Brain aging and Alzheimer’s disease both demonstrate the accumulation of beta-amyloid protein containing “plaques” and tau protein containing “tangles” that contribute to accelerated memory loss and cognitive decline. In the present investigation we identified a specific plant extract and its constituents as a potential alternative natural solution for preventing and reducing both brain “plaques and tangles”. PTI-00703 cat’s claw ( Uncaria tomentosa from a specific Peruvian source), a specific and natural plant extract from the Amazon rain forest, was identified as a potent inhibitor and reducer of both beta-amyloid fibrils (the main component of “plaques”) and tau protein paired helical filaments/fibrils (the main component of “tangles”). PTI-00703 cat’s claw demonstrated both the ability to prevent formation/aggregation and disaggregate preformed Aβ fibrils (1–42 and 1–40) and tau protein tangles/filaments. The disaggregation/dissolution of Aβ fibrils occurred nearly instantly when PTI-00703 cat’s claw and Aβ fibrils were mixed together as shown by a variety of methods including Thioflavin T fluorometry, Congo red staining, Thioflavin S fluorescence and electron microscopy. Sophisticated structural elucidation studies identified the major fractions and specific constituents within PTI-00703 cat’s claw responsible for both the observed “plaque” and “tangle” inhibitory and reducing activity. Specific proanthocyanidins (i.e. epicatechin dimers and variants thereof) are newly identified polyphenolic components within Uncaria tomentosa that possess both “plaque and tangle” reducing and inhibitory activity. One major identified specific polyphenol within PTI-00703 cat’s claw was epicatechin-4β-8-epicatechin (i.e. an epicatechin dimer known as proanthocyanidin B2) that markedly reduced brain plaque load and improved short-term memory in younger and older APP “plaque-producing” (TASD-41) transgenic mice (bearing London and Swedish mutations). Proanthocyanidin B2 was also a potent inhibitor of brain inflammation as shown by reduction in astrocytosis and gliosis in TASD-41 transgenic mice. Blood-brain-barrier studies in Sprague-Dawley rats and CD-1 mice indicated that the major components of PTI-00703 cat’s claw crossed the blood-brain-barrier and entered the brain parenchyma within 2 minutes of being in the blood. The discovery of a natural plant extract from the Amazon rain forest plant (i.e. Uncaria tomentosa or cat’s claw) as both a potent “plaque and tangle” inhibitor and disaggregator is postulated to represent a potential breakthrough for the natural treatment of both normal brain aging and Alzheimer’s disease.

Two new sesquiterpene dialdehydes, cinnamate 7 and coumarate 8, were isolated from the fruits of Pseudowintera colorata. The known sesquiterpene dialdehydes polygodial 1 and 9-deoxymuzigadial 2 were also found in these fruits, at 5% w/w compared to 0.5% in the leaves. Fruits of Pseudowintera axillaris contained no sesquiterpene dialdehyde cinnamates, even though these are present in the leaves, but did contain prenylated flavanones 11–13. Compounds 7 and 8 are further examples of the rare sesquiterpene dialdehyde cinnamate combination, found exclusively in the family Winteraceae. This is the first report of the uncommon prenylated flavanones in Winteraceae.

Bioactivity-directed separation of a foliage extract from the New Zealand shrub Pseudowintera axillaris led to a compound with fungicidal activity against the plant pathogen Phytophthora infestans. This was identified as a new sesquiterpene dialdehyde cinnamate named paxidal. Two 6-hydroxy derivatives were present at lower levels in the extract. A further nine derivatives were synthesized from these natural products for a structure-activity study against a range of important food crop pathogens. The cinnamate group was important for fungicidal effects, and protection of the dialdehyde as a dimethyl acetal gave more potent, broader spectrum activity.

NMR studies have shown that seven new sesquiterpenoids, 3,4, 5a, and 7-10, isolated from dried samples of the New Zealand liverwort Lepidolaena hodgsoniae have the same substituted cyclopentapyran ring system as the previously described insecticidal sesquiterpene diene hodgsonox (1), which has been reported only from this plant. In all but one compound, 10, the 1,1-disubstituted double bond of hodgsonox has migrated into an endocyclic position, but only two, 5a and 9, have the double bonds in conjugation. These seven new compounds represent a variety of different oxidation levels. Two of the new derivatives, 9 and 10, were isolated only from an aged sample and are presumably artifacts. The only other terpenoid isolated in significant quantity was (7R,10R)-calamenene (2).

