Optimization of Insecticidal Triterpene Derivatives by Biomimetic Oxidations with Hydrogen Peroxide and Iodosobenzene Catalyzed by MnIII and FeIII Porphyrin Complexes.

Semisynthetic functionalized triterpenes (4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3ß-yl acetate; 4α,14-dimethyl-5α-cholest-8-ene-3,7,11-trione; 4α,14-dimethyl-5α-cholesta-7,9(11)-dien-3-one and 4α,14-dimethyl-5α-cholest-8-en-3ß-yl acetate), previously prepared from 31-norlanostenol, a natural insecticide isolated from the latex of Euphorbia officinarum, have been subjected to oxidation with hydrogen peroxide (H2 O2 ) and iodosobenzene (PhIO) catalyzed by porphyrin complexes (cytochrome P-450 models) in order to obtain optimized derivatives with high regioselectivity. The main transformations were epoxidation of the double bonds and hydroxylations of non-activated C-H groups and the reaction products were 25-hydroxy-4α,14-dimethyl-5α-cholesta-7,9(11)-dien-3ß-yl acetate (59 %), 25-hydroxy-4α,14-dimethyl-5α-cholest-8-ene-3,7,11-trione (60 %), 4α,14-dimethyl-5α,7ß-7,8-epoxycholest-9(11)-en-3-one (22 %), 8-hydroxy-4α,14-dimethyl-5α-cholest-9(11)-ene-3,7-dione (16 %), 12α-hydroxy-4α,14-dimethyl-5α,7ß-7,8-epoxycholest-9(11)-en-3-one (16 %), and 4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3ß-yl acetate (26 %), respectively. We also investigated the insect (Myzus persicae, Rhopalosiphum padi and Spodoptera littoralis) antifeedant and postingestive effects of these terpenoid derivatives. None of the compounds tested had significant antifeedant effects, however, all were more effective postingestive toxicants on S. littoralis larvae than the natural compound 31-norlanostenol, with 4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3ß-yl acetate being the most active. The study of their structure-activity relationships points out at the importance of C3 and C7 substituents.

Insect Antifeedant Components of Senecio fistulosus var. fistulosus-Hualtata.

From a bioactive methanolic extract of Senecio fistulosus, the antifeedant effects of the alkaloidal and non-alkaloidal fractions were tested against the insects Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi, with the non-alkaloidal fraction being antifeedant. The phytochemical study of the non-alkaloidal fraction of S. fistulosus, resulted in the isolation of four compounds, two 9-oxo-furanoeremophilanes (1, 2), an eremophilanolide, 1ß,10ß-epoxy-6-acetoxy-8α-hydroxy-eremofil-7(11)-en-8ß,12-olide (3) and a maaliol derivative (4). The alkaloidal fraction yielded two known pyrrolizidine alkaloids (5, 6). Compounds 1, 3 and 4 are new natural products. Furanoeremophilane 2 was a strong antifeedant against S. littoralis and maaliane 4 inhibited the settling of M. persicae.

Studies on the sesquiterpene lactones from Laurus novocanariensis lead to the clarification of the structures of 1-epi-tatridin B and its epimer tatridin B.

The germacranolide 1-epi-tatridin B has been isolated from the aerial parts of Laurus novocanariensis. We have observed that the identification of this lactone and its epimer tetradin B in the scientific literature is confusing and contradictory. We have therefore studied this issue clarifying errors and contributing to the structural elucidation of other related products. Moreover, we have isolated from this plant a lactone with an 1,5-ether bridge, previously obtained from Austrolabium candidum. We have now named it austroliolide, reassigned its 13C NMR spectrum and compared its structure with that of badgerin. In addition, we have also isolated from L. novocanariensis the known germacranolides artemorin, costunolide, tatridin A, tulirinol and verlotorin, the eudesmanolides ß-cyclopyrethrosin, 1ß-hydroxy-arbusculin A, magnoliaolide and reynosin, and the guaianolide dehydrocostus lactone.

