{"id":2264,"date":"2017-01-26T21:55:22","date_gmt":"2017-01-27T05:55:22","guid":{"rendered":"http:\/\/www.wou.edu\/chemistry\/?page_id=2264"},"modified":"2017-04-17T11:23:19","modified_gmt":"2017-04-17T18:23:19","slug":"ch105-chapter-6-hydrocarbons","status":"publish","type":"page","link":"https:\/\/wou.edu\/chemistry\/courses\/online-chemistry-textbooks\/ch105-consumer-chemistry\/ch105-chapter-6-hydrocarbons\/","title":{"rendered":"CH105: Chapter 6 – A Brief History of\u00a0Natural Products and Organic Chemistry"},"content":{"rendered":"

Chapter 6:\u00a0A Brief History of\u00a0Natural Products and Organic Chemistry<\/span><\/strong><\/h2>\n

6.1 Definition and Uses<\/strong><\/span><\/a><\/h3>\n

6.2 Natural Product Function<\/strong><\/span><\/a><\/h3>\n

6.3 Primary Metabolites<\/strong><\/span><\/a><\/h3>\n

6.4 Secondary Metabolites<\/strong><\/span><\/a><\/h3>\n

6.5 Where Do We Find Natural Products?<\/strong><\/span><\/a><\/h3>\n

Prokaryotic Organisms<\/span><\/strong><\/a><\/h4>\n
Bacteria<\/span><\/em><\/a><\/h5>\n
Archaea<\/span><\/em><\/a><\/h5>\n

Eukaryotic Organisms<\/span><\/strong><\/a><\/h4>\n
Fungi<\/span><\/em><\/strong><\/a><\/h5>\n
Plants<\/span><\/em><\/strong><\/a><\/h5>\n
Animals<\/span><\/em><\/strong><\/a><\/h5>\n

6.6 Foundations in Organic and Natural Products Chemistry<\/a>\u00a0<\/span><\/strong><\/h3>\n

Early Investigations<\/span><\/strong><\/a><\/h4>\n

Structural Theories<\/strong><\/span><\/a><\/h4>\n

Expanding the Concept<\/strong><\/span><\/a><\/h4>\n

Milestones<\/strong><\/span><\/a><\/h4>\n

6.7 Chapter Summary<\/strong><\/span><\/a><\/h3>\n

6.8 References<\/strong><\/span><\/a><\/h3>\n
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6.1 Definition and Uses<\/span><\/strong><\/span><\/h3>\n

What is a natural product chemistry and why should we be interested in studying it? The broadest definition of a\u00a0natural product<\/strong> <\/em>is anything that is produced by life, and includes biotic materials (e.g. wood, silk), bio-based materials (e.g. bioplastics, cornstarch), bodily fluids (e.g. milk, plant exudates), and other natural materials that were once found in living organisms\u00a0(e.g. soil, coal). A more restrictive definition of a natural product<\/em> <\/strong>is any organic compound that is synthesized by a living organism.\u00a0 The science of organic chemistry, in fact,\u00a0has its origins in the study of natural products, and has given rise to the fields of synthetic organic chemistry\u00a0<\/strong><\/em>where\u00a0scientists create organic molecules in\u00a0the laboratory,\u00a0and semi-synthetic organic chemistry<\/strong> <\/em>where scientists modify existing natural products to improve or alter\u00a0their activities.<\/p>\n

Natural products have high structural diversity and unique pharmacological or biological activities due to the natural\u00a0selection\u00a0and evolutionary processes that have shaped their utility over hundreds of thousands of years.\u00a0 In fact, the structural diversity of natural products far exceeds the capabilities of synthetic organic chemists within the laboratory. Thus, natural products\u00a0have been utilized in\u00a0both traditional and modern medicine for\u00a0treating diseases. Currently, natural products are often used as starting points for drug discovery followed by synthetic modifications to help reduce side effects and increase bioavailabilty. In fact, natural products are the inspiration for approximately half of U.S. Food and Drug Administration (FDA) approved drugs. In addition to medicine, natural products and their\u00a0derivatives are commonly used as food additives in the form of spices and herbs, antibacterial agents, and antioxidants to protect food freshness and longevity. In fact, natural organic products find their way into almost every facet of our lives,\u00a0from the clothes on our backs, to\u00a0plastics and rubber products,\u00a0health and beauty products, and even\u00a0the\u00a0energy we use to power our automobiles.<\/p>\n

