David R. Appleton

Malabaricone C from Myristica cinnamomea Exhibits Anti-Quorum Sensing Activity

A methanol-soluble extract of the bark of Myristica cinnamomea was found to exhibit anti-quorum sensing activity, and subsequent bioassay-guided isolation led to the identification of the active compound malabaricone C (1). Compound 1 inhibited violacein production by Chromobacterium violaceum CV026 when grown in the presence of a cognate signaling molecule, N-3-oxohexanoyl-homoserine lactone. Furthermore, 1 inhibited the quorum sensing-regulated pyocyanin production and biofilm formation in Pseudomonas aeruginosa PAO1. These results suggest that the anti-quorum sensing activity of 1 and related molecules should be investigated further.

Rossinones A and B, Biologically Active Meroterpenoids from the Antarctic Ascidian, Aplidium species

Rossinones A (1) and B (2), biologically active meroterpene derivatives, were isolated from an Antarctic collection of the ascidian Aplidium species and structurally characterized with spectroscopic methods. The absolute configuration of 1 was deduced by using the modified Mosher method. The rossinones exhibit anti-inflammatory, antiviral and antiproliferative activities.

Isodiplamine, cystodytin K and lissoclinidine: novel bioactive alkaloids from the New Zealand ascidian Lissoclinum notti

Abstract A study of the bioactive crude extract of the New Zealand ascidian Lissoclinum notti led to the isolation of the new pyridoacridine alkaloids isodiplamine ( 4 ), cystodytin K ( 5 ) and lissoclinidine ( 6 ), as well as the known pyridoacridine alkaloids diplamine ( 7 ) and cystodytin J ( 8 ) and the benzopentathiepin varacin ( 3 ) and related trithiane varacin A. The new alkaloids were characterised using standard spectroscopic techniques, including 2D 1H–15N NMR experiments. Pyridoacridine alkaloids 4–8 were assayed for a range of biological activities including antitumour and antibiotic properties.

Novel tryptophan-derived dipeptides and bioactive metabolites from the sea hare Aplysia dactylomela

Abstract Dactylamides A ( 1 ) and B ( 2 ), two new tryptophan-derived dipeptides were isolated from the sea hare Aplysia dactylomela and structurally characterised by spectroscopic methods and synthesis of deoxy-analogues. Isolaurenisol, allolaurinterol, their respective acetates and aplysioviolin, isolated as the bioactive constituents of the sea hare, were also structurally characterised and evaluated in a range of biological assays.

Distomadines A and B, novel 6-hydroxyquinoline alkaloids from the New Zealand ascidian, Pseudodistoma aureum

Abstract Distomadines A and B, novel tetracyclic guanidine-containing 6-hydroxyquinoline alkaloids were isolated from the New Zealand ascidian Pseudodistoma aureum and characterised by interpretation of spectroscopic data and chemical derivatisation. Distomadine A exhibited mild antifungal activity but failed to exhibit any biological activity in a range of antitumour, cytotoxicity, anti-inflammatory, and antimycobacterial tests. The known methyl esters of fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid and eicosatetraenoic acid were also identified in the extract with EPA methyl ester exhibiting mild cytotoxicity to a non-malignant cell line.

In Vitro and In Vivo Anti-Inflammatory Activity of 17-O-Acetylacuminolide through the Inhibition of Cytokines, NF-κB Translocation and IKKβ Activity

Background and Purpose 17-O-acetylacuminolide (AA), a diterpenoid labdane, was isolated for the first time from the plant species Neouvaria foetida. The anti-inflammatory effects of this compound were studied both in vitro and in vivo. Experimental Approach Plant extracts were initially tested against LPS-stimulated release of tumor necrosis factor alpha (TNF-α) from murine macrophages (RAW264.7 cells). Based on bioassay-guided fractionation, the active compound was identified as AA. AA was tested for its ability to reduce nitric oxide (NO) production, and the inducible nitric oxide synthase (iNOS) expression. The inhibition of a panel of inflammatory cytokines (TNF, IL-1β, IL-6, KC, and GM-CSF) by AA was assessed at the expression and the mRNA levels. Moreover, the effect of AA on the translocation of the transcription factor nuclear factor kappa B (NF-κB) was evaluated in LPS-stimulated RAW264.7 cells and in TNF-stimulated L929 cells. Subsequently, AA was tested in the inhibitor of NF-κB kinase beta (IKKβ) activity assay. Lastly, the anti-inflammatory activity of AA in vivo was evaluated by testing TNF production in LPS-stimulated Balb/c mice. Key Results AA effectively inhibited TNF-α release with an IC50 of 2.7 µg/mL. Moreover, AA significantly inhibited both NO production and iNOS expression. It significantly and dose-dependently inhibited TNF and IL-1β proteins and mRNA expression; as well as IL-6 and KC proteins. Additionally, AA prevented the translocation of NF-κB in both cell lines; suggesting that it is acting at a post receptor level. This was confirmed by AAs ability to inhibit IKKβ activity, a kinase responsible for activating NF-κB, hence providing an insight on AAs mechanism of action. Finally, AA significantly reduced TNF production in vivo. Conclusions and Implications This study presents the potential utilization of this compound, as a lead for the development of an anti-inflammatory drug.

1,3-dimethyl-8-oxoisoguanine, a new purine from the New Zealand ascidian Pseudodistoma cereum.

A new purine, 1,3-dimethyl-8-oxoisoguanine (2) was isolated from the New Zealand ascidian Pseudodistoma cereum. The structure of 2 was elucidated by the use of standard spectroscopic techniques, including natural abundance 1H-15N 2D NMR.

A Convenient New Route to 4-Substituted Benzo[de][3,6]Phenanthrolin-6(6H)-Ones: Important Intermediates in the Synthesis of Ring-A Analogues of the Cytotoxic Marine Alkaloid Ascididemin

Abstract 4-ethylthio- and 4-(4″-methylphenylthio)benzo[de][3,6]phenanthrolin-6(6H)-one have been synthesised in 4 steps from benzoquinone and then readily converted to the 4-amino (6d) and 4-methoxy (6c) analogues by nucleophilic substitution. Further elaboration of 6d leads to the synthesis of 11-hydroxyascididemin, which we have found to exhibit antiviral activity in vitro.

An Investigation on Bioactive Constituents from Persea declinata (bl.) Kosterm

The Persea declinata (Bl.) Kosterm belongs to the family Lauraceae, is another Persea species with potential medicinal values. It is widely distributed in Borneo, Java, Malaysia (Penang, Kelantan, Terengganu, Pahang, Selangor) and Singapore. It shares the same genus with the infamously studied Persea americana, or better known as the avocado, however, there are no documentation of this plant being investigated chemically or biologically. This paper will discuss the antioxidant and anticancer activities of the bark crude extract and fractions of Persea declinata (Bl.) Kosterm through DPPH and ORAC assay, and MTT assay using human breast carcinoma cells (MCF-7), human non-small cell lung cancer cells (A549) and human normal hepatic WRL-68 cell type.