Structure-Dependent Cytotoxic Effects of Eremophilanolide Sesquiterpenes.

The aim of this research was to determine the cytotoxic action of sixteen structurally-related eremophilane-type sesquiterpenes, isolated from several species of Senecio, against a panel of cancer cell lines. The cytotoxic activities were evaluated by WST-I test and the ICso values calculated. The investigated compounds exerted dose-dependent cytotoxic actions against selected cancer cell lines and no-tumoral HS5 cell line. The comparative structure-activity relationships demonstrated the importance of C-1, C-6, and C-8 substituents in the molecule. Our results show that eremophilane-type sesquiterpenes may represent an important source of novel potential antitumor agents due to their pronounced cytotoxic actions towards malignant cells.

Biotransformation of an africanane sesquiterpene by the fungus Mucor plumbeus.

Biotransformation of 8ß-hydroxy-african-4(5)-en-3-one angelate by the fungus Mucor plumbeus afforded as main products 6α,8ß-dihydroxy-african-4(5)-en-3-one 8ß-angelate and 1α,8ß-dihydroxy-african-4(5)-en-3-one 8ß-angelate, which had been obtained, together with the substrate, from transformed root cultures of Bethencourtia hermosae. This fact shows that the enzyme system involved in these hydroxylations in both organisms, the fungus and the plant, acts with the same regio- and stereospecificity. In addition another twelve derivatives were isolated in the incubation of the substrate, which were identified as the (2'R,3'R)- and (2'S,3'S)-epoxy derivatives of the substrate and of the 6α- and 1α-hydroxy alcohols, the 8ß-(2'R,3'R)- and 8ß-(2'S,3'S)-epoxyangelate of 8ß,15-dihydroxy-african-4(5)-en-3-one, the hydrolysis product of the substrate, and three isomers of 8ß-hydroxy-african-4(5)-en-3-one 2ξ,3ξ-dihydroxy-2-methylbutanoate. The insect antifeedant effects of the pure compounds were tested against chewing and sucking insect species along with their selective cytotoxicity against insect (Sf9) and mammalian (CHO) cell lines.

Insect Antifeedant and Ixodicidal Compounds from Senecio adenotrichius.

Nine eremophilane sesquiterpenes 1 - 9, two flavonoids 11 and 12, and two known pirrolizidine alkaloids 13 and 14, were isolated from Senecio adenotrichius DC. Their structures were elucidated on the basis of spectroscopic data and by comparison with previously reported spectroscopic data of similar compounds. Compounds 5, 7, and 9 have not been previously reported as natural products. The antifeedant activity of these compounds was tested against Spodoptera litoralis and Myzus persicae. Eremophilanes 1, 3, and 8 were strong antifeedants to M. persicae, and 1 and 8 to Spodoptera littoralis. Their ixodicidal activity was tested against the tick Hyalomma lusitanicum, with eremophilanes 1, 3, and 8, being strong ixodicidal agents.

Sesquiterpenes, flavonoids, shikimic acid derivatives and pyrrolizidine alkaloids from Senecio kingii Hook.

Twenty-four compounds including eleven eremophilanolides (1-11), one eremophilane (13), five shikimic acid derivatives (14-18), six flavonoids (19-24), and the macrocyclic unsaturated pyrrolizidine alkaloid integerrimine (25) were isolated from Senecio kingii, an endemic species from the Magallanes Region (Chile). Compounds 3, 5, 6, 8-11 and 13-18 have not been previously reported as natural products. Their molecular structures were determined by NMR spectroscopic analysis and comparison with published NMR data. An X-ray-analysis of compound 3 has been performed. Their insecticidal and antifungal activities were tested, being compound 3 the strongest insect antifeedant. Compounds 6, 9 and 18 were moderate antifungals.

Bioactive compounds from transformed root cultures and aerial parts of Bethencourtia hermosae.

