Current Organic Chemistry - Volume 7, Issue 12, 2003

Natural product chemistry covers various aspects of research into compounds from different plant, animal and microbial sources: their analysis, isolation, biological and pharmacological activities. In the 2003 Natural Product Chemistry issue of Current Organic Chemistry, there are five contributions which illustrate this diversity. The first refers to a survey of phytohormones. As their name implies, these hormones are of plant origin and they can take the form of different classes of chemical compound: isoflavones, lignans, coumestans and stilbenes. They are found in numerous foodstuffs (one source being soy products) and can reduce the incidence of gynecological cancers, cardiovascular diseases and osteoporosis in postmenopausal women Certain human estrogens and androgens are also found in small amounts in plants. Another article on bioactive compounds, by Cos, Vanden Berghe, De Bruyne and Vlietinck, reviews the latest developments in natural products used as antiviral agents. In the treatment of viral infections, there are problems of tolerance and drug resistance associated with the existing drugs. For this reason, the demand for new antiviral agents is high. The emphasis is given to plant-derived substances with anti-human immunodeficiency virus (anti-HIV) activity, with special reference to their mechanisms of action. Compounds with anti-herpes simplex virus (anti-HSV) are similarly listed: these include alkaloids, carbohydrates, flavonoids, lignans, tannins, terpenes and proteins. The third contribution is a more specialized review on the occurrence of brominated diterpenes from marine organisms, by Kornprobst and Al-Easa. These have only been found in red algae and gastropods but they give rise to a great diversity of different structures. Some of these have biological activities, including cytotoxicity and antimicrobial properties. Their spectroscopic data and biogenetic relationships are also presented. Finally, two articles describe the synthesis of bioactive natural products and their derivatives. Morzycki and co-workers report efforts directed towards the synthesis of cytostatic natural products. The first two classes, the cephalostatins and the ritterazines, are found in marine organisms and belong to the family of trisdecacyclic pyrazines, consisting of two steroid units. Cephalostatin 1 notably shows considerably higher antitumour activity than currently used chemotherapeutics. The other group of active compounds is found in the bulbs of Ornithogalum saundersiae (Liliaceae) and consists of cholestane glycosides. Barua and co-workers summarize synthetic work on 1,2,4-trioxane-type artemisinin analogues. Artemisinin, a sesquiterpene lactone from the Chinese plant Artemisia annua (Asteraceae), is a very effective antimalarial compound which is important for the treatment of patients affected by resistant strains of the parasite. The 1,2,4-trioxane ring system is essential for the activity of artemisinin and hence much synthetic work involves the production of analogues with this structural feature. I would like to express my sincere thanks to all contributors in this volume for the excellent reviews of natural product research that they have produced.

Phytohormones describe substances of plant origin with a hormonal activity. Epidemiological studies have shown a high health care potential for phytoestrogens. They are plant secondary metabolites with structural analogies to estradiol and with an influence on the estrogenic hormonal pathways. The main chemical classes are isoflavones, lignans, coumestans, prenylflavonoids and stilbene derivatives and occur in food and many health products. Soy and soy isoflavones represent an important source of phytoestrogens. Some human natural estrogens and androgens, or analogues, also occur in plants. Other hormones, such as melatonin, have also been found in plants.

Since our review in Current Organic Chemistry in 1997 (Curr. Org. Chem. 1997, 1, p. 307-344), important advances have been made in the field of natural products antiviral research. Therefore, we provide here a comprehensive review of the latest developments on plant substances as antiviral agents. The review is mainly focused on plant-derived substances with an anti-human immunodeficiency virus (anti-HIV) and an anti-herpes simplex virus (anti-HSV) activity. The anti-HIV activity of the plant substances is discussed according to their mechanism of action, targeting the critical steps of the HIV replicative cycle, i.e. adsorption, virus-cell fusion, virus uncoating, reverse transcription, integration, proviral DNA transcription, transcription, translation, assembly, and budding. Some of the anti-HIV active compounds show also immune stimulating properties, which can provide an additional benefit in the treatment of AIDS. The anti-HSV activities of the plant substances are discussed according to their in vitro and in vivo activity against HSV-1 and HSV-2, including acyclovir-resistant strains, and where relevant, their activity against cytomegalovirus is mentioned. Finally, the antiviral activities of plant substances against the influenza virus are briefly outlined.

Between 1971 and 2000, eighty brominated diterpenes were isolated from only two groups of marine organisms: red algae and gastropods, so it is likely that all bromoditerpenes only originate from Rhodophyceae and herbivorous molluscs which feed on them. Occurrence and general considerations on the encountered carbon skeletons are presented in the two first parts of this review. All brominated diterpenes are presented in third part with physicochemical properties and spectroscopic data available in the literature. The fourth part is devoted to biogenesis schemes for each carbon skeleton and the fifth part summarises the published data on biological activities of brominated diterpenes. This review covers the literature up to 2000; three new bromoditerpenes characterized in 2001 from two red algae are described in an addendum. This review ends with a general index for all mentioned compounds.

Artemisinin, a highly oxygenated sesquiterpene lactone endoperoxide isolated by Chinese researchers in 1971 has been found to be a superior plasmocidal and blood schizontocidal agent to conventional antimalarial drugs against malarial strains. Since then, an enormous amount of work has been done on this molecule by different groups covering aspects such as characterisation, total synthesis, understanding of the mechanism of action through QSAR studies, etc. which has unveiled tremendous amount of information about this molecule and resulted in a large number of published and patented literature. These studies have enabled scientists during the nineties to delineate the basic structural requirement - the 1,2,4-trioxane ring system as the essential pharmacophore. Since then a large number of simpler molecules containing mainly the core pharmacophore have been synthesized and evaluated against different malaria strains; many of which have shown even better plasmocidal activity than the parent molecule. Recent studies have also generated information on toxicity of some of the initial derivatives, viz. arteether, artemether, etc. A lot of efforts have been made to produce structural changes viz. synthesis of C-10 carba-analogues, ring-contracted derivatives, fluoro derivatives, simple 1,2,4-trioxanes etc. These studies aim to produce derivatives having maximum potency and minimum toxicity.

Secondary metabolites of marine invertebrates continue to attract the attention of organic chemists, biochemists, and pharmacologists due to their novel structures and potent biological activities. One such example is cephalostatin 1 isolated from the Indian Ocean hemichordate Cephalodiscus gilchristi, which exhibited remarkable cytotoxic activity against a broad spectrum of malignant tumor cells. Similar marine alkaloids (e.g. ritterazine G) were found in the lipophilic extract of the tunicate Ritterella tokioka collected off the coast of Japan. These very potent compounds, cephalostatins and ritterazines, belong to the large family of trisdecacyclic pyrazines, consisting of two steroid units. The two steroid halves of cephalostatin 1 and other highly cytotoxic members of the family are different. The biological activity of the dimeric steroid-pyrazine marine alkaloids and their limited availability coupled with the new and intriguing structure make them an attractive challenge for the synthetic organic chemists. A few years ago a group of cholestane glycosides was isolated from the bulbs of Ornithogalum saundersiae, a species of the lily family without any medicinal folkloric background. Similar glycosides were recently isolated from Galtonia candicans. The major component of the mixture of saponins, OSW-1, exhibited sub-nanomolar antineoplastic activity. While OSW-1 is exceptionally cytotoxic against various tumor cells, it showed little toxicity to normal human pulmonary cells. The cytotoxicity profile of OSW-1 against different cancer cell lines was found to be surprisingly similar to that of the cephalostatins, which appears to imply a related mechanism of action. In this review article the synthetic efforts towards these compounds are described.