A. Norrie Pearce

Natural product growth inhibitors of Mycobacterium tuberculosis

This review covers natural products (secondary metabolites) with reported growth inhibitory activity towards Mycobacterium tuberculosis or related organisms. Such compounds have been isolated from a variety of sources including terrestrial and marine plants and animals, and microorganisms, with the express intent of identifying novel scaffolds for the development of new antituberculosis agents. The literature from January 2003 to December 2005 (inclusive) is reviewed and 146 references to 353 compounds are cited. The compounds are presented in order of chemical type, namely lipids/fatty acids and simple aromatics, phenolics and quinones, peptides, alkaloids, terpenes (monoterpenoids, diterpenes, sesquiterpenes and triterpenes), steroids and miscellaneous structures.

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.

Synthesis and anti-inflammatory structure–activity relationships of thiazine–quinoline–quinones: Inhibitors of the neutrophil respiratory burst in a model of acute gouty arthritis

Sixteen new thiazine-quinoline-quinones have been synthesised, plus one bicyclic analogue. These compounds inhibited neutrophil superoxide production in vitro with IC(50)s as low 60 nM. Compounds with high in vitro anti-inflammatory activity were also tested in a mouse model of acute inflammation. The most active compounds inhibited both neutrophil infiltration and superoxide production at doses 2.5 micromol/kg, highlighting their potential for development as novel NSAIDs.

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.

Efficient and Convenient Pyridine Ring-E Formation of the Cytotoxic Marine Alkaloid Ascididemin and Related Analogues.

Abstract Conversion of tetracyclic quinone 1 to the cytotoxic pentacyclic alkaloid ascididemin (2) in 80% yield is achieved by reaction with paraformaldehyde and ammonium chloride in refluxing acetic acid. High yielding annelations are aiso observed for the related analogues N-8 deaza ascididemin (3) and kuanoniamine A (4).

Investigation of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin B

The mechanisms of action of the cytotoxic marine pyrroloiminoquinone alkaloids the discorhabdins are unknown. We have determined that discorhabdin B acts as an electrophile towards biomimetic thiol nucleophiles leading to debrominated adducts. In contrast, less potent cytotoxins discorhabdins D and Q failed to react, supporting an SAR model of cytotoxicity requiring an orchestrated combination of an electrophilic Δ(1) carbon centre and a nucleophilic N-18 amine for potent activity. The stereospecific nature of nucleophile trapping exhibited by both enantiomers of discorhabdin B implies the biogenesis of ovothiol A substituted discorhabdins H, H(2), K and K(2) need not be mediated by enzymatic processes.

Total Synthesis of (−)-Bicubebin A, B, (+)-Bicubebin C and Structural Reassignment of (−)-cis-Cubebin

The first total synthesis of (-)-bicubebin A, and two previously unreported dilignans, (-)-bicubebin B and (+)-bicubebin C has been achieved through the dimerization of (-)-cubebin, confirming the structure and absolute stereochemistry of (-)-bicubebin A. Analysis of the data for (-)-bicubebin B showed it matched that of reported compound (-)-cis-cubebin. The NMR data of the subsequently synthesized proposed structure of cis-cubebin confirmed that its original proposed structure was incorrect.