Phytochemistry Reviews (v.12, #1)

Serine protease inhibitors in plants: nature’s arsenal crafted for insect predators by Farrukh Jamal; Prabhash K. Pandey; Dushyant Singh; M. Y. Khan (1-34).
Plant serine protease inhibitors are defense proteins crafted by nature for inhibiting serine proteases. Use of eco-friendly, sustainable and effective protein molecules which could halt or slow down metabolism of nutrients in pest would be a pragmatic approach in insect pest management of crops. The host-pest complexes that we observe in nature are evolutionary dynamic and inter-depend on other defense mechanisms and interactions of other pests or more generally speaking symbionts with the same host. Insects have co-evolved and adapted simultaneously, which makes it necessary to investigate serine protease inhibitors in non-host plants. Such novel serine protease inhibitors are versatile candidates with vast potential to overcome the host inhibitor-insensitive proteases. In a nutshell exploring and crafting plant serine proteinase inhibitors (PIs) for controlling pests effectively must go on. Non-host PI seems to be a better choice for coevolved insensitive proteases. Transgenic plants expressing wound inducible chimaeric PIs may be an outstanding approach to check wide spectrum of gut proteinases and overcome the phenomenon of resistance development. Thus, this article focuses on an entire array of plant serine protease inhibitors that have been explored in the past decade, their mode of action and biological implications as well as applications.
Keywords: Serine protease inhibitors; Mechanism; Transgenic plants, chimaeric inhibitors, smart serpins; Resistance development; Pest management

Analysis of betalains from fruits of Opuntia species by Sanjay P. Chauhan; N. R. Sheth; I. S. Rathod; B. N. Suhagia; Rajnikant B. Maradia (35-45).
Betalains are of great taxonomic significance in higher plants and occur only in 10 families of the order Caryophyllales (Centrospermae). They are water-soluble nitrogenous pigments. They can be divided into two major structural groups, the red to red-violet betacyanins and the yellow betaxanthins. Betalains are widely used as natural red food colorant as well as antioxidant potentials. Several methods have been published for the determination of betalain in fruits of Opuntia species. The purpose of the current review is to provide a systematic survey of the analytical techniques for the determination of betalain from fruits of Opuntia species.
Keywords: Betalain; Betacyanin; Cactaceae; Opuntia; Prickly pear

Secondary metabolites during early development in plants by Iván De-la-Cruz Chacón; Christian Anabi Riley-Saldaña; Alma Rosa González-Esquinca (47-64).
Early development is a critical stage in a plant’s life, as the plant must establish itself in the ecosystem during this period. The secondary metabolites (SM) during this phase is a strategy that contributes to the survival of plant species. Through a review of the literature, a number of reports were found that investigated the presence of SM during germination and early plant development (phases 0 and 1 according to the Zadoks and BBCH scales). A total of 250 reports were found that investigated 99 species and nearly 200 SM that accumulate during this period of the plant life cycle. A large portion of the SM are biosynthesised de novo, whereas the remainder are derived in part or in total from the mother plant. In many cases, the resources for biosynthesis are supplied only by the reserve material of the endosperm or cotyledons, which allows for independent photosynthesis. The presence of SM at these stages confers characteristics of more advanced stages, such as tissue-specific distribution, spatio-temporal regulation, and the individual regulation of all of the biosynthesised SM. The amount and diversity of SM are not universally related to the progress of plant development, but it is a widespread phenomenon. The early production of SM has ecological implications that involve defence mechanisms, relationships with microorganisms, and the role of these compounds as nitrogen reserves. This review contributes to the systematisation of studies on SM in the early stages of development.
Keywords: Natural products; Early metabolism; Early defence; Germination; Seedling development

Phytochemicals as a potential source for TNF-α inhibitors by Muzamal Iqbal; Robert Verpoorte; Henrie A. A. J. Korthout; Natali Rianika Mustafa (65-93).
Cytokines play an important role in the immune system. Any disorder in the regulation of cytokines can lead to the development of inflammatory diseases. Tumor necrosis factor-α (TNF-α) is one of the most important inflammatory cytokines that controls different types of cell functions. The overproduction of TNF-α is linked with the development of various diseases such as asthma, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, septic shock, diabetes and atherosclerosis. Plants are considered as excellent sources of pharmacologically active compounds. Currently, scientists are searching for natural products with anti-TNF-α properties for the treatment of various inflammatory disorders. At present, protein-based drugs are available for the inhibition of TNF-α, however these have some limitations. Plant might provide an alternative and cost-effective source of drugs that can regulate TNF-α levels. This review briefly highlights the physiological and pathological roles of TNF-α along with a description of plant-derived compounds capable of interfering with TNF-α activity and production.
Keywords: Inflammatory disorders; TNF-α inhibitors; Plants; Medicines; Natural products