A chemical study of Bethencourtia hermosae, aerial parts and in vitro root cultures, transformed by Agrobacterium rhizogenes, afforded the hitherto unreported sesquiterpenes ceratopicanol angelate (1), 8ß-hydroxy-african-4(5)-en-3-one tiglate (4), 8ß-hydroxy-african-4(5)-en-3-one 3'-angeloxy-2'-methylbutanoate (5), 1α,8ß-dihydroxy-african-4(5)-en-3-one 8ß-angelate (7) and 6α,8ß-dihydroxy-african-4(5)-en-3-one 8ß-angelate (8). In addition, 8ß-hydroxy-african-4(5)-en-3-one (6) was isolated for the first time from a natural source, along with the rare sesquiterpenoid senecrassidiol (10) and two jacaranone derivatives 14 and 16. Known pyrrolizidine alkaloids, together with previously unreported hermosine (23), have also been isolated from this plant. The insect antifeedant activities of the extracts and compounds were studied together with their cytotoxic effects against insect (Sf9) and mammalian (CHO) cell lines.

Antiparasitic indole alkaloids from Aspidosperma desmanthum and A. spruceanum from the Peruvian Amazonia.

Twenty-three indole alkaloids were isolated from Aspidosperma desmanthum and A. spruceanum. Alkaloids 1-4 were isolated from the leaves, 5-8 from the stem bark and 9-15 from the root bark of A. desmanthum. Alkaloids 5, 11, 16, 17 and 19 were isolated from the stem bark, 18 and 20-22 from the root bark and 23 from the flowers of A. spruceanum. Compounds 4, 14, and 15 have not been previously reported as natural products while 16 and 20 have been isolated for the first time from the genus Aspidosperma. Their structures were determined by spectroscopic techniques including 1D and 2D NMR experiments (COSY, NOESY, HSQC, HMBC). The antiparasitic activity of these compounds was tested against Trypanosoma cruzi and Leishmania infantum and their non-specific cytotoxicity on mammalian cells. The most active compounds were 10, 12, 13, and 14 from A. desmanthum, and 19, 21 and 22 from A. spruceanum. Aspidolimine (10) aspidocarpine (12) and tubotaiwine (21) showed selective activity against L. infantum.

Antifeedant activity of fatty acid esters and phytosterols from Echium wildpretii.

Crude extracts and fractions from Echium wildpretii H. Pearson ex Hook. f. subsp. wildpretii (Boraginaceae) have been tested against insect species Spodoptera littoralis, Leptinotarsa decemlineata, and the aphids Myzus persicae, Diuraphis noxia, Metopolophium dirhodum, Rhopalosiphum maidis, and Rhopalosiphum padi. The EtOH extract and the lipid and steroidal fractions of E. wildpretii exhibited significant antifeedant activities against the aphids and L. decemlineata. Two bioactive mixtures composed of fatty acid esters and n-alkanes were obtained from the lipid fraction. The bioguided fractionation of the steroidal fraction resulted in the isolation of glutinol, ß-sitosterol, (3ß,7α)-stigmast-5-ene-3,7-diol, and (3ß,7α)-7-methoxystigmast-5-en-3-ol. The latter two compounds exhibited potent antifeedant activities against L. decemlineata indicating that the presence of an O-bearing C(7) was responsible for the activities of these molecules.

Defensive sesquiterpenes from Senecio candidans and S. magellanicus, and their structure-activity relationships.

Eleven eremophilanolides, 1-3 and 6-13, and two eremophilanes, 24 and 25, were isolated from Senecio candidans and S. magellanicus from the Magallanes Region (Chile). Compounds 2, 3, 9, and 10 have not been previously reported as natural products. Their structures were established by NMR spectroscopic analysis and chemical transformations. The X-ray analysis of compounds 11, 13, and 17 were also performed. Different semisynthetic analogs from eremophilanolide 11 were generated to carry out a structure-activity relationship study. Their possible plant defensive role was tested against herbivorous insects (Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae) and plants (Lactuca sativa). Additionally, their effects on insect (Sf9) and mammalian (CHO) cell lines were tested.

Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants.

Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different solvents (hexane, chloroform, and 70% ethanol-water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional (1)H and (13)C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1-2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S,S')-12-O-methyl(+)-curine (5); and cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity.

Antileishmanial and antitrypanosomal activity of triterpene derivatives from latex of two Euphorbia species.

The in vitro activity on Leishmania infantum promastigotes and Trypanosoma cruzi epimastigotes of 25 semisynthetic terpenoid derivatives has been evaluated. These compounds were obtained through chemical modifications of the major components of Euphorbia resinifera (alpha-euphol and alpha-euphorbol) and Euphorbia officinarum (obtusifoliol and 31-norlanosterol). Leishmaniasis and Chagas' disease are major worldwide health problems. The drugs of choice for their treatment are still problematic in both cases, and therefore there is an urgent need to discover new drugs with high activity and low side effects. Natural products have become a key source of new drugs in the last years. The genus Euphorbia has been the subject of abundant phytochemical and pharmacological research because of its potential medical applications, but the antiparasitic effects of derivatives from plants of this genus are still unknown. Our results showed that 76% and 64% of the test compounds had antiparasitic effects on L. infantum and T cruzi, respectively. The different activities on both parasites, especially their moderate effects on mammalian cells, indicate an interesting selective toxicity.

Indole alkaloids from Aspidosperma rigidum and A. schultesii and their antiparasitic effects.

Five oxindole alkaloids, three plumerane-type alkaloids, subtype haplophitine, and one aspidospermatane-type alkaloid, subtype tubotaiwine, were isolated from the medicinal plants Aspidosperma rigidum and A. schultesii. One compound was identified as the transoid conformer of 18-oxo-O-methylaspidoalbine which was not previously described. The antiparasitic activity of all compounds against Trypanosoma cruzi and Leishmania infantum and their non-specific cytotoxicity against mammalian cells were also determined.

Absolute configuration of tropane alkaloids from Schizanthus species by vibrational circular dichroism.

The absolute configuration (AC) of 6beta-hydroxy-3alpha-senecioyloxytropane (1), 3alpha-hydroxy-6beta-tigloyloxytropane (2), 3alpha-hydroxy-6beta-senecioyloxytropane (3), and 3alpha-hydroxy-6beta-angeloyloxytropane (4) was assigned as (1R,3R,5S,6R) using density functional theory (DFT) calculations at the B3LYP/DGDZVP level of theory in combination with experimental vibrational circular dichroism (VCD) measurements and comparison with the spectra of similar tropanes. The AC of 1 followed from a sample isolated from Schizanthus grahamii, while those of the mixture of 2 and 3, isolated from the same source, were determined by comparing the VCD measurement to a weighted calculation of the individual VCD spectra according to a 69:31 ratio of 2:3 determined by (1)H NMR signal integration. In turn, Schizanthus pinnatus provided a 7:3 mixture of 1:4 whose AC was determined using the experimental VCD absorptions in the 1150-950 cm(-1) spectral region which were compared with those observed for 1-3 and with those described for other 3alpha,6beta-tropanediol derivatives.

Megalanthine, a bioactive sesquiterpenoid from Heliotropium megalanthum, its degradation products and their bioactivities.

The new bioactive sesquiterpenoid (3R,6E)-2,6,10-trimethyl-3-(3-p-hydroxyphenylpropanoyloxy)-dodeca-6,11-diene-2,10-diol, named megalanthine, was isolated from the resinous exudates of Heliotropium megalanthum. The degradation products of this compound were identified. Several plant-defensive properties (insecticidal, antifungal, and phytotoxic) were evaluated after obtaining positive results in a preliminary etiolated wheat coleoptile bioassay. This bioassay showed the need to have both the phenolic and sesquiterpene moieties of the natural product present to achieve a biological effect. This result was confirmed in phytotoxicity bioassays. Megalanthine was ruled out as a significant plant-plant defense agent because of its lack of stability. The positive results recorded in the antifungal and antifeedant tests suggest, however, that this chemical is relevant in several ecological interactions involving H. megalanthum.

