Antiparasitic activity of prenylated benzoic acid derivatives from Piper species

Fractionation of dichloromethane extracts from the leaves of Piper heterophyllum and P. aduncum afforded three prenylated hydroxybenzoic acids, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid, 3-[(2E,6E,10E)-11-carboxy-13-hydroxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl]-4,5-dihydroxybenzoic acid and 3-[(2E,6E,10E)-11-carboxy-14-hydroxy-3,7,15-trimethyl-2,6,10,15-hexadecatetraenyl]-4,5-dihydroxybenzoic acid, along with the known compounds, 4,5-dihydroxy-3-(E,E,E-11-formyl-3,7,15-trimethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid (arieianal), 3,4-dihydroxy-5-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 4-hydroxy-3-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid, 4-hydroxy-3-(3,7-dimethyl-2,6-octadienyl)benzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid. Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. Riguera ester reactions and optical rotation measurements established the compounds as racemates. The antiparasitic activity of the compounds were tested against three strains of Leishmania spp., Trypanosoma cruzi and Plasmodium falciparum. The results showed that 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid exhibited potent and selective activity against L. braziliensis (IC₅₀ 6.5 μg/ml), higher that pentamidine used as control. Moreover, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl- 2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid showed moderate antiplasmodial (IC₅₀ 3.2 μg/ml) and trypanocidal (16.5 μg/ml) activities, respectively.     

Phenolic derivatives from Wigandia urens with weak activity against the chemokine receptor CCR5

Three compounds, 2,3-dihydroxy-4-methoxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (1), 8-methoxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-6-ol (2) and 4-methoxy-3-(3-methyl-2-butenyl)-benzoic acid (3), have been isolated from Wigandia urens. The structures of compounds 1, 2 and 3 were determined from spectroscopic data and showed activity in a CCR5 assay with IC(50) values of 33, 46 and 26 muM respectively.     

Coumarins and chromones from Lomatium macrocarpum

Roots of Lomatium macrocarpum (Hook. & Arn.) C. & R. yielded osthol (7-methoxy-8-[3-methyl-2-butenyl]-coumarin) and a chromone, 2-methyl-5-hydroxy-6-[3-methyl-2-butenyl]-7-methoxychromone, identified spectroscopically and by synthesis. The aerial parts of the plant also contained this chromone along with sibiricin (5,7-dimethoxy-8-[3-methyl-2,3-epoxybutyl]-coumarin) and a new coumarin named macrocarpin. By spectroscopy and chemical degradation macrocarpin was shown to be 7-methoxy-8-(3-methyl-4-[2-methyl-cis-2-butenoyloxy]-cis-2-butenyl)coumarin. These products were not found in four other Lomatium species examined.     

Antibacterial and antifungal flavanones from Eysenhardtia texana

An activity-guided fractionation of a methanol-dichloromethane extract obtained from the aerial parts of Eysenhardtia texana led to the isolation of two novel antibacterial and antifungal flavanones together with a known flavanone. Their structures were established as 4',5,7-trihydroxy-8-methyl-6-(3-methyl-[2-butenyl])-(2S)-flavanone, 4',5,7-trihydroxy-6-methyl-8-(3-methyl-[2-butenyl])-(2S)-flavanone and 4',5-dihydroxy-7-methoxy-6-(3-methyl-[2-butenyl])-(2S)-flavanone on the basis of their UV, 1D and 2D-NMR spectra.     