Natural products may be classified according to their biological function, biosynthetic pathway, or their source.<\/p>\n

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6.2 Natural Product Function<\/span><\/strong><\/span><\/h3>\n

Natural products are often divided into two major classes: primary and secondary metabolites. Primary metabolites<\/strong><\/em>\u00a0<\/strong>are organic molecules that\u00a0<\/em>have an intrinsic function that is essential to the survival of the organism that produces them (i.e. the organism would die without these metabolites). Examples of primary metabolites include the core building\u00a0block molecules (nucleic acids, amino acids, sugars, and fatty acids)\u00a0required to make the major macromolecules (DNA, RNA, proteins, carbohydrates, and lipids)\u00a0responsible for sustaining life.\u00a0Secondary metabolites<\/strong><\/em> in contrast are organic molecules that typically have an extrinsic function that mainly affects other organisms outside of the producer. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment.<\/p>\n

Natural products, especially within the field of organic chemistry, are often defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of medicinal chemistry <\/strong><\/em>and <\/strong>pharmacognosy<\/strong><\/em>, the study and use of natural products in medicine.<\/p>\n

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6.3 Primary metabolites<\/span><\/strong><\/span><\/h3>\n

Primary metabolites are components of basic metabolic pathways that are required for life. They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth\/development. They have a wide species distribution that span many phyla and frequently more than one kingdom. Primary metabolites include the building blocks required to make the four major macromolecules within the body:\u00a0carbohydrates, lipids, proteins, and nucleic acids (DNA and RNA).<\/p>\n

These are large polymers of the body that are built up from repeating smaller monomer units (Fig. 6.1). The monomer units for building the nucleic acids, DNA and RNA, are the nucleotide bases, whereas the monomers for proteins are amino acids, for carbohydrates are sugar residues, and for lipids are fatty acids or acetyl groups.<\/span><\/p>\n

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Figure 6.1:\u00a0 The Molecular building blocks of life are made from organic compounds. <\/strong><\/p>\n

Modified from:\u00a0Boghog<\/a><\/p>\n

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Primary metabolites that are involved with energy production include numerous enzymes that breakdown food molecules, such as carbohydrates and lipids, and capture the energy released in molecules of adenosine triphosphate (ATP). Enzymes<\/strong><\/em> are biological catalysts that speed up the\u00a0rate of chemical reactions. Typically they are proteins, which\u00a0are composed of amino acid building blocks. The basic structure of cells and of organisms are also composed of primary metabolites. These include cell membranes (e.g. phospholipids), cell walls (e.g. peptidoglycan, chitin), and cytoskeletons (proteins). DNA and RNA which store and transmit genetic information are composed of nucleic acid primary metabolites. Primary metabolites also include molecules involved in cellular signaling, communication and transport. <\/span><\/p>\n

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6.4 Secondary metabolites<\/span><\/strong><\/span><\/h3>\n

Secondary metabolites, in contrast to primary metabolites are dispensable and not absolutely required for survival. Furthermore, secondary metabolites typically have a narrow species distribution. For example, the deadly nightshade, Atropa belladonna<\/em><\/a>, produces toxic hallucinogenic compounds, like scopolamine, but other plant species do not have this capacity. To date hundreds of thousands of secondary metabolites have been discovered!<\/p>\n

Secondary metabolites have a broad range of functions. These include pheromones<\/strong><\/em> that act as social signaling molecules with other individuals of the same species, other communication molecules that attract and activate symbiotic organisms, agents that solubilize and transport nutrients, known as siderophores<\/em><\/strong>, and competitive weapons (repellants, venoms, toxins etc.) that are used against competitors, prey, and predators. The function of many other secondary metabolites is unknown. One hypothesis is that they confer a competitive advantage to the organism that produces them. An alternative view is that, in analogy to the immune system, these secondary metabolites have no specific function, but having the machinery in place to produce these diverse chemical structures is important. A\u00a0few secondary metabolites are, therefore, produced and selected for depending on what the organism is exposed to during its lifetime.<\/p>\n