(-)-istanbulin a.

THE TITLE COMPOUND (SYSTEMATIC NAME: 9a-hydr-oxy-3,4a,5-trimethyl-4a,6,7,8a,9,9a-hexa-hydro-4H,5H-naphtho[2,3-b]furan-2,8-dione), C(15)H(20)O(4), is a sesquiterpene lactone showing the typical eremophilanolide skeleton, which has been isolated from the plant Senecio candidans collected in the Chilean Magallanes region. The present study confirms the atomic connectivity assigned on the basis of (1)H and (13)C NMR spectroscopy, as well as the relative stereochemistry of the 4α-methyl,5α-methyl,8ß-hydr-oxy,10ß-H unit. The crystal structure is stabilized by inter-molecular O-H⋯O hydrogen bonds involving the hydr-oxy group as donor and the oxo group as acceptor, giving chains along the a axis. The absolute structure was not determined because of the lack of suitable anomalous scatters.

Bioactive triterpene derivatives from latex of two Euphorbia species.

We have investigated the antifeedant and toxic effects of 23 semisynthetic terpenoid derivatives obtained through chemical modifications of the major components of Euphorbia resinifera (alpha-euphol and alpha-euphorbol) and E. officinarum (obtusifoliol and 31-norlanostenol) latex on several insect species (Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi), their selective cytotoxicity on insect Sf9 and mammalian CHO cells and their phytotoxic effects on Lactuca sativa. The conversions focused mainly on positions 3,7,11, and 24 with several oxidizing agents. A total of 18 compounds affected S. littoralis growth (IGR). Our results support the importance of the C-3 substituent, suggest the involvement of the C-7 substituent and indicate that the C-3 hydroxyl is not essential for the IGR effect. Overall, Sf9 cells were more sensitive to the active compounds than CHO cells. All of these compounds had non selective moderate phytotoxic effects on radicle elongation of L. sativa.

Bioactive furanoeremophilanes from Senecio otites Kunze ex DC.

The furanoeremophilanes 6 beta-angeloyloxy-1,10-dehydrofuranoeremophilan-9-one (1), 6 beta-hydroxy-1,10-dehydrofuranoeremophilan-9-one (2) and 6 beta-propionyloxy-1,10-dehydrofuranoeremophilan-9-one (3) were isolated from Senecio otites, their structures elucidated by spectral analyses, and their insecticidal and phytotoxic properties evaluated. Compounds 1-3 proved to be effective aphid antifeedants against Myzus persicae and Rhopalosiphum padi and had postingestive negative effects on Spodoptera littoralis larvae. These compounds did not have any phytotoxic effects on Lactuca sativa.

In vitro cytotoxicity of norditerpenoid alkaloids.

Forty-three norditerpenoid alkaloids isolated from Aconitum, Delphinium and Consolida species have been evaluated for their cytotoxic effects on the tumor cell lines CT26 (murine colon adenocarcinoma), SW480 (human colon adenocarcinoma), HeLa (human cervical adenocarcinoma), SkMel25 (human melanoma) and SkMel28 (human malignant melanoma) with several multidrug resistance mechanisms and the non-tumor cell line CHO (Chinese hamster ovary cells). Neoline (5), 8-O-methylcolumbianine (6), 1,14-diacetylcardiopetaline (9), 18-O-demethylpubescenine (13), 14-deacetylpubescenine (14), pubescenine (15), 14-deacetylajadine (25), lycoctonine (26), browniine (28), delphatine (29), dehydrotakaosamine (34), and ajadelphinine (37) exhibited selective cytotoxicity to cancerous versus non-cancerous cells. Some of these compounds had an irreversible effect on SW480 (5, 15, 25, 26, and 34), HeLa (15, 34, and 37) and SkMel25 (15 and 34) cell lines. In order to gain insights into the mechanism of irreversible cytotoxic action of these compounds we compared the cell viability by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and the acid phosphatase (AP) methods. Our results suggest that the effects of these compounds could be related to the inhibition of ATP production.