Cryptic Epoxytiglianes from the Kernels of the Blushwood Tree (Fontainea picrosperma).

The kernels of the Australian blushwood tree (Fontainea picrosperma) are the source of the veterinary anticancer drug tigilanol tiglate (2a, Stelfonta) and contain a concentration of phorboids significantly higher than croton oil, the only abundant source of these compounds previously known. The oily matrix of the blushwood kernels is composed of free fatty acids and not by glycerides as found in croton oil. By active partitioning, it was therefore possible to recover and characterize for the first time a cryptic tigliane fraction, that is, the diterpenoid fraction that, because of its lipophilicity, could not be obtained by solvent partition of crude extracts. The cryptic tigliane fraction accounted for ca. 30% of the tigliane kernel titer and was quantified by 1H NMR spectroscopy and profiled by HPLC-MS. Long-chain (linoleates and/or oleates) 20-acyl derivatives of the epoxytigliane diesters tigilanol tiglate (EBC-46, 2a), EBC-47 (4a), EBC-59 (5a), EBC-83 (6a), and EBC-177 (7a) were identified. By chemoselective acylation of EBC-46 (2a) and EBC-177 (7a) the natural triesters 2b and 7b and a selection of analogues were prepared to assist identification of the natural compounds. The presence of a free C-20 hydroxy group is a critical requirement for PKC activation by phorbol esters. The unexpected activity of 20-linoleoyl triester 2b in a cytotoxicity assay based on PKC activation was found to be related mainly to its hydrolysis to tigilanol tiglate (2a) under the prolonged conditions of the assay, while other esters were inactive. Significant differences between the esterification profile of the epoxytigliane di- and triesters exist in F. picrosperma, suggesting a precise, yet elusive, blueprint of acyl decoration for the tigliane polyol 5-hydroxyepoxyphorbol.

Antibacterial 5α-Spirostane Saponins from the Fruit of Cordyline manners-suttoniae.

Antibacterial-activity-guided fractionation of a dichloromethane extract from the fruit of Cordyline manners-suttoniae and subsequent structure-activity investigations resulted in the identification of 10 new (1-10) and one known (11) 5α-spirostane saponin. The structures of the new compounds were established by 1D and 2D NMR analyses. The absolute configurations of the isolated compounds were determined by X-ray diffraction analysis or chemical derivatizations. The most active compound, suttonigenin F (6), inhibited the Gram-positive bacteria Staphylococcus aureus with MIC75 values that were comparable to those of the antibiotic chloramphenicol. Structure-activity relationships were also obtained from the assessment of antibacterial and cytotoxic activities of the isolated saponins.

Furofuran lignans from the Simpson Desert species Eremophila macdonnellii.

The Eremophila plant family, which occurs in the arid zones of Australia, have witnessed extensive investigation, mostly inspired by Aboriginal traditional medicine. A wide and varied biological and phytochemical profile has been reported for over 18 individual species of Australian Eremophila, although E. macdonnellii from the Simpson Desert has not yet been investigated. Isolation and elucidation of one new and six known furofuran lignans are reported. The new lignan, epimethoxypiperitol, displayed moderate anti-cancer activity against the breast cancer cell line (MCF-7).

Unprecedented 1,14-seco-crotofolanes from Croton insularis: oxidative cleavage of crotofolin C by a putative homo-Baeyer-Villiger rearrangement.

EBC-162 isolated from Croton insularis, obtained from the northern rainforest of Australia, was structurally affirmed as crotofolin C (4). Novel oxidative degradation products, EBC-233 and EBC-300, which are the first crotofolane endoperoxides, were also isolated. Both endoperoxides were found to be stable intermediates, which are proposed to undergo an unprecedented homo-Baeyer-Villiger biosynthetic rearrangement to give a new class of 1,14-seco-crotofolane diterpenes. Prolonged storage of all isolates assisted in authenticating their natural product status. Anticancer activities of reported compounds are presented.

The value of nature's natural product library for the discovery of New Chemical Entities: the discovery of ingenol mebutate.