Cubitane: a rare diterpenoid skeleton by Johannes Wefer; Kristina Simon; Thomas Lindel (95-105).
There are only 15 diterpenoids known sharing the rare cubitane skeleton (1,3-diisopropyl-6,10-dimethylcyclododecane, Fig. 1) named after the natural product (+)-cubitene ((+)-1) from the termite Cubitermes umbratus. Cubitane-type diterpenoids (“cubitanoids”) have since then been isolated from gorgonian corals and there are reports that cubitene also occurs in plants. The twelve-membered ring of the cubitanoids is an interesting feature for which we have developed a novel synthesis involving bicyclic precursors. In this review, we discuss the state-of-research regarding isolation, structure elucidation, biological activity, biosynthesis, and total synthesis of cubitane-type diterpenoids. Fig. 1 Cubitane skeleton and cubitanoids from termites
Keywords: Diterpenoids; Total synthesis; Structure elucidation; Cubitane

Rational use of Jatropha curcas L. in food and medicine: from toxicity problems to safe applications by Muhamad Insanu; Chryssa Dimaki; Richard Wilkins; John Brooker; Piet van der Linde; Oliver Kayser (107-119).
Jatropha curcas L. has become an important plant for biorefinery and production of biodiesel. From its ethnobotanical use, the plant is known for several activities which are associated with high toxicity. The latest development in engineering technology enables detoxification of native oil and other parts of the plant for new pharmaceutical purposes. Hence a revised look to the rich metabolic spectra of partly structurally rare secondary compound becomes an interesting field of research to be explored. In this review, we discuss recent developments in the technology of detoxification process and give insight about how this ethnomedicinal plant can be applied to new fields of experimental medicine. The review highlights recent data on biological activities and discusses concepts and strategies for turning a poison plant into a valuable crop with high pharmaceutical potential.
Keywords: Biorefinery; Detoxification; Secondary natural products; Anticancer; Toxicity; Phorbol esters; Cyclic peptides; Biochemical engineering

Chrysobalanaceae: secondary metabolites, ethnopharmacology and pharmacological potential by Fausto Carnevale Neto; Alan Cesar Pilon; Vanderlan da Silva Bolzani; Ian Castro-Gamboa (121-146).
Many Chrysobalanaceae species, in special Licania and Parinari, are widely used in folk medicine to treat several diseases. This review describes some aspects of their ethnopharmacology potential, biological activities and the secondary metabolites reported so far for Chrysobalanaceae. The chemical constituents of this family include triterpenoids, diterpenoids, steroids and phenylpropanoids like flavonoids as well as chromones derivatives.
Keywords: Chrysobalanaceae; Kaurane diterpene; Glycoside flavonoid; Triterpene; Ethnopharmacology

Guttation 1: chemistry, crop husbandry and molecular farming by Sanjay Singh; T. N. Singh (147-172).
Guttation is one of the most conspicuous visible phenomena in plants occurring in a wide range of plants. The guttation fluids, though look clear and translucent, carry a number of organic and inorganic constituents. The organic component may include sugars, amino acids, general proteins, antimicrobial phylloplane proteins, transport proteins for transporting sucrose, purine and cytokinins, toxic elements etc. and enzymes such as peroxidases, dehydrogenases, ATPases, in addition to mRNA, ATP, reductants and other important ingredients of plant life. Guttation fluids also contain a number of natural plant hormones such as auxins, gibberellins, cytokinins, abscisic acid etc., apart from several vitamins. Recent discoveries have revealed the presence of a number of salts, ions, nutrients and macromolecules in guttation fluid playing significant role in enhancing disease resistance, tolerance to toxic elements, photosynthetic efficiency, biomass production and economic yield of agricultural crops. In the light of aforementioned discoveries in guttation transgenic plants have been created to serve as bio-factories for producing various kinds of phytochemicals of immense agricultural, pharmaceutical, nutriceutical, therapeutic, cosmeceutic and commercial significance impacting food productivity and human health adding happiness to life.
Keywords: Hydathodes; Molecular cloning; Plant-based biopharmaceuticals; Organic and inorganic phytochemicals; Xylem and phloem saps

For a hectare of oil palm plantation, about 21.63 tonnes of biomass comprising 20.43 % empty fruit bunches, 5.09 % palm kernel shells, 11.65 % oil palm trunks, 50.30 % oil palm fronds and 12.53 % palm pressed fibre is produced per year as wastes which keep raising many environmental concerns as most of them are incinerated and dumped at open sites. Oil palm wastes are found to contain phytochemicals which have anti-cancer, antioxidants and other vital biological activities. About 17–65 kg of carotenoids, 0.1–60 kg phenolic compounds, 0.6–39 kg sterols and 4.0–62 kg tocols could be extracted from these wastes which would not only boost the economy but also help improve human health and promote clean environments. This study assesses the phytochemistry of oil palm wastes and their pharmacological activities beneficial to the nutraceutical industry with the view of utilizing oil palm wastes for sustainable development.
Keywords: Oil palm sustainability; Oil palm phytochemicals; Oil palm wastes utilization; Biological activities