Secondary metabolites\u00a0have a diversity of structures and\u00a0include examples such as\u00a0alkaloids, phenylpropanoids, polyketides and terpenoids, as shown in Figure 6.2.\u00a0 Alkaloids<\/em><\/strong><\/a> are secondary metabolites that contain nitrogen as a component of their organic structure and can be divided into many subclasses of compounds.\u00a0Nicotine<\/a>, the addictive substance in tobacco is provided as an\u00a0example alkaloid (Fig 6.2).\u00a0The P<\/strong>henylpropanoids<\/b><\/em><\/a> are a diverse family of organic compounds that are synthesized from the amino acids phenylalanine and tyrosine (phenylalanine is shown in\u00a0Figure 6.2). Cinnamic acid<\/a> one of the volatile flavor molecules found in cinnamon is a phenylpropanoid. Polyketides<\/span><\/strong><\/em><\/a> are\u00a0assembled from the building blocks of acetate and malonate to form\u00a0large, complex structures.\u00a0\u00a0Alflatoxin B1<\/a>, shown below,\u00a0is a polyketide structure produced by fungi from the Aspergillus<\/em> genus. These types of molds commonly grow of stored food crops, such as corn and peanuts and contaminate them with aflatoxins.\u00a0Aflatoxins damage DNA molecules and act as a carcinogen<\/span><\/strong><\/em>, or cancer causing agent.\u00a0Food crops contaminated with aflatoxins have been linked with\u00a0cases of liver cancer.\u00a0Terpenoids<\/em><\/strong><\/a> are another large class of natural products that are constructed from 5-carbon monomer units called isoprene (Fig 6.2). Natural rubber<\/a> is a good example of a terpenoid-based structure.\u00a0 It is assembled from multiple reapeating isoprene units (Fig 6.2). <\/span>As we explore organic structures in more detail in the next few chapters we will continue to\u00a0evaluate examples from these diverse classes of metabolites and how they impact our lives.<\/span><\/p>\n

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6.2. Representative examples of each of the major classes of secondary metabolites<\/strong><\/p>\n

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6.5 Where Do We Find Natural Products?<\/span><\/strong><\/span><\/h3>\n

Natural products may be extracted from the cells, tissues, and secretions of microorganisms, plants and animals. A crude (unfractionated) extract from any one of these sources will contain a range of structurally diverse and often novel chemical compounds. Chemical diversity in nature is based on biological diversity, so researchers travel around the world obtaining samples to analyze and evaluate in drug discovery screens or bioassays. This effort to search for natural products is known as bioprospecting<\/em><\/strong>.<\/p>\n

The discipline of pharmacognosy, <\/strong><\/em><\/strong>which is the study of natural products with biological activity,\u00a0provides the tools to identify, select and process natural products destined for medicinal use. Usually,\u00a0a natural\u00a0extract has some form of biological activity that can be detected and attributed to a single compound or a set of related compounds produced by the organism. These active compounds can be used in drug discovery and development directly as they are, or they may be synthetically modified to enhance biological properties or reduce side effects.\u00a0\u00a0Examples of biological sources used to find new natural products are described below.<\/p>\n

Prokaryotic Organisms<\/span><\/strong><\/span><\/h4>\n

A prokaryote<\/b><\/em> is a unicellular organism that lacks a membrane-bound nucleus(karyon), mitochondria, or any other membrane-bound organelle. The word prokaryote<\/i> comes from the Greek \u03c0\u03c1\u03cc (pro<\/i>) “before” and \u03ba\u03b1\u03c1\u03c5\u03cc\u03bd (karyon<\/i>) “nut” or “kernel”. Prokaryotes can be divided into two domains, Archaea and Bacteria. In contrast, species with nuclei and organelles (Animals, Plants,\u00a0Fungi and Protists)\u00a0are placed in the domain Eukaryota.<\/p>\n

