Yeun-Mun Choo

Structure-Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

Characterization of Quorum Sensing and Quorum Quenching Soil Bacteria Isolated from Malaysian Tropical Montane Forest

We report the production and degradation of quorum sensing N-acyl-homoserine lactones by bacteria isolated from Malaysian montane forest soil. Phylogenetic analysis indicated that these isolates clustered closely to the genera of Arthrobacter, Bacillus and Pseudomonas. Quorum quenching activity was detected in six isolates of these three genera by using a series of bioassays and rapid resolution liquid chromatography analysis. Biosensor screening and high resolution liquid chromatography-mass spectrometry analysis revealed the production of N-dodecanoyl-L-homoserine lactone (C12-HSL) by Pseudomonas frederiksbergensis (isolate BT9). In addition to degradation of a wide range of N-acyl-homoserine lactones, Arthrobacter and Pseudomonas spp. also degraded p-coumaroyl-homoserine lactone. To the best of our knowledge, this is the first documentation of Arthrobacter and Pseudomonas spp. capable of degrading p-coumaroyl-homoserine lactone and the production of C12-HSL by P. frederiksbergensis.

Grandilodines A−C, Biologically Active Indole Alkaloids from Kopsia grandifolia

Three new indole alkaloids (1-3), named grandilodines A-C, and five known ones were obtained from the Malayan Kopsia grandifolia. The structures were established using NMR and MS analyses and, in the case of 1 and 2, were confirmed by X-ray diffraction analyses. Alkaloids 1, 3, and lapidilectine B (8) were found to reverse multidrug resistance in vincristine-resistant KB cells.

Alkaloids from the stem-bark of Alstonia macrophylla

Three new indole alkaloids, viz. 10-methoxyaffinisine, 10-methoxycathafoline and alstonerinal, in addition to alstonerine, alstonisine, alstonal, alstophylline, vincamajine, lochnerine and cathafoline were isolated from the stem-bark extract of Alstonia macrophylla.

Coexistence of quorum-quenching and quorum-sensing in tropical marine Pseudomonas aeruginosa strain MW3A

A chemically defined medium called KGm medium was used to isolate from a sample of sea water a bacterial strain, MW3A, capable of using N-3-oxohexanoyl-l-homoserine lactone as the sole carbon source. MW3A was clustered closely to Pseudomonas aeruginosa by 16S ribosomal DNA sequence analysis. It degraded both N-acylhomoserine lactones (AHLs) with a 3-oxo group substitution and, less preferably, AHLs with unsubstituted groups at C3 position in the acyl side chain, as determined by Rapid Resolution Liquid Chromatography. Its quiP and pvdQ homologue gene sequences showed high similarities to those of known acylases. Spent supernatant of MW3A harvested at 8-h post inoculation was shown to contain long-chain AHLs when assayed with the biosensor Escherichia coli [pSB1075], and specifically N-dodecanoyl-l-homoserine lactone and N-3-oxotetradecanoyl-l-homoserine lactone by high resolution mass spectrometry. Hence, we report here a novel marine P. aeruginosa strain MW3A possessing both quorum-quenching and quorum-sensing properties.

Kopsifolines A, B, and C, indole alkaloids with a novel hexacyclic carbon skeleton from Kopsia

Three indole alkaloids, viz., kopsifolines A, B, and C, characterized by a novel carbon skeleton, were obtained from a Malayan Kopsia species and the structures established by spectroscopic analysis.

Structure and biomimetic, electrochemically-mediated semisynthesis of the novel pentacyclic indole danuphylline

Abstract The structure of the novel pentacyclic indole, danuphylline, from Kopsia dasyrachis was established by spectral analysis. Anodic oxidation of the hexacylic alkaloid methyl 11,12-methylenedioxychanofruticosinate on platinum in TEAP/MeCN-CH2Cl2 (2 F mol−1) yielded an iminium ion salt which on silica gel chromatography underwent a facile retro-aldol process to give danuphylline. Allowing the oxidation to proceed until consumption of 4 F mol−1 of charge resulted in an unprecedented electrochemically-mediated aromatic chlorination yielding 10-chlorodanuphylline.

Novel Macroline Oxindoles from a Malayan Alstonia

Abstract Seven new macroline-type oxindole alkaloids, including several with novel structural features, were obtained from the Malayan Alstonia macrophylla and their structures established by spectral analysis.

Strychnan and secoangustilobine A type alkaloids from Alstonia spatulata. Revision of the C-20 configuration of scholaricine.

A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.

Indole and monoterpene alkaloids from the leaves of Kopsia dasyrachis

Abstract A new monoterpene alkaloid, kinabalurine G, in addition to 11 indole alkaloids and the catechine–skytanthine compound, kopsirachine, was obtained from the leaf extract of Kopsia dasyrachis. The structure of the novel alkaloid, danuphylline, was confirmed by an X-ray analysis.