Rhodococcus erythropolis DCL14 Contains a Novel Degradation Pathway for Limonene

Strain DCL14, which is able to grow on limonene as a sole source of carbon and energy, was isolated from a freshwater sediment sample. This organism was identified as a strain of Rhodococcus erythropolis by chemotaxonomic and genetic studies. R. erythropolis DCL14 also assimilated the terpenes limonene-1,2-epoxide, limonene-1,2-diol, carveol, carvone, and (−)-menthol, while perillyl alcohol was not utilized as a carbon and energy source. Induction tests with cells grown on limonene revealed that the oxygen consumption rates with limonene-1,2-epoxide, limonene-1,2-diol, 1-hydroxy-2-oxolimonene, and carveol were high. Limonene-induced cells of R. erythropolis DCL14 contained the following four novel enzymatic activities involved in the limonene degradation pathway of this microorganism: a flavin adenine dinucleotide- and NADH-dependent limonene 1,2-monooxygenase activity, a cofactor-independent limonene-1,2-epoxide hydrolase activity, a dichlorophenolindophenol-dependent limonene-1,2-diol dehydrogenase activity, and an NADPH-dependent 1-hydroxy-2-oxolimonene 1,2-monooxygenase activity. Product accumulation studies showed that (1S,2S,4R)-limonene-1,2-diol, (1S,4R)-1-hydroxy-2-oxolimonene, and (3R)-3-isopropenyl-6-oxoheptanoate were intermediates in the (4R)-limonene degradation pathway. The opposite enantiomers [(1R,2R,4S)-limonene-1,2-diol, (1R,4S)-1-hydroxy-2-oxolimonene, and (3S)-3-isopropenyl-6-oxoheptanoate] were found in the (4S)-limonene degradation pathway, while accumulation of (1R,2S,4S)-limonene-1,2-diol from (4S)-limonene was also observed. These results show that R. erythropolis DCL14 metabolizes both enantiomers of limonene via a novel degradation pathway that starts with epoxidation at the 1,2 double bond forming limonene-1,2-epoxide. This epoxide is subsequently converted to limonene-1,2-diol, 1-hydroxy-2-oxolimonene, and 7-hydroxy-4-isopropenyl-7-methyl-2-oxo-oxepanone. This lactone spontaneously rearranges to form 3-isopropenyl-6-oxoheptanoate. In the presence of coenzyme A and ATP this acid is converted further, and this finding, together with the high levels of isocitrate lyase activity in extracts of limonene-grown cells, suggests that further degradation takes place via the β-oxidation pathway.     

Detailed biosynthetic pathway to decaprenoxanthin diglucoside in Corynebacterium glutamicum and identification of novel intermediates

Carotenogenic mutants of Corynebacterium glutamicum were analyzed for their carotenoid content. Mutant MV10 accumulated the same carotenoids as the wild-type, decaprenoxanthin, decaprenoxanthin monoglucoside, and (2R,6R,2'R,6'R)-decaprenoxanthin di-(beta-D)-glucoside, but in three-fold higher amounts. In addition, decaprenoxanthin diglucoside fatty acid esters and the intermediates nonaprene, 2-(3-methyl-2-butenyl)-epsilon,psi-carotene, and sarcinene, 2,2'-bis(3-methyl-2-butenyl)-epsilon,epsilon-carotene were identified as minor carotenoids. The pink mutants MV40 and MV60 synthesized only lycopene. From another pink mutant, MV70, novel C(50)-carotenoids were isolated. By NMR and mass spectroscopy, nonaflavuxanthin, 2-(4-hydroxy-3-methyl-2-butenyl)-1,16-didehydro-1,2-dihydro-psi,psi-carotene, and flavuxanthin, 2,2'-bis(4-hydroxy-3-methyl-2-butenyl)-1,16,1',16'-tetradehydro-1,2,1',2'-tetrahydro-psi,psi-carotene, were identified. The identification of these intermediates revealed the detailed pathway for the formation of decaprenoxanthin derivatives in Corynebacterium glutamicum.     

Formation of edulinine and furoquinoline alkaloids from quinoline derivatives by cell suspension cultures of Ruta graveolens

The formation of furoquinoline alkaloids and of edulinine, elaborated by cell suspension cultures of Ruta graveolens, was found to occur by way of 4-hydroxy-2-quinolone. Other substrates transformed to furoquinolines included 4-hydroxy- and 4-methoxy-3-(3-methyl-2-butenyl)-2-quinolone, known earlier as natural precursors in studies with whole plants. Involvement of dictamnine as a natural precursor of 8-methoxydictamnine (γ-fagarine) and skimmianine was proved using ¹⁴C-labelled compounds. Edulinine in the cell suspensions was formed from such substrates as 4-hydroxy-N-methyl-2-quinolone, 4-hydroxy-3-(3-methyl-2-butenyl)-N-methyl-2-quinolone and its 4- methyl ether; this is probably the natural biosynthetic sequence. Changes in alkaloid yields were noted upon prolonged subculturing.     

Benzophenones of Garcinia pseudoguttifera (Clusiaceae)

Four biogenetically related benzophenones have been isolated from the Fijian Garcinia pseudoguttifera. They are: 6-hydroxy-2,4-dimethoxy-3,5-bis(3-methyl-2-butenyl)benzophenone (myrtiaphenone-A); 2,2-dimethyl-8-benzoyl-7-hydroxy-5-methoxy-6-(3-methyl-2-butenyl)benzopy ran (myrtiaphenone-B); 2,6-dihydroxy-4-methoxy-3,5-bis(3-methyl-2-butenyl)benzophenone (vismiaphenone-C) and a new benzophenone, 2,2-dimethyl-8-benzoyl-3,7-dihydroxy-5-methoxy- 6-(3-methyl-2-butenyl)-3,4-dihydrobenzopyran (pseudoguttiaphenone-A). Pseudoguttiaphenone-A could be biogenetically derived from vismiaphenone-C. The major component of G. pseudoguttifera was identified as eupha-8,24-dien-3 beta-ol.     