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Figure 6.3. Phylogenetic Tree of Life Based on Genetic Sequencing of Ribosomal RNA.<\/strong>\u00a0 Developed by: Maulucioni<\/a>.<\/p>\n

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In the prokaryotes, all the intracellular water-soluble<\/span> components (proteins<\/span>, DNA<\/span> and metabolites<\/span>) are located together in the cytoplasm<\/span> enclosed by the cell membrane<\/span>, rather than in separate cellular compartments<\/span>. Prokaryotes are also much smaller than eukaryotic cells.<\/p>\n

Bacteria<\/span><\/em><\/strong><\/span><\/h5>\n
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Typically a few micrometres<\/span> in length, bacteria<\/a> have a number of shapes<\/span>, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth<\/span>, and are present in most of its habitats<\/span>. Bacteria inhabit soil, water, acidic hot springs<\/span>, radioactive waste<\/span>, and the deep portions of Earth’s crust<\/span>. Bacteria also live in symbiotic<\/span> and parasitic<\/span> relationships with plants and animals. Most bacteria have not been characterised, and only about half of the bacterial phyla<\/span> have species that can be grown<\/span> in the laboratory. The study of bacteria is known as bacteriology<\/span>, a branch of microbiology<\/span>.\u00a0 <\/span>There are typically 40 million bacterial cells<\/span> in a gram of soil and a million bacterial cells in a millilitre of fresh water<\/span>. Bacteria are a prominent source of natural products.\u00a0\u00a0Figure 6.4 shows a\u00a0few examples of bacterial\u00a0natural products that have had an impact on our society, including several antibiotics. <\/span><\/p>\n

The serendipitous discovery and subsequent clinical success of penicillin prompted a large-scale search for other environmental microorganisms that might produce anti-infective natural products. Soil and water samples were collected from all over the world, leading to the discovery of streptomycin (derived from the bacterium,\u00a0Streptomyces griseus<\/i>), and the realization that bacteria, not just fungi, represent an important source of\u00a0antibacterial natural products.\u00a0 <\/span><\/sup>This, in turn, led to the development of an impressive arsenal of antibacterial and antifungal agents including amphotericin B, chloramphenicol, erythromycin, neomycin B, daptomycin and tetracycline (all from Streptomyces<\/i> spp.), <\/span><\/sup>the polymyxins (from Paenibacillus polymyxa<\/i>), and the rifamycins (from Amycolatopsis rifamycinica<\/i>).<\/span><\/p>\n

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Figure 6.4. Bacteria isolated from soil are prolific producers of antibacterial compounds. <\/span><\/strong><\/p>\n

Soil photo by: Pam Dumas.\u00a0Available at: Flicker<\/a>\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 <\/span><\/p>\n

Soil bacteria photo by: Alexander Raths. Available at: Shutterstock<\/a><\/span><\/p>\n

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Although most of the drugs derived from bacteria are employed as anti-infectives, some have found use in other fields of medicine. Botulinum toxin (from Clostridium botulinum<\/i>) and bleomycin (from Streptomyces verticillus<\/i>) are two examples. Botulinum toxin is the neurotoxin responsible for botulism food poisoning (Fig. 6.5).\u00a0 It is caused by the bacterium, Clostridium botulinum, which can grow in improperly sterilized canned meats and other preserved foods.\u00a0The poisoning can be fatal depending on how much of the toxin is ingested.\u00a0 It causes muscle weakness and paralysis.\u00a0\u00a0This toxin<\/span>\u00a0is now used cosmetically to help reduce\u00a0facial wrinkles.\u00a0It is\u00a0injected in small doses\u00a0into\u00a0areas such as the forehead to cause paralysis to the muscles that create wrinkles.\u00a0 Also, the glycopeptide bleomycin is used for the treatment of several cancers including Hodgkin’s lymphoma, head and neck cancer, and testicular cancer. Newer trends in the field include the metabolic profiling and isolation of natural products from novel bacterial species present in underexplored environments. Examples include secondary metabolite discovery from\u00a0symbionts<\/strong> <\/em>or endophytes. Symbionts <\/em><\/strong>are organisms that live in close association with another, often larger, organism known as a host<\/em><\/strong>. Endophytes<\/strong> <\/em>are non-harmful symbionts that are associated with plants for at least part of their life cycle.\u00a0In addition, discovery of organisms from tropical environments, subterranean bacteria found deep underground via mining\/drilling, and marine bacteria\u00a0continue to add to the\u00a0complexity of secondary metabolites discovered.<\/span><\/p>\n