NMR studies have shown that seven new sesquiterpenoids, 3, 4, 5a, and 7-10, isolated from dried samples of the New Zealand liverwort Lepidolaena hodgsoniae have the same substituted cyclopentapyran ring system as the previously described insecticidal sesquiterpene diene hodgsonox (1), which has been reported only from this plant. In all but one compound, 10, the 1,1-disubstituted double bond of hodgsonox has migrated into an endocyclic position, but only two, 5a and 9, have the double bonds in conjugation. These seven new compounds represent a variety of different oxidation levels. Two of the new derivatives, 9 and 10, were isolated only from an aged sample and are presumably artifacts. The only other terpenoid isolated in significant quantity was (7R,10R)-calamenene (2).

The incorporation of [1-13C] labelled glucose into hodgsonox, a sesquiterpene epoxide with a unique, doubly allylic ether functionality has been studied in axenic cultures of the liverwort Lepidolaena hodgsoniae. Quantitative 13C NMR spectroscopic analysis showed that the isoprene units are derived exclusively from the methylerythritol phosphate pathway.

Extracts of the New Zealand liverwort Schistochila glaucescens were cytotoxic. Bioactivity-directed isolation led to the new sesquiterpene lactone glaucescenolide 1 as the main cytotoxic component with an IC50 of 2.3μg/ml against P388 leukaemia cells. Also isolated were three known bisbibenzyls, neomarchantins A 2 and B 3 and marchantin C 4, which were also cytotoxic (P388 IC50s 8–18μg/ml). Two new compounds GBB A 5 and B 6 are the first examples of a bisbibenzyl connected to a sesquiterpene moiety. A biosynthetic route to 1, 5 and 6, via a shared intermediate, furanosesquiterpene 7, is proposed.

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Bioactivity-directed isolation work on the New Zealand liverwort Hepatostolonophora paucistipula afforded the sesquiterpene lactones (-)- ent-costunolide (1) and (-)- ent-arbusculin B (2) as cytotoxic compounds. This is the first report of 1, enantiomeric to the known germacranolide (+)-costunolide (3).

A bioactivity-directed investigation of an extract of the New Zealand clubmoss, Lycopodium varium, collected on subantarctic Campbell Island, has led to the isolation of the alkaloid huperzine A (1) as the major antifeedant and insecticidal component. Huperzine A showed insecticidal activity against the Australian carpet beetle, Anthrenocerus australis (LD(50) = 110 ppm), the Australian sheep blowfly, Lucilia cuprina (LD(50) = 2380 ppm), and the webbing clothes moth, Tineola bisselliella (LD(50) = 630 ppm). Feeding by A. australis was reduced by 97% at 63 ppm.

Hodgsonox (1), a new insecticidal sesquiterpene, has been isolated from the New Zealand liverwort Lepidolaena hodgsoniae. The structure was elucidated on the basis of 2D NMR analysis of 1 and a synthetic epoxide derivative (2). Hodgsonox represents a new class of sesquiterpene with a cyclopenta[5,1-c]pyran ring system fused to an oxirane ring. The combination of a mono- and a 1,1 disubstituted double bond flanking the oxygenated carbon of a the pyran ring is a unique structural feature. Hodgsonox is toxic to larvae of the blowfly Lucilia cuprina.

A total of 69 species of lichens have been collected from various locations around New Zealand. Screening of extracts of these species for antimicrobial, antiviral and cytotoxic activity showed a high proportion with biological activity. Active extracts were generally from species known to contain phenolic compounds. Bioactivity-directed isolation work onCladia retipora, Pseudocyphellaria glabra and P. homoeophylla led to the identification of usnic acid as the main antimicrobial, cytotoxic and antiviral component in these three species.

Earina autumnalis Hook. f. (Orchidaceae, raupeka), an orchid endemic to New Zealand (1), yielded an ethanolic extract cytotoxic towards P388 murine leukaemia and BSC cell lines. Bioassay-directed fractionation using P388 led to the isolation of bulbophyllanthrone (1), as the major cytotoxic component. Plants were collected from the Catlins area of New Zealand's South Island (Voucher No. 951211-18). Air dried plant rnateri-al (69.1 g) was chopped and ground under liquid N2, blended with EtOH (300 ml, 3 x 150 ml) and CHC13 (150 ml) to give a crude extract (4.6 g, IC50: 10 jig/mI). Chromatography on C-18 (lOg) with a H20, MeCN, CHC13 gradient gave a major active fraction which eluted with 1: 1 MeCN : H20 (692 mg, IC50: 1.6 jig/mI). Two silica columns, the first using a CHCI3/acetone gradient system and the second an EtOAc/hexane system gave a fraction (13 mg, IC50: 0.4 jig/mI) from which bulbophyllan-throne (1) (II mg, 0.2% w/w from extract) was obtained by precipitation from a CHCI3 solution. The structure of 1 was determined by NMR and by preparation of acetate (2) (2).

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