Frontiers in Natural Product Chemistry

In the early 1980s, there were occasional reports of natural products isolated from marine invertebrates that were either identical to compounds from terrestrial sources, or were close chemical relatives. Since that time period it has become evident that microbes, whether they can currently be fermented under “normal conditions” or require genetic analyses and subsequent elaboration in surrogate hosts etc., are very heavily involved in the production of marine invertebrate secondary metabolites. In the last few years, the situation with plant-derived natural products is very reminiscent of the early 1980s / marine invertebrate stories, as there are now significant numbers of reports invoking microbes (usually endophytic fungi), in the production of nominally plant-derived natural products. In one particular case, that of maytansine, the production by epiphytic root bacteria in the nominal producing plant is definitive. Each issue of current journals covering genetic analyses of plants or marine invertebrates, often contains at least one article (basic science or review), that furthers the potential involvement of microbes in the production of even well-known molecules such as taxol, vinca alkaloids, homoharringtonine on the plant side and pederin-related (e.g. onnamide) derivatives on the marine side. We will also give information on bacterial, fungal and algal interactions that together lead to the production of natural products, though the exact involvement may not yet be known. We will broadly discuss the current situation and then hone in on areas where microbial involvement is definitive, and give the evidence for areas where it is still circumstantial.

Nonribosomal peptides display a broad range of biological activities, including antimicrobial, antitumor and immunosuppressive agents, as well as signaling molecules and virulence factors. Many of these nonribosomal peptides are biosynthesized by large, highly versatile multifunctional proteins known as nonribosomal peptide synthetases (NRPSs). The results of genetic, biochemical, and bioinformatic investigations over the past three decades have offered a profound understanding of the functional characteristics and molecular basis underpinning the enzymology of nonribosomal peptide biosynthesis; however, studies at the proteomic level are limited. This chapter will focus on tools recently developed not only for studies aimed at visualizing, monitoring and tracking NRPS proteins but also for rapid labeling, isolation, identification and enzymatic characterization of NRPS family members as required for proteomics in natural product biosynthesis.

Oligosaccharides are low molecular weight carbohydrates with a degree of polymerisation ranging from 3 to 10 sugar residues. These compounds have attracted an increasing attention because of their functional effects on human health, as well as their physicochemical properties, which are of interest for various applications in food technology. The functionality of oligosaccharide depends on its chemical structure, which relies on the nature of the building sugar residues, the linkage type, and the degree of polymerisation. Oligosaccharides can be found naturally in foods (from plants and animals) or are produced by the synthesis from disaccharide substrates or by the hydrolysis of polysaccharides (physical, chemical and/or biotechnological process). Certain oligosaccharides present important beneficial properties for consumers, including anti-carcinogenic effect, low caloric value and prebiotic properties. Prebiotics are selectively fermented ingredients that allow specific changes in the composition and/or activity of the gastrointestinal microbiota, which provides health benefits and well-being to the consumer. In the food industries, the oligosaccharides have been applied as dietary fiber, sweetener, and weight control agent, and as a humectant in confectioneries, bakeries and breweries. Thus, oligosaccharides are natural compounds that have been widely studied and used in science and industry. This chapter reviews (i) the chemical structure, (ii) emerging trends in production, (iii) applications in science and technology, as well as (iv) the beneficial health of oligosaccharides. In general, this chapter is useful for teachers, students and researchers seeking to understand the chemistry and the future research of oligosaccharides

The best and safest treatment for pain is with topical treatments on the skin. This is most evident with acupuncture that occurs in the skin, is safe and effective. Even broken bones, post-operative pain, replaced hips, replaced knees, cancer pain and other severe pain can be treated effectively and safely with topical medicines. A liniment is available that has been used in many acute and chronic pain patients with success as will be discussed. Cyclooxygenase-2 is found in the skin and is induced in chronic pain conditions. Oral medications do not reach high enough concentrations in the skin to inhibit the enzyme. Instead, oral nonsteroidal anti-inflammatory medications poison the body and are toxic to the stomach and kidneys. These oral medications cause at least 10,000 ulcer deaths yearly in the USA. They also cause clotting problems that lead to heart attacks and strokes. Pain is sensed in the skin at sensory afferent neurons. The activities of pain sensing transient receptor potential cation channels in these neurons are increased by prostaglandins made by cyclooxygenase-2. Pain is best treated with topical preparations that penetrate the skin in small amounts, inhibit cyclooxygenase-2 and are not poisonous to the body. Sesquiterpenes are 15 carbon compounds found in plants and can penetrate the skin. These compounds down regulate the transcription of cyclooxygenase-2 through an NF-kB mediated mechanism and may also inhibit cyclooxygenase-2 and other targets directly. This review is a discussion of the medicinal chemistry and pharmacology of sesquiterpenes that permits these molecules to relieve severe and chronic pain.

2,6-Disubstituted piperidinols are one of the most investigated groups of compounds owing to their potential therapeutic use and unique structures. They show a wide variety of biological activities, including inhibition of superoxide anion production, influence on the central nervous system, antibacterial, and plant growth inhibition. For these reasons, 2,6-disubstituted piperidinols have attracted attention from medicinal, phyto-, and synthetic organic chemists. In this review, the biological profile and chemistry of 2,6-disubstituted piperidinols are described. Recent developments in synthetic methods for 2,6-disubstituted piperidinols are also discussed.

Isoflavones are a relatively small, structurally well defined, group of plant secondary metabolites (natural products), which are of particular interest as biologically active, non-nutrient constituents of animal feed and human food. Chronologically, they were noticed at the beginning of XIXth century phytochemical studies as a class of plant pigments of considerable practical importance, but gained more significance after discovery of their estrogenic activity and interference with hormonal homeostasis of sheep, during 1940s. Contemporary studies of isoflavones are inseparably connected with soy, which is not only one of the principal agricultural crops of global significance, but also the richest source of genistein, daidzein and glycitein, which can occur as glycosides, aglycones or partly acylated glycosides. The presence of isoflavones in food products, which are derived from processing of soybean are generally considerd safe and beneficial for human health. Relatively recently, sufficiently selective and accurate analytical methods have been developed. These techniques have enabled the study of metabolic fates of isoflavones in experimental animals, as well as human patients, at the nanomolar levels which result from soy products ingestion or administration of pure isoflavones preparations. Although isoflavones share many physicochemical and biochemical characteristics with more numerous groups of natural products: flavonoids and polyphenolics (which are recognized as antioxidants, scavengers of the reactive oxygen species and antiinflammatory agents), they also feature some selective activities, like estrogenicity or multitarget and pluripotent anticancer action. The large amount of isoflavone pharmacological data accumulated tend to become less consistent as we advance from molecular level, through animal models, to human clinical trials, which indicates shortcomings of traditional approaches and the need for including systems biology methods and interpretations. Natural isoflavones remain interesting molecular probes, and lead compounds for several therapeutic directions; their presence in certain food products and variety of dietary supplements seems to be generally accepted, but it becomes evident that prospective drug development must take into account considerable differences in individual metabolism, which results in large part from very different microbiota which harbors in human intestines. On the other hand, synthetic chemistry of phenylpropanoids in general, and isoflavones in particular, is well developed and capable of delivering modified structures in both: form of structurally diverse dedicated libraries, and also in form of a scalable process for manufacturing of an active pharmaceutical ingredient featuring selected structure.

It is described in this book chapter structural features of natural benzophenones and an overview of their various biological activities. These compounds have been isolated mainly from plant species belonging to the Clusiaceae family. Biosynthetic processes involved in their formation are also presented.