Formation of Glucose Isomerase by Streptomyces sp.

Sophoradin (I) [2′,4,4′-trihydroxy-3,3′,5-tris(3-methyl-2-butenyl)chalcone] which had been isolated from “Guang-Dou-Gen” (the root of Sophora subprostrata Chun et T. Chen) was synthesized through Claisen rearrangement. The reaction of p-hydroxybenzaldehyde and 3-chloro-3-methyl-1-butyne (III) gave 4-(1,1-dimethylpropargyloxy)benzaldehyde (VIII), which was catalytically hydrogenated over Lindlar catalyst to afford 4-(1,1-dimethylallyloxy)benzaldehyde (IX). IX was converted to 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde (X) by Claisen rearrangement. The reaction of X and III gave 3-(3-methyl-2-butenyl)-4-(1,1-dimethylpropargyloxy)benzaldehyde (XI). Condensation of 2-hydroxy-4-(1,1-dimethylpropargyloxy)acetophenone (IV) and XI in alkaline solution gave a chalcone (XIII), which was catalytically hydrogenated over Lindlar catalyst to give 2′-hydroxy-4,4′-bis(1,-dimethylallyloxy)-3-(3-methyl-2-butenyl)chalcone (XIV). XIV was converted to I by Claisen rearrangement.     

Synthesis-guided structure revision of the monoterpene alcohol isolated from Mentha haplocalyx

The monoterpene isolated from Mentha haplocalyx, 3,3,5-trimethyl-2-oxabicyclo[2.2.2]oct-5-en-4-ol, was synthesized according to its proposed structure. However, the NMR data of the synthetic sample were not in agreement with those reported for the natural product. After considerable efforts, the genuine structure was confirmed as (1R*,2R*)-4-(1′-hydroxy-1′-methylethyl)-1-methylycyclohex-3-ene-1,2-diol.     

Phenylpropene,benzoic acid and flavonoid derivatives from fruits of jamaican Piper species

1-Allyl-2,3-(methylenedioxy)-4,5-dimethoxybenzene, 4-methoxy-3,5-bis(3'-methyl-2'-butenyl)-benzoic acid, and the known compounds 5-hydroxy-7-methoxyflavanone and 2,6-dihydroxy-4-methoxydihydrochalcone have been isolated from the fruits of Jamaican Piper aduncum and Piper hispidum.     

Two new coumarins in Boenninghausenia albiflora

Two new isomeric coumarins were isolated from leaves of Boenninghausenia albiflora Reichb. Their structures were elucidated as (E)-7-hydroxy-6-(3-hydroxy-3-methyl-1-butenyl)-2(H)-1-benzpyran-2-one and (Z)-7-hydorxy-6-(3-hydroxy-3-methyl-1-butenyl)-2(H)-1-benzopyran-2-one.     

Coumarins from Amyris balsamifera

Two new coumarins have been isolated from the aerial parts of Amyris balsamifera. On the basis of spectral and chemical data, these have been identified as (R)-(+)-6-(2′-hydroxy-3′-methyl-3′-butenyl)-7-methoxycoumarin and balsamiferone, 7-hydroxy-3,6-bis (3′-methyl-2′-butenyl)-coumarin.     

Lignans of Larix leptolepis

Five lignans have been isolated from wood of Larix leptolepis. They are identified as 1-(4-hydroxy-3-methoxyphenyl)-2-4-[2-formyl-(E)-vinyl]-2-methoxyphenoxy-propane- 1,3-diol, 1-(4-hydroxy-3-methoxyphenyl)-2-2-methoxy-4-[1-(E)-propen-3-ol]-phenoxy- propane-1,3-diol, 1-(4-hydroxy-3-methoxyphenyl)-2-(4-formyl-2-methoxyphenoxy)-propane-1,3-diol, 1,2-bis-(4-hydroxy-3-methoxyphenyl)-propane-1,3-diol and a trilignol, leptolepisol C.     

