Two cage-type lupin alkaloids from Sophora franchetiana

Two new cage-type lupin alkaloids, (?)-tsukushinamine-B and tsukushinamine-C, have been isolated from the fresh epigeal parts of Sophora franchetiana, along with (?)-cytisine, (?)-N-formylcytisine, (?)-rhombifoline, (?)-anagyrine, (?)-baptifoline and (±)-ammodendrine, as well as (?)-tsukushinamine-A. The structures of these novel tsukushinamine-type lupin alkaloids were determined by spectroscopic data and partly by a chemical reaction. Variations of the alkaloid contents in the seeds, seedlings and various parts of S. franchetiana were also examined.     

Lupin alkaloids from Echinosophora koreensis

The nine known lupin alkaloids, (?)-cytisine, (?)-N-methylcytisine, (?)-N-(?3-oxobutyl)-cytisine, (?)-N-formylcytisine, (?)-rho     

(−)-Epilamprolobine and its N-oxide,lupin alkaloids from Sophora tomentosa

From the fresh leaves of Sophora tomentosa, three new lupin alkaloids, (?)-epilamprolobine, (+)-epilamprolobine N-oxide and 5-(3′-methoxycarbonylbutyroyl)aminomethyl-trans-quinolizidine N-oxide, have further been isolated along with (+)-matrine, (+)-matrine N-oxide, (+)-sophocarpine N-oxide, (?)-anagyrine, (?)- baptifoline, (?)-cytisine, (?)-N-methylcytisine, (?)-N-formylcytisine, (?)-N-acetylcytisine and (±)-ammodendrine. The absolute configurations of (+)-epilamprolobine N-oxide (1R:5R:6S) and (?)-epilamprolobine (5R:6S) have also been established by spectroscopic data and by comparison with synthetic (+)-epilamprolobine (5S:6R)derived from (?)-lupinine (5R:6R). (?)-Epilamprolobine is a diastereomer of (+)-lamprolobine (5R:6R) in Lamprolobium fruticosum and 5-(3′-methoxycarbonylbutyroyl) aminomethyl-trans-quinolizidine N-oxide is presumed to be an artefact. A biosynthetic pathway for the formation of (?)-epilamprolobine is also proposed.     

Alkaloids of Thermopsis Lupinoides

Ammodendrine, together with seven other known lupin alkaloids, was isolated from Thermopsis lupinoides. (+)-Lupanine (+)-17-oxolupanine occurred together with (?)anagyrine, (?)-baptifoline, (?)-cytisine, (?)-N-methylcytisine (?)N-formylcytisine. These alkaloids have the opposite stereochemistry to that of (+)-lupanine and (+)-17-oxolupanine. The distribution of alkaloids in fresh flowers, leaves, stems roots of this plant was also examined.     

Four new N-acetylnoraporphine alkaloids from Liriodendron tulipifera

Four new naturally occurring N-acetylnoraporphine alkaloids were obtained from the heartwood of Liriodendron tulipifera; (?)-N-acetylanonaine, (?)-N-acetylnornuciferine, (?)-N-acetylasimilobine, and (?)-tuliferoline. Structure determination was accomplished by physical and chemical methods.     

Lignans from Piper cubeba

From the hot petrol extract of Piper cubeba ftuits, six lignans were isolated. Two of these, which have been obtained from a natural source for the first time, have been characterized as (2R,3R)-2-(3″,4″,5″-trimethoxybenzyl)-3-(3′,4′-methylenedioxybenzyl)-1,4-butanediol [(?)-dihydroclusin] and (3R,4R)-3,4-bis-(3,4,5-trimethoxybenzyl)tetra-hydro-2-furanol [(?)-cubebinin]. (?)Cubebin, (?)-hinokinin, (?)-clusin and (?)-dihydrocubebin were also found in this plant. Only (?)-cubebin has been reported so far from this source.     

Alkaloids of formosan Fissistigma and Goniothalamus species

Separation of the basic fractions from Formosan Fissistigma glaucescens, F. oldhamii and Goniothalamus amuyon afforded one new quaternary phenanthrene alkaloid, N-methylatherosperminium (15), along with the known alkaloids, (?)-discretamine (1), (?)-tetrahydropalmatine (2), palmatine (3), (?)-asimilobine (4), (?)-norannuradhapurine (5), (?)-crebanine (6), (?)-calycinine (fissoldine, fissistigine A) (7a), (?)-anolobine (8), (?)-xylopine (9), (?)-anonaine (10a), oxocrebanine (11), liriodenine (12), atherosperminine (13), N-noratherosperminine (14) and (+)-O-methylflavinantine (O-methylpallidine) (16).     

A benzopyrroloisoquinoline alkaloid from Ficus fistulosa

A new benzopyrroloisoquinoline alkaloid, fistulosine (1), was isolated from the stem-bark of Ficus fistulosa (Moraceae) collected in Singapore, along with three known phenanthroindolizidine alkaloids, (?)-13aα-antofine (2), (?)-14β-hydroxyantofine (3) and (?)-13aα-secoantofine (4). (?)-13aα-Antofine (2) accounted for the antifungal activity against Aspergillus fumigatus and Candida albicans originally observed in the crude alkaloid extract.     

Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia

hNav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards hNav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (?)-6, which led to the identification of aminocyclohexene analogues (?)-9 and (?)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (?)-9 and (?)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models.     

Structures of some minor pterocarpans of Neorautanenia edulis

The constitution of five new compounds, (?)-neorautenol, (?)-neodunol, (?)-homoedudiol, neorauteen and neoduleen, has been established in the root bark of Neorautanenia edulis.     

Sesquiterpenes from Lansium anamalayanum

The essential oil from the wood of Lansium anamalayanum Bedd. is shown to consist essentially of (?)-α-gurjunene (34%), (?)-α-trans-bergamotene (26%) and (?)-β-bisabolene (35%). The previously reported ‘chigadmarene’ has been found to be impure α-gurjunene. This essential oil is the richest known source for (?)-α-trans-bergamotene.     

Usnic acid derivatives from Leprocaulon microscopicum

In addition to known dibenzofuran derivatives such as (?)-usnic acid, (?)-isousnic acid and (?)-placodiolic acid, a Leprocaulon microscopicum acetone extract yielded a new compound, (±)-9-O-methylplacodiolic acid in a keto-enol equilibrium focused on the C-ring. Structures were established using mass spectrometry and combination of 1D and 2D NMR spectral data. ¹³C assignments of placodiolic acid were revised. Tautomers of the (±)-9-O-methylplacodiolic acid were only separated by GC and a thorough fragmentation study confirmed the structural features. To complete the study, evaluation of antiproliferative effects on HT-29 human colorectal cancer cells showed moderate activity for (?)-usnic acid only.     

Kaurane and kaurene diterpenes from the stem bark of Xylopia acutiflora

Four diterpenes were isolated from the stem bark of Xylopia acutiflora and characterized as (?)-kauran-16α-ol, 7,8-acetoxy-(?)-kaur-16-en-19-oic acid, 15-oxo-(?)-kaur-16-en-19-oic acid, and 16α- hydroxy-(?)-kauran-19-oic acid.     

Mucronulatol,mucroquinone and mucronucarpan,isoflavonoids from Machaerium mucronulatum and M. villosum

Additionally to the cinnamylphenols described in a previous paper, wood samples of Machaerium mucronulatum and M. villosum contain isoflavones, besides (?)-duartin, (?)- and (±)-mucronulatol [(3S)- and rac-7,3′-dihydroxy-2′,4′-dimethoxyisoflavan], (?)-mucroquinone [(3S)-2-methoxy-5-(7-hydroxy-8-methoxychroman-3-yl)-1,4-benzoquinone] and (+)-mucronucarpan [(6aS,11aS)-2,10-dihydroxy-3,9-dimethoxypterocarpan]. The constitutions of mucronulatol, mucroquinone and mucronucarpan were deduced by spectra and degradations, and confirmed by syntheses.     

Highly enantioselective oxidation of racemic phenyl-1,2-ethanediol to optically pure (R)-(−)-mandelic acid by a newly isolated Brevibacterium lutescens CCZU12-1

Enantioselective oxidation of racemic phenyl-1,2-ethanediol into (R)-(?)-mandelic acid by a newly isolated Brevibacterium lutescens CCZU12-1 was demonstrated. It was found that optically active (R)-(?)-mandelic acid (e.e.p?>?99.9 %) is produced leaving the other enantiomer (S)-(+)-phenyl-1,2-ethanediol intact. Using fed-batch method, a total of 172.9 mM (R)-(?)-mandelic acid accumulated in the reaction mixture after the seventh feed. Moreover, oxidation of phenyl-1,2-ethanediol using calcium alginate-entrapped resting cells was carried out in the aqueous system, and efficient biocatalyst recycling was achieved as a result of cell immobilization in calcium alginate, with a product-to-biocatalyst ratio of 27.94 g (R)-(?)-mandelic acid g^?1 dry cell weight cell after 16 cycles of repeated use.     

The influence of Ceratocystis polonica inoculation and methyl jasmonate application on terpene chemistry of Norway spruce,Picea abies