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Figure 6.5. Botulinum toxin.<\/strong> (A) Diagram of botulinum toxin A. Consuming food products tainted with the neurotoxin produced by (B) the bacterium Clostridium botulinum<\/em>, can cause paralysis and death.\u00a0 Interestingly, the neurotoxin (marketed as Botox, Dysport, Xeomin, and MyoBloc)\u00a0has been adapted for medicinal use to reduce epileptic seizures and for\u00a0cosmetic use to reduce wrinkles and frown lines by paralyzing muscle tissue in the forehead. Diagram (A) provided\u00a0at Wikipedia<\/a>. \u00a0Diagram (B) provided by the CDC Prevention’s Public Health Image Library<\/a><\/span><\/p>\n

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Archaea<\/span><\/strong><\/span><\/em><\/h5>\n

The discovery of organisms now classified as Archaea is fairly recent in our history, dating back to 1977 by the researchers,\u00a0Carl Woese <\/a>and\u00a0George E. Fox<\/a>.\u00a0 Genetic sequencing was used to show that a separate branch of ancient prokaryotic organisms diverged at an early stage in the history of life on Earth (Fig. 6.3). Thus, Woese suggested\u00a0dividing the prokaryotic organisms into two major\u00a0categories, Bacteria and Archaea,\u00a0based on these genetic differences.\u00a0\u00a0It is noteworthy that many Archaea have adapted to life in extreme environments such as the polar regions, hot springs, acidic springs, alkaline springs, salt lakes, and the high pressure of deep ocean water. These\u00a0Archaea species\u00a0are\u00a0known as extremophiles<\/em><\/strong>.\u00a0<\/span><\/p>\n

Before the discovery by Woese and Fox, scientists thought that\u00a0prokaryotic extremophiles were bacteria evolved from\u00a0common bacterial species\u00a0that are\u00a0more familiar to us. Now,\u00a0evidence suggests that\u00a0they are actually very\u00a0ancient lifeforms, and may have robust evolutionary connections to\u00a0early life forms\u00a0on Earth. Woese’s work on Archaea is significant in its implications for the search for life on other planets, as extremophiles may be hearty enough to exist in the extreme environments\u00a0located on distant worlds. <\/span><\/sup>Because many Archaea have adapted to life in extreme environments they also possess enzymes that are functional under quite unusual conditions. These enzymes are of potential use in the food, chemical, and pharmaceutical industries, where biotechnological processes frequently involve high temperatures, extremes of pH, high salt concentrations, and \/ or high pressure. <\/span><\/p>\n

For example, Pyrococcus furiosus<\/i> is an extremophili<\/span>c species of Archaea (Fig. 6.6).<\/span>\u00a0It can be classified as a hyperthermophile <\/strong><\/em>because it thrives best under extremely high temperatures\u2014higher than those preferred of a thermophile<\/span>. It is notable for having an optimum growth temperature\u00a0of boiling water –\u00a0100\u00b0C\u00a0(a temperature that would destroy most living organisms). Recently, Dr. Tang’s research group\u00a0<\/a> isolated a thermostable enzyme from this species that can breakdown lactose, a disaccharide sugar found in milk (Fig. 6.6).\u00a0Lactose intolerance is a common health concern causing gastrointestinal symptoms and avoidance of dairy products by afflicted individuals. Since milk is a primary source of calcium and vitamin D, lactose intolerant individuals often obtain insufficient amounts of these nutrients which may lead to adverse health outcomes. Production of lactose-free milk can provide a solution to this problem, although it requires use of lactase from microbial sources and increases potential for contamination. Use of thermostable lactase enzymes can overcome this issue by functioning under pasteurization conditions. Early explorations of this enzyme show that it has optimal activity at 100o<\/sup>C and that it is thermostable even at 110o<\/sup>C (Fig. 6.6).<\/span><\/p>\n

