Phytochemistry Reviews (v.10, #4)

Preface by Max Henry (457-458).

Biosynthesis of saponins in the genus Medicago by Aldo Tava; Carla Scotti; Pinarosa Avato (459-469).
Saponins from Medicago species are glycosidic compounds with an aglycone moiety formed through the enzymatic cyclization of 2,3-oxidosqualene by the β-amyrin cyclase. All the saponins from Medicago genus possess the triterpenic pentacyclic nucleus belonging to the class of β-amyrin. The so formed β-amyrin skeleton can be further modified by oxidative reactions, mediated by cytochromes belonging to the class of cytochrome P450, to give different saponin compounds, characterized by the presence of hydroxyl or carboxyl groups located in specific positions of the triterpenic skeleton. Based on the position and the oxidation degree of the substituents, it is possible to distinguish two groups of saponins (sapogenins) in Medicago spp: (1) sapogenins possessing an OH group on C-24 (soyasapogenols A, B and E) without any substituent at the C-28 atom, and (2) sapogenins possessing the COOH group at C-28 that are associated with different oxidation degrees (zero, OH, CHO, COOH) at C-23. These results seem to indicate that the oxidation at C-24 and the presence of the COOH group at C-28 are mutually exclusive. The subdivision in the aglycone moiety is reflected also in the sugar moiety, operated by glycosyltranferases, as the saponins of the two groups differ for the position and the nature of the sugar chains. Based on these findings, new considerations on the biosynthesis of saponins in the genus Medicago can be drawn and a biosynthetic scheme is proposed.
Keywords: Triterpenes; Sapogenins; Biosynthesis; Cytochrome P450; Medicagenic acid

Influence of environmental abiotic factors on the content of saponins in plants by Anna Szakiel; Cezary Pączkowski; Max Henry (471-491).
Saponins are a large group of secondary metabolites occurring in significant amounts in many plant species. However, the saponin content of plants is variable and it can be influenced by the surrounding environment. The local geoclimate, seasonal changes, external conditions such as light, temperature, humidity and soil fertility, as well as cultivation techniques, affect both the quantitative amount and qualitative composition of saponins. Such variation substantially impacts on the quality and properties of wild and cultivated plants exploited for pharmaceutical, nutritional and industrial applications. This review summarizes the available data on the effects of abiotic environmental factors on saponin level in plants, especially those of considerable economic importance, highlighting current problems such as the reduction in natural plant resources, over-exploitation and destruction of wild habitats, climate shifts as well as the consequences of the growing demand for plant-derived medicinal and industrial products. The need for a theoretical basis for a reasonable harvest, attempts at the domestication of wild plant species and the development of new agricultural technologies allowing high production under optimized conditions are also discussed.
Keywords: Abiotic factors; Environmental influence; Saponin content; Seasonal variations

Influence of environmental biotic factors on the content of saponins in plants by Anna Szakiel; Cezary Pączkowski; Max Henry (493-502).
Saponins occur constitutively in many plant species as part of their defense system. However, saponin content in plants seems to be dynamic, responding to many external factors including various biotic stimuli connected to herbivory attack and pathogenic infection, as well as involved in plant mutualistic symbioses with rhizobial bacteria and mycorrhizal fungi. Thus, not only saponins influence the living organisms interacting with plants, but in turn, all these interactions can impact the plant saponin content. According to their constitutive occurrence in plants, saponins are regarded mainly as phytoanticipins. Nevertheless, some presented data clearly point out to induced biosynthesis of saponins, especially in plant response to insect herbivory or inoculation with root symbionts, while the best studied examples of interactions between plants and their microbial pathogens show rather qualitative change of saponin composition based on chemical modifications of preformed, pre-infectional precursors. Simultaneously, despite evident inducibility of saponin production in plant cell cultures, the possible role of these compounds as phytoalexins synthesized in intact plants after pathogen infection is still not well documented. Some practical patterns and ecological consequences of biotic factors influencing saponin content in plants are briefly highlighted, with the special attention paid to microbial inoculants applied for optimisation of saponin synthesis in cultivated medicinal plants.
Keywords: Biotic factors; Herbivory; Pathogenic infection; Saponin content; Symbioses

Control of plant parasitic nematodes with active saponins and biomass from Medicago sativa by T. D’Addabbo; T. Carbonara; P. Leonetti; V. Radicci; A. Tava; P. Avato (503-519).
Medicago sativa L., alfalfa, is the most known plant species within the Medicago genus. The plant has been extensively studied for its content of saponins, mainly consisting of triterpene glycosides of medicagenic acid, possessing several biological properties including a biocidal activity on different soil microorganisms. Phytoparasitic nematodes are responsible for heavy economic damages to numerous agricultural crops and, due to their large distribution, they are among the most difficult crop pests to control. Attention on environmental safety and human and animal health has led to the progressive dismission of many synthetic formulations for the control of those pests and to the search of alternative strategies, including the use of natural metabolites from plants. Saponins from M. sativa may be good candidates for natural nematicide formulations, as in our in vitro studies the saponin mixtures from M. sativa tissues have been found effective in vitro against the virus-vector nematode Xiphinema index, the root-knot nematode Meloidogyne incognita and the potato cyst parasite, Globodera rostochiensis. A structure–activity relationship among saponins and related prosapogenins and sapogenin, respectively, has also been analyzed. The nematicidal efficacy differed among the three assayed nematode species, G. rostochiensis being the most susceptible to the active compounds from alfalfa. The in vitro results were also confirmed by experiments in potting mixes infested by M. incognita or G. rostochiensis and amended with dry top and root material from M. sativa, and in field trials on M. incognita and carrot cyst nematode Heterodera carotae with M. sativa pelleted meal. All amendments reduced root and soil population densities of target nematode species compared to non-treated and chemical controls, with a general improvement of plant growth and yield performances.
Keywords: Alfalfa; Biocide; Medicagenic acid; Phytoparasite nematodes; Sapogenins