Neuroprotective metabolites from the endophytic fungus Penicillium citrinum of the mangrove Bruguiera gymnorrhiza

Two new compounds, named as (Z)-7,4′-dimethoxy-6-hydroxy-aurone-4-O-β-glucopyranoside (1), and (1S,3R,4S)-1-(4′-hydroxyl-phenyl)-3,4-dihydro-3,4,5-trimethyl-1H-2-benzopyran-6,8-diol (2), were isolated from the endophytic fungus Penicillium citrinum of Bruguiera gymnorrhiza. Their structures were elucidated on the basis of spectroscopic analysis. Additionally, compound 1 exhibited potent neuroprotective activity in 1-methyl-4-phenylpyridinium-induced oxidative damage in PC12 cells.     

Microbiological Hydroxylation of Cinerone to Cinerolone

Cinerone [2-(2′-cis-butenyl)-3-methyl-2-cyclopenten-1-one] is hydroxylated to cinerolone [2-(2′-cis-butenyl)-3-methyl-4-hydroxy-2-cyclopenten-1-one] by a number of streptomycetes, bacteria, and fungi. Aspergillus niger ATCC 9,142 and Streptomyces aureofaciens ATCC 10,762 were found to be the most effective hydroxylators. The optical activity of the product was found to range from [α]_D²⁵ 0° to -8.6°, depending on the organism and conditions of culture. Two additional hydroxylated products of cinerone have been isolated and identified as 2-n-butyl-4-hydroxy-3-methyl-2-cyclopenten-1-one and 2-(2′-cis-butenyl-4′-hydroxy)-3-methyl-2-cyclopenten-1-one, respectively.     

Synthesis of novel GABA uptake inhibitors. Part 6: preparation and evaluation of N-Omega asymmetrically substituted nipecotic acid derivatives

In a previous series of potent GABA uptake inhibitors published from this laboratory, we noticed that asymmetry in the substitution pattern of the bis-aromatic moiety in known GABA uptake inhibitors such as 4 [1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid] and 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid] was beneficial for high affinity. This led us to investigate asymmetric analogues of known symmetric GABA uptake inhibitors in which one of the aryl groups has been exchanged with an alkyl, alkylene or cycloalkylene moiety as well as other modifications in the lipophilic part. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound, and it was found that several of the novel compounds inhibit GABA uptake as potently as their known symmetrical reference analogues. Several of the novel compounds were also evaluated for their ability to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in vivo. Some of the compounds, for example 18 [(R)-1-(2-(((1,2-bis(2-fluorophenyl)ethylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid], show a high in vivo potency and protective index comparable with that of our recently launched anticonvulsant product, 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid], and may therefore serve as second-generation drug candidates.     

New Cholinesterase Inhibitory Constituents from Lonicera quinquelocularis

A phytochemical investigation on the ethyl acetate soluble fraction of Lonicera quinquelocularis (whole plant) led to the first time isolation of one new phthalate; bis(7-acetoxy-2-ethyl-5-methylheptyl) phthalate (3) and two new benzoates; neopentyl-4-ethoxy-3, 5-bis (3-methyl-2-butenyl benzoate (4) and neopentyl-4-hydroxy-3, 5-bis (3-methyl-2-butenyl benzoate (5) along with two known compounds bis (2-ethylhexyl phthalate (1) and dioctyl phthalate (2). Their structures were established on the basis of spectroscopic analysis and by comparison with available data in the literature. All the compounds (1–5) were tested for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in dose dependent manner. The IC₅₀ (50% inhibitory effect) values of compounds 3 and 5 against AChE were 1.65 and 3.43 µM while the values obtained against BChE were 5.98 and 9.84 µM respectively. Compounds 2 and 4 showed weak inhibition profile.     

Antioxidative phenylpropanoids from berries of Pimenta dioica

A phenylpropanoid, threo-3-chloro-1-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol, was isolated from the berries of Pimenta dioica together with five known compounds, eugenol, 4-hydroxy-3-methoxycinnamaldehyde, 3,4-dimethoxycinnamaldehyde, vanillin and 3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol. In addition, the stereochemistry of 3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol was determined. The phenylpropanoids inhibited autoxidation of linoleic acid in a water-alcohol system.     

Anthraquinones from Vismia species

1,8-Dihydroxy-3-methyl-6-methoxyanthraquinone (physcion) and two derivatives, 7-(trans-3-methyl-1-butenyl)-physcion (vismiaquinone) and 7-(3-methyl-2-oxobutyl)-physcion (vismiaquinone B), were isolated respectively from Vismia cayennensis and V. japurensis.