Biotechnological approaches to enhance the biosynthesis of ginkgolides and bilobalide in Ginkgo biloba by A. B. Sabater-Jara; S. Souliman-Youssef; E. Novo-Uzal; L. Almagro; S. Belchí-Navarro; M. A. Pedreño (191-205).
Ginkgo biloba is one of the oldest living tree species and its extracts or powdered leaves are one of the best selling herbal preparations. The main bioactive constituents are flavonoids and the terpene trilactones, ginkgolides and bilobalide, which are responsible for their pharmacological activity. However, there are many difficulties for ginkgo leaves supply and the chemical synthesis is far from of being applicable for commercial-scale production. G. biloba cell cultures have arisen as a useful alternative source of pharmacologically active terpene trilactones. This review sheds light on the chemistry and biosynthesis of terpene trilactones with the aim of increasing the production of these high value compounds by biotechnological approaches. Different biotechnological strategies to improve ginkgolides and bilobalide production will be discussed, including screening and selection of in vitro ginkgo cultures, cell differentiation levels of these cultures, optimization of culture conditions, feeding and elicitation strategies. Special attention will be paid in developing new methodologies to enhance ginkgo cell biomass and provide high amounts of these bioactive terpene trilactones using large-scale cell cultures.
Keywords: Biotechnology; In vitro cultures; Secondary metabolites; Terpene trilactones

Rosmarinic acid: new aspects by Maike Petersen (207-227).
Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid which is one of the most frequently occurring caffeic acid esters in the plant kingdom besides chlorogenic acid. RA has numerous biological and pharmacological activities. Its occurrence is spread all over the land plant kingdom. Enzymes and genes of its biosynthesis are well investigated. RA can be produced in high amounts in in vitro cultivated plant cells which offers the possibility of an economical exploitation. The review reports about recent findings in the biosynthesis of RA and related caffeic acid esters and discusses some aspects of the evolution of the biosynthetic enzymes.
Keywords: Caffeic acid esters; Phenylpropanoid metabolism; Biosynthesis; Evolution; Plant in vitro cultures

Lichens: a promising source of antibiotic and anticancer drugs by Gajendra Shrestha; Larry L. St. Clair (229-244).
Lichens are symbiotic associations between fungi and a photosynthetic alga and/or cyanobacteria. Lichenized fungi have been found to produce a wide array of secondary metabolites, most of which are unique to the lichenized condition. These secondary metabolites have shown an impressive range of biological activities including antibiotics, antifungal, anti-HIV, anticancer, anti-protozoan, etc. This review focuses primarily on the antibiotic and anticancer properties of lichen secondary chemicals. We have reviewed various publications related to antibiotic and anticancer drug therapies emphasizing results about specific lichens and/or lichen compounds, which microbes or cancer cells were involved and the main findings of each study. We found that crude lichen extracts and various isolated lichen compounds often demonstrate significant inhibitory activity against various pathogenic bacteria and cancer cell lines at very low concentrations. There were no studies examining the specific mechanism of action against pathogenic bacteria; however, we did find a limited number of studies where the mechanism of action against cancer cell lines had been explored. The molecular mechanism of cell death by lichen compounds includes cell cycle arrest, apoptosis, necrosis, and inhibition of angiogenesis. Although lichens are a reservoir for various biologically active compounds, only a limited number have been tested for their biological significance. There is clearly an urgent need for expanding research in this area of study, including in depth studies of those compounds which have shown promising results as well as a strong focus on identifying specific mechanisms of action and extensive clinical trials using the most promising lichen based drug therapies followed by large scale production of the best of those compounds.
Keywords: Lichens; Biological role; Natural products; Secondary metabolites; Anti-bacteria; Anti-cancer

Biofilm resistance to biocides is becoming a global issue with an impact on many fields, including health care, agriculture, the environment, society and industry. Plants offer a virtually inexhaustible and sustainable resource of very interesting classes of biologically active, low-molecular-weight compounds (parvome). In the past, the plant parvomes were screened mainly for their lethal effects, disregarding concentrations and ecologically relevant functions of these molecules in the natural context. Testing sub-lethal concentrations of plant-derived compounds mimicking environmental levels may be critical to reveal mechanisms subtler than the killing activity, e.g. those influencing the multicellular behavior, offering an elegant way to develop novel biocide-free antibiofilm strategies. In a cross-disciplinary fashion, we illustrated recent successes of sub-lethal concentrations of plant-derived compounds, their ecological insight, pro et contra, future directions and impacts, envisioning implications for policy making and resource management.
Keywords: Biofilm; Plant-derived compounds; Biocide-free strategies; Sub-lethal concentrations