Advances in the synthesis and pharmacological activity of lupane-type triterpenoid saponins by Charles Gauthier; Jean Legault; Marianne Piochon-Gauthier; André Pichette (521-544).
Lupeol, betulin and betulinic acid are members of the so-called lupane-type triterpenoids. These natural products found worldwide in quite of lot of vegetables, fruits and plant species exhibit promising pharmacological activities including anti-inflammatory, anti-HIV and antitumor activities. Nevertheless, the poor pharmacokinetic properties of these cholesterol-like triterpenoids hampered further pharmaceutical developments. The synthesis of lupane-type saponins, i.e., sugar-derived lupanes, seems to be a good avenue to improve both their water solubility and pharmacological activity. The aims of this review are twofold: first, to describe the biological activity of naturally occurring lupane-type saponins, and second, report the different methodologies employed for the elaboration of glycosidic linkages at the C-3 and/or C-28 positions on the lupane core. The synthesis of both natural and unnatural lupane-type saponins is discussed with an emphasis on molecules exhibiting relevant biological activities.
Keywords: Chemical glycosylation; Triterpenoid saponins; Lupeol; Betulin; Betulinic acid

The continued advance of HIV-AIDS makes the development of relatively inexpensive, freely accessible, and mechanistically more diverse antiviral therapies an urgent need. Natural products are, directly or indirectly, an important potential source of compounds meeting these conditions. A review of the recent literature indicates that some hemisynthetic triterpenoid derivatives, particularly belonging to the lupane, oleanane and ursane series, may be nearing a stage where they can be used to complement existing therapeutic approaches. On the other hand, although some natural derivatives of tetracyclic terpenoid families have revealed many novel structures and some promise as anti-HIV substances, their chemical modification to improve their potency and selectivity remains practically untouched. While ongoing work with the more ‘classical’ pentacyclic triterpenoids will continue to be a fertile field for HIV-AIDS drug discovery, the other structural groups offer unprecedented opportunities for the development of additional substances with useful properties and for the discovery of novel targets for antiviral therapy.
Keywords: AIDS; Antiviral activity; Natural products; Triterpenes; Structural modification

A review of acacic acid-type saponins from Leguminosae-Mimosoideae as potent cytotoxic and apoptosis inducing agents by Marie-Aleth Lacaille-Dubois; Dieudonné Emmanuel Pegnyemb; Olivier Placide Noté; Anne-Claire Mitaine-Offer (565-584).
The aim of this review is to highlight updated results on the biologically active saponins from Leguminosae-Mimosoideae. Acacic acid-type saponins (AATS), is a class of very complex glycosides possessing a common aglycon unit of the oleanane-type (acacic acid = 3β, 16α, 21β trihydroxy-olean-12-en-28 oic acid), having various oligosaccharide moieties at C-3 and C-28 and an acyl group at C-21. About sixty molecules of this type have been actively explored in recent years from Leguminosae family, from a chemical point of view and some fifty were reported to possess cancer related activities. These include cytotoxic/antitumor, immunomodulatory, antimutagenic, and apoptosis inducing properties and appear to depend on the acylation and esterification by different moieties at C-21 and C-28 of the acacic acid-type aglycone. One can observe that the (6S) configuration of the outer monoterpenyl moiety (MT) seems more potent in mediating high cytotoxicity than its (6R) isomer. Furthermore, the trisaccharide moiety {β-d-Xylopyranosyl-(1→2)-β-d-Fucopyranosyl-(1→6)- N-Acetamido 2-β-d-Glucopyranosyl-} at C-3, the tetrasaccharide moiety {β-d-Glucopyranosyl-(1→3)-[α-L-Arabinofuranosyl-(1→4)]-α-l-Rhamnopyranosyl-(1→2)-β-d-Glucopyranosyl} at C-28 of the aglycone, and the inner MT hydroxylated at its C-9, having a (6S) configuration can be important substituent patterns for the induction of apoptosis of AATS. Because of their interesting cytotoxic/apoptosis inducing activity, some AATS can be useful in the search for new potential antitumor agents from Fabaceae. Furthermore, the sequence 28-O-{Glc-(1→3)-[Araf-(1→4)]-Rha-(1→2)-Glc-Acacic acid}, often encountered in the genera Acacia, Albizia, Archidendron, and Pithecellobium may represent a chemotaxonomic marker of the Mimosoideae subfamily.
Keywords: Mimosoideae; Fabaceae (=Leguminosae); Acacic acid-type saponins; Cytotoxicity; Apoptosis inducing agents