genus Planaltoa afforded, in addition to known compounds, a new toxol derivative and two ent-labdane derivatives, closely related to austrofolin. The structures were elucidated by high field ¹H NMR spectroscopy. The chemotaxonomic situation is discussed briefly.     

Diterpenes from Baccharis species

The aerial parts of Baccharis minutiflora afforded in addition to known compounds eight new ent-kaurane derivatives, one being a homo kaurane, while the aerial parts of B. alatemoides gave two pairs of epimeric clerodane derivatives, which, however, had to be modified chemically before they could be separated. The stereochemistry of these diterpenes could not be elucidated with certainty.     

Constituents of the genus Oxylobus

The aerial parts of Oxylobus arbutifolius and O. adscendens gave eudesmanolides and labdane derivatives as well as two new euparin derivatives.     

Sesquiterpenes and acetylenes from Argyranthemum adauctum ssp. jacobaeifolium

The roots of Argyranthemum adauctum ssp. jacobaeifolium, a rare endemic from Gran Canaria, afforded two new derivatives of the aromatic acetylene frutescin and 8-isovaleryloxymyrcene, while the aerial parts gave a new bisabolol derivative. Furthermore several known compounds were isolated. The structures were elucidated by high field ¹H NMR spectroscopy and a few chemical reactions.     

Antimalarial and antitubercular nostocarboline and eudistomin derivatives: Synthesis,in vitro and in vivo biological evaluation

The synthesis of nine nostocarboline derivatives with substitutions of the 2-methyl group by alkyl, aryl and functionalized residues, 10 symmetrical bis cationic dimers linking 6-Cl-norharmane through the 2-position and fifteen derivatives of the marine alkaloids eudistomin N and O is reported. These compounds were evaluated in vitro against four parasites (Trypanosoma brucei rhodesiense STIB 900, Trypanosoma cruzi Tulahuen C2C4, Leishmania donovani MHOM-ET-67/L82 axenic amastigotes, and Plasmodium falciparum K1 strain), against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc²155 and Corynebacterium glutamicum ATCC13032, and cytotoxicity was determined against L6 rat myoblast cells. Nostocarboline and derivatives displayed potent and selective in vitro inhibition of P. falciparum with weak cytotoxicity. The dimers displayed submicromolar inhibition of L. donovani and T. brucei, and nanomolar activity against P. falciparum, albeit with pronounced cytotoxicity. One dimer showed a MIC₉₉ value against M. tuberculosis of 2.5 μg/ml. The alkylated eudistomin N and O derivatives displayed activities down to 18 nM against P. falciparum for N-Me Eudistomin N. Four dimers, nostocarboline and three eudostomin derivatives were evaluated in an in vivo Plasmodium berghei mouse model. No significant activity was observed for the dimers, but a 50% reduction in parasitaemia was observed at 4 × 50 mg/kg ip for nostocarboline.     

Dibrefeldins A and B,A pair of epimers representing the first brefeldin A dimers with cytotoxic activities from Penicillium janthinellum

Dibrefeldins A and B (1 and 2), two unexpected brefeldin A (BFA) dimers, as well as brefeldin F (3), brefeldin G (4), and 14-hydroxy-BFA (5), three new BFA derivatives, together with three new naturally occurring BFA derivatives (6–8) and four known analogues (9–12), were isolated from the fungus Penicillium janthinellum. Dibrefeldins A and B (1 and 2) represent the first examples of BFA dimers formed by an esterification between two BFA monomer units. Brefeldin F (3) has an α,β-unsaturated γ-lactone ring, and this moiety was first discovered in naturally occurring BFA derivatives. The structures and relative/absolute configurations of these derivatives were elucidated by extensive spectroscopic methods, ¹³C NMR calculations, and single-crystal X-ray diffraction. Compounds 1, 2, 8, and 9 showed excellent cytotoxic activities against six cancer cell lines with IC₅₀ values ranging from 0.01 to 4.45 μM.     

A novel combinatorial biocatalytic approach for producing antibacterial compounds effective against Mycobacterium tuberculosis (TB)

Two bacterial hosts expressing cloned aromatic oxygenases were used to catalyze the oxidation and polymerization of indole and related substrates, creating mixtures of indigoid compounds comprised of novel dimers and trimers. Crude extracts and purified compounds were tested for their ability to inhibit the growth of Gram-positive organisms, in general, and Mycobacterium tuberculosis (TB), in particular. Of the 74 compounds tested against M. tuberculosis, ~66 % had minimum inhibitory concentrations (MIC) of 5 μg/ml or less. The most effective antibiotic found was designated SAB-P1, a heterodimer of indole and anthranil, which had a MIC of 0.16 μg/ml, and did not inhibit kidney cells (IC⁵⁰) at concentrations of >8 μg/ml. Combinatorial biocatalysis was used to create a series of halogenated derivatives of SAB-P1 with a wider therapeutic window. None of the derivatives had MIC values that were superior to SAB-P1, but some had a wider therapeutic window because of decreased kidney cell toxicity. Generally, the indigoid dimers that were effective against TB appeared to be specific for TB. Some of the trimers generated, however, had a broader spectrum of activity inhibiting not only TB (MIC?=?1.1 μg/ml) but also the growth of Mycobacterium smegmatis MC2 155, Bacillus cereus, Enterococcus faecalis, Staphylococcus epidermidis, Bacillus subtilis 168, and Clostridium acetobutylicum. The structure of two of the novel dimers (SAB-C4 and SAB-P1) and a trimer (SAB-R1) were solved using X-ray crystallography.     