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Figure 6.6 The Extremophile Pyrococcus furiosus. <\/i><\/strong>(A) Shows a computer recreation of P. furiosus<\/em>.\u00a0 (B) Shows the effects of temperature on the stability of the lactase enzyme, \u03b2-glucosidase.<\/span><\/p>\n

(A) Recreation of P. <\/i>furiosus<\/i> by: Fulvio314<\/a> <\/span><\/p>\n

(B) Effects of temperature figure on P. furiousus<\/em> lactase activity and text adapted from: Li, et al. (2013) BMC <\/i>Biotechnol<\/i>. <\/i>13:73<\/a> <\/span><\/p>\n

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Eukaryotic Organisms<\/span><\/strong><\/h4>\n

Eukaryotic organisms include four major kingdoms: Protista, Fungi, Plantae, and Animalia (Fig 6.7).\u00a0<\/span> Fungi <\/em><\/strong>are heterotrophic, eukaryotic organisms, either single-celled or multicellular, that are primarily decomposers within the environment.\u00a0Heterotrophs<\/em> <\/strong>are\u00a0organisms that cannot produce their own food. Plants<\/strong><\/em>\u00a0are multicellular eukaryotic\u00a0organisms that are autotrophic<\/strong><\/em>, or capable of producing their own food. Plants are also characterized by having true roots, stems and leaves. Animals<\/strong><\/em> are multicellular, eukaryotic organisms\u00a0that\u00a0are heterotrophic, and are characterized by being mobile at some point in their lifetime.\u00a0The term Protista (or sometimes Protoctista)<\/em><\/strong>\u00a0is still often used to describe all other eurkaryotic organisms that do not fit in the Fungi, Plantae, or Animalia kingdoms.\u00a0 However, it is not an ideal grouping, as there are protists that are animal-like, plant-like and fungi-like grouped under one umbrella term. Many scientists prefer to reclassify the protist kingdom into sub-groupings of related organisms based on phylogenetic data, rather than use the older protist classification. In fact, the phylogenetic classification proposed by Carl Woese breaks\u00a0Kingdom Protista into three major groups;\u00a0 the ciliates, the flagellates, and the microsporidia (Fig 6.3). In the following section, we will focus on natural product examples from the Fungi, Plant, and Animal kingdoms. However, keep in mind that\u00a0many protists are also producers of interesting natural products.<\/span><\/p>\n

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Figure 6.7 The Major Domains and Kingdoms of Life. By<\/span>: Maulucioni y Dorid\u00ed<\/a><\/p>\n

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Fungi<\/span><\/em><\/span><\/h5>\n
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As mentioned above,<\/span> Fungi <\/a><\/span>are heterotrophic, eukaryotic organisms that are primarily decomposers within the environment.\u00a0 They include single-celled organisms such as yeast and molds, and multicellular organisms that have fruiting bodies, such as mushrooms. Fungi produce a myriad of secondary natural products.\u00a0 Some are very toxic and have spurred common names such as death cap, destroying angel, and fool’s mushroom.\u00a0 Others have found great utility in medicine. For example,<\/span> several anti-infective medications have been derived from fungi including the penicillins<\/a> and the cephalosporins<\/a> (antibacterial drugs from Penicillium chrysogenum<\/i> <\/a>and Cephalosporium acremonium<\/i><\/a>, respectively), and griseofulvin<\/a> (an antifungal drug from Penicillium griseofulvum<\/i><\/a>) (Fig 6.8, parts A-C).\u00a0\u00a0Another medicinally useful fungal metabolite\u00a0is lovastatin<\/a> (from Aspergillus<\/i> terreus<\/em><\/a>), which became a lead for the statins, a series of drugs\u00a0commonly used to\u00a0lower cholesterol levels (Fig 6.8, part D).\u00a0<\/span><\/p>\n