In recent decades, 'Big Pharma' has invested billions of dollars into ingenious and innovative strategies designed to develop drugs using high throughput screening of small molecule libraries generated on the laboratory bench. Within the same time frame, screening of natural products by pharmaceutical companies has suffered an equally significant reduction. This is despite the fact that the complexity, functional diversity and druggability of nature's natural product library are considered by many to be superior to any library any team of scientists can prepare. It is therefore no coincidence that the number of New Chemical Entities reaching the market has also suffered a substantial decrease, leading to a productivity crisis within the pharmaceutical sector. In fact, the current dearth of New Chemical Entities reaching the market in recent decades might be a direct consequence of the strategic decision to move away from screening of natural products. Nearly 700 novel drugs derived from natural product New Chemical Entities were approved between 1981 and 2010; more than 60% of all approved drugs over the same time. In this review, we use the example of ingenol mebutate, a natural product identified from Euphorbia peplus and later approved as a therapy for actinic keratosis, as why nature's natural product library remains the most valuable library for discovery of New Chemical Entities and of novel drug candidates.

Structure and bioactivity of steroidal saponins isolated from the roots of Chamaelirium luteum (false unicorn).

Phytochemical investigation of Chamaelirium luteum ("false unicorn") resulted in the isolation of 15 steroidal glycosides. Twelve of these (1, 2, 4-9, 11-13, and 15) are apparently unique to this species, and eight of these (6-9, 11-13, and 15) are previously unreported compounds; one (15) possesses a new steroidal aglycone. In addition, the absolute configuration of (23R,24S)-chiograsterol A (10) was defined, and its full spectroscopic characterization is reported for the first time. The structures and configurations of the saponins were determined using a combination of multistage mass spectrometry (MS(n)), 1D and 2D NMR experiments, and chemical degradation. The antiproliferative activity of nine compounds obtained in the present work, and eight related compounds generated in previous work, was compared in six human tumor cell lines, with aglycones 3 and 10 and related derivatives 16, 17, 19, and 20 all displaying significant antiproliferative activity.

Potential molecular targets for inhibiting bone invasion by oral squamous cell carcinoma: a review of mechanisms.

Bone invasion is a common characteristic of oral squamous cell carcinoma (OSCC), with adverse affects on patient functionality and survival. Recent studies suggest that it is osteoclasts, rather than malignant keratinocytes themselves, which play the major role in facilitating the entry of the tumour into bone, and its progression within bone. Osteoclasts respond to a variety of local signalling pathways, initiated by products of the malignant epithelial cells. In the present review, we firstly introduce the clinical patterns of bone invasion, and then summarise these signalling pathways and their diverse roles in sequential phases of bone invasion. We also review current researches regarding the incidence and mechanisms of distant metastases to bone, and explain briefly the concept of epithelial-mesenchymal transition, which may generate cancer stem cells and initiate the bone invasion. Finally, we discuss more briefly approaches to the diagnosis and management of OSCC patients with bone invasion. With all these studies and some recent discoveries in our own laboratory, an enhanced understanding of bone invasion will be achieved, which should indicate potential molecular targets for future biotherapies.

Serum omega-3 and omega-6 fatty acids and cutaneous p53 expression in an Australian population.

BACKGROUND: There is some evidence from experimental studies that long-chain n-3 and n-6 fatty acids may be able to modify early skin carcinogenesis, but whether this applies in the general population is not known. METHODS: We investigated associations between serum polyunsaturated fatty acid concentrations and p53 expression in normal skin, as a biomarker of early UV-induced carcinogenesis, in an unselected sample of Australian adults. Participants in the Nambour Skin Cancer Prevention Trial provided a dorsal hand punch biopsy which was used for immunohistochemical assessment of p53 immunoreactivity. Cross-sectional associations with serum fatty acid concentrations were analyzed in 139 participants, adjusting for confounding variables including skin phenotype, past sun exposure, and smoking status. RESULTS: There was an inverse association, showing a dose-response relationship, between total n-3 fatty acid serum concentrations and p53 immunoreactivity in the whole epidermis and the basal layer. This was particularly due to eicosapentanoic acid and docosahexanoic acid concentrations. There was no evidence for increased p53 immunoreactivity in participants with relatively high serum n-6 fatty acid concentrations. The ratio of n-3 to n-6 fatty acid concentrations was not associated with p53 immunoreactivity. CONCLUSION: These results add to growing evidence that long-chain fatty acids may be able to modify early skin carcinogenesis. IMPACT: The prospect that increased intake of n-3 fatty acids could help prevent skin cancer is attractive.