Antiproliferative activity of withanolide derivatives from Jaborosa cabrerae and Jaborosa reflexa. Chemotaxonomic considerations

Three withanolides were isolated from the aerial parts of Jaborosa reflexa Phil. Jaborosa cabrerae Barboza yielded five sativolide withanolides (including jaborosalactones R, S, 38, and 39) and two trechonolide withanolides epimeric at C-23 (trechonolide A and jaborosalactone 32). In addition, five derivatives were obtained by chemical derivatization of jaborosalactone 38, and all compounds were fully characterized by 1D and 2D NMR spectroscopic studies. The in vitro antiproliferative activities of the major natural withanolides and the semisynthetic derivatives were examined against HBL-100, HeLa, SW1573, T-47D, and WiDr human solid tumor cancer cell lines. Some chemotaxonomic considerations are discussed.     

Fourteen heliangolides from Calea species

The investigation of two further Calea species afforded, in addition to known compounds, fourteen new heliangolides, most of them being 11,13-epoxides. One lactone is a new type, a heliangolide substituted with a monoterpene residue. Furthermore, a new chromene and a new dithienyl derivative were isolated. The structures were elucidated by spectroscopic methods. The chemotaxonomic situation is discussed briefly.     

Presence of di- and polyamines covalently bound to protein in rat liver

Acid hydrolysis of trichloroacetic acid precipitate from rat tissue (liver, kidney and testis) homogenate released significant amounts of acid-insoluble putrescine, spermidine and spermine. Following incubation of liver homogenate with [1,4-¹⁴C]putrescine, 1.4% of total radioactivity and 1.0% of labelled diamine were recovered in the acid-insoluble fraction. Exhaustive digestion of acid-precipitable material with proteinases (Pronase, aminopeptidase M, carboxipeptidase A, B and Y) revealed the presence of di- and polyamines and of N¹-(γ-glutamyl)spermidine, N¹-(γ-glutamyl)sperminine and N¹, N¹²-bis(γ-glutamyl)spermine. These derivatives were identified both by chromatographic analysis and by enzymatic digestion with purified γ-glutamylamine cyclotransferase. The finding of di- and polyamine γ-glutamyl derivatives in the proteinase-digested acid-insoluble fraction of homogenate may be considered as a proof of the in vivo transglutaminase-catalyzed binding of polyamines to proteins. This evidence suggests that di- and polyamines might have an important role in mammalian tissues through covalent binding to proteins by either one or both the primary amino groups.     

Spiramine derivatives induce apoptosis of Bax−/−/Bak−/− cell and cancer cells

Spiramine C–D, the atisine-type diterpenoid alkaloids isolated from the Chinese herbal medicine Spiraea japonica complex, are shown to have anti-inflammatory effects in vitro. In this study, we report that spiramine derivatives of spiramine C–D bearing α,β-unsaturated ketone induce apoptosis of Bax^−/−/Bak^−/− MEFs cell, which is positively corresponding their cytotoxicity of tumor cell lines including multidrug resistance MCF-7/ADR. The results indicated that oxazolidine ring is necessary, and derivatives bearing double ‘Michael reaction acceptor’ group would significantly increased activities both of inducing apoptosis of Bax^−/−/Bak^−/− cells and cytotoxicity of tumor cells. The result indicated that spiramine derivative with α,β-unsaturated ketone group is a new anti-cancer agent with a capability of inducing apoptosis of cancer cells in Bax/Bak-independent manner.     

Sandaracopimarene derivatives from Senecio subrubriflorus

Several new sandaracopimarene derivatives were isolated from Senecio subrubriflorus. A triphenyl acetate of shikimic acid and a 4, 7-oxide of bisabolene were also present. The structures were elucidated by high field ¹H NMR spectroscopy. The chemistry of this species differs considerably from that of other Senecio species.     

Four oplopanone and bisabolone derivatives from Rugelia nudicaulis

Rugelia nudicaulis afforded, in addition to known compounds, three new highly oxygenated oplopanone derivatives and a bisabolone derivative. The structures were elucidated by high field ¹H NMR spectroscopy. The chemotaxonomic situation is discussed briefly.     

Grindelane diterpenoid acids from Grindelia humilis: Feeding deterrency of diterpene acids towards aphids

Two new labdane diterpene acids have been isolated from Grindelia humilis. The spectroscopic properties of the acids and their derivatives, as well as conversion to methyl 6-oxogrindelate, showed that they were the epimeric pair 6α-hydroxy- and 6β- hydroxygrindelic acid. A series of 11 diterpene acids were surveyed for their feeding deterrency towards the aphid Schizaphis graminum. The substances tested showed a wide range of activity.