Constitutive and inducible terpene production is involved in conifer resistance against bark beetles and their associated fungi. In this study 72 Norway spruce (Picea abies) were randomly assigned to methyl jasmonate (MJ) application, inoculation with the bluestain fungus Ceratocystis polonica, or no-treatment control. We investigated terpene levels in the stem bark of the trees before treatment, 30 days and one year after treatment using GC–MS and two-dimensional GC (2D-GC) with a chiral column, and monitored landing and attack rates of the spruce bark beetle, Ips typographus, on the trees by sticky traps and visual inspection. Thirty days after fungal inoculation the absolute amount and relative proportion of (+)-3-carene, sabinene, and terpinolene increased and (+)-α-pinene decreased. Spraying the stems with MJ tended to generally increase the concentration of most major terpenes with minor alteration to their relative proportions, but significant increases were only observed for (?)-β-pinene and (?)-limonene. Fungal inoculation significantly increased the enantiomeric ratio of (?)-α-pinene and (?)-limonene 1 month after treatment, whereas MJ only increased that of (?)-limonene. One year after treatment, both MJ and fungal inoculation increased the concentration of most terpenes relative to undisturbed control trees, with significant changes in (?)-β-pinene, (?)-β-phellandrene and some other compounds. Terpene levels did not change in untreated stem sections after treatment, and chemical induction by MJ and C. polonica thus seemed to be restricted to the treated stem section. The enantiomeric ratio of (?)-α-pinene was significantly higher and the relative proportions of (?)-limonene were significantly lower in trees that were attractive to bark beetles compared to unattractive trees. One month after fungal inoculation, the total amount of diterpenes was significantly higher in putative resistant trees with shorter lesion lengths than in putative susceptible trees with longer lesions. Thus, terpene composition in the stem bark may be related to resistance of Norway spruce against I. typographus and C. polonica.     

Catalytic asymmetric total synthesis of (S)-(−)-zearalenone,a novel lipoxygenase inhibitor

A catalytic asymmetric synthesis of (S)-(?)-zearalenone is reported using asymmetric allylic alkylation for the introduction of the stereocenter. (S)-(?)-Zearalenone turned out to be a novel lipoxygenase inhibitor.     

Synthesis and comparison of antiplasmodial activity of (+), (−) and racemic 7-chloro-4-(N-lupinyl)aminoquinoline

Recently the N-(?)-lupinyl-derivative of 7-chloro-4-aminoquinoline ((?)-AM-1; 7-chloro-4-{N-[(1S,9aR)(octahydro-2H-quinolizin-1-yl)methyl]amino}quinoline) showed potent in vitro and in vivo activity against both Chloroquine susceptible and resistant strains of Plasmodium falciparum. However, (?)-AM-1 is synthesized starting from (?)-lupinine, an expensive alkaloid isolated from Lupinus luteus whose worldwide production is not sufficient, at present, for large market purposes. To overcome this issue, the corresponding racemic compound, derived from synthetic (±)-lupinine was considered a cheaper alternative for the development of a novel antimalarial agent. Therefore, the racemic and the 7-chloro-4-(N-(+)-lupinyl)aminoquinoline ((±)-AM-1; (+)-AM-1) were synthesized and their in vitro antimalarial activity and cytotoxicity compared with those of (?)-AM-1. The (+)-lupinine required for the synthesis of (+)-AM-1 was obtained through a not previously described lipase catalyzed kinetic resolution of (±)-lupinine. In terms of antimalarial activity, (±)-AM1 and (+)-AM1 demonstrated very good activity in vitro against both CQ-R and CQ-S strains of P. falciparum (range IC₅₀ 16–35 nM), and low toxicity against human normal cell lines (therapeutic index >1000), comparable with that of (?)-AM1. These results confirm that the racemate (±)-AM1 could be considered as a potential antimalarial agent, ensuring a decrease of costs of synthesis compared to (?)-AM1.     

Selective Interaction of Colistin with Lipid Model Membranes

Although colistin’s clinical use is limited due to its nephrotoxicity, colistin is considered to be an antibiotic of last resort because it is used to treat patients infected with multidrug-resistant bacteria. In an effort to provide molecular details about colistin’s ability to kill Gram-negative (G(?)) but not Gram-positive (G(+)) bacteria, we investigated the biophysics of the interaction between colistin and lipid mixtures mimicking the cytoplasmic membrane of G(+), G(?) bacteria as well as eukaryotic cells. Two different models of the G(?) outer membrane (OM) were assayed: lipid A with two deoxy-manno-octulosonyl sugar residues, and Escherichia coli lipopolysaccharide mixed with dilaurylphosphatidylglycerol. We used circular dichroism and x-ray diffuse scattering at low and wide angle in stacked multilayered samples, and neutron reflectivity of single, tethered bilayers mixed with colistin. We found no differences in secondary structure when colistin was bound to G(?) versus G(+) membrane mimics, ruling out a protein conformational change as the cause of this difference. However, bending modulus K_C perturbation was quite irregular for the G(?) inner membrane, where colistin produced a softening of the membranes at an intermediate lipid/peptide molar ratio but stiffening at lower and higher peptide concentrations, whereas in G(+) and eukaryotic mimics there was only a slight softening. Acyl chain order in G(?) was perturbed similarly to K_C. In G(+), there was only a slight softening and disordering effect, whereas in OM mimics, there was a slight stiffening and ordering of both membranes with increasing colistin. X-ray and neutron reflectivity structural results reveal colistin partitions deepest to reach the hydrocarbon interior in G(?) membranes, but remains in the headgroup region in G(+), OM, and eukaryotic mimics. It is possible that domain formation is responsible for the erratic response of G(?) inner membranes to colistin and for its deeper penetration, which could increase membrane permeability.