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Figure 6.8.\u00a0 Examples of fungal secondary metabolites.<\/strong><\/span><\/p>\n

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Ergometrine<\/a> (from Claviceps<\/i> spp<\/a>.) acts as a vasoconstrictor, and is used to prevent bleeding after childbirth (Fig 6.8, part E). You will notice in the photograph of Claviceps spp.<\/em> that this genus of fungi commonly grows on grain crops such as wheat and barley.\u00a0 Contamination of grain\u00a0crops with this fungi can lead to human poisoning if\u00a0high quantities of the fungi are consumed. This type of poisoning is\u00a0known as ergotism<\/a> and can cause convulsions.\u00a0 The vasoconstrictive properties of ergometrine can also cause gangrenous side effects when ingested in toxic doses.\u00a0 Distal structures that are more poorly vascularized like the fingers and the toes are affected first.\u00a0 This can cause loss of peripheral sensation, edema, and ultimately the death and loss of affected tissues. <\/span><\/p>\n

Cyclosporin<\/a> is another amazing example of a fungal metabolite with important medical implications. Cyclosporin is an alkaloid structure that is assembled from amino acid building blocks that forms a cyclic peptide structure (Fig 6.9).\u00a0 Its\u00a0major\u00a0biological activity is\u00a0to suppress the immune response.\u00a0 Thus, it is widely prescribed to patients following\u00a0an organ transplant,\u00a0to help reduce the chance of organ rejection.\u00a0Cyclosporin was isolated in 1971 from the fungus Tolypocladium inflatum <\/i><\/a><\/span>(Fig 6.9)<\/span><\/span>.\u00a0<\/span><\/i>After 12 years of\u00a0laboratory investigations and clinical testing, it was approved by the FDA for use in 1983.<\/span>\u00a0It is on the World Health Organization’s List of Essential Medicines<\/a><\/span>, as one of\u00a0the most effective and safe medicines needed in a health system. Of note, T. inflatum<\/em> is the asexual, single-celled form of a fungus that can also take on a sexually-reproducing multicellular life-stage, where it is\u00a0known as the fungi,\u00a0Cordyceps subsessilis <\/em>(Fig 6.9). Cyclosporin is only produced during the asexual life-stage of the organism, demonstrating that gene expression can vary dramatically within an organism due to life-stage or other factors present within the environment of the organism. <\/span><\/p>\n

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Photos By:<\/span> Kathie Hodge<\/a><\/p>\n

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Cyclosporin Structure from<\/span> Yikrazuul<\/a><\/p>\n

Figure 6.9 Fungal Production of Cyclosporin.\u00a0<\/strong> (A) Multicellular life-stage of the fungus, known as Cordyceps subsessilis<\/i>, (B) unicellular life-stage of the fungus, known as<\/span> Tolypocladium inflatum. <\/i>(C) Structure of cyclosporine.<\/span><\/span><\/p>\n

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Plants<\/span><\/em><\/strong><\/span><\/h5>\n
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Life\u00a0forms\u00a0that are classified in the Plant Kingdom\u00a0are multicellular eukaryotic\u00a0organisms that are autotrophic<\/strong><\/em>, or capable of producing their own food. They produce their own food through the process of photosynthesis<\/strong><\/em>, where they\u00a0utilize light energy from the sun to convert carbon dioxide and water into simple sugars.\u00a0\u00a0Oxygen is a by-product of this reaction.\u00a0 Thus, plants are a major source of oxygen on the planet. It is estimated that there are approximately 250,000 to 300,000 different species of plants on the planet. In addition to producing oxygen and being utilized as a food source,\u00a0plants are also a major source of complex and highly structurally diverse secondary metabolites. This structural diversity is attributed in part to the natural selection of organisms producing potent compounds to deter herbivory (feeding deterrents).\u00a0 Though the number of plants that have been extensively studied is relatively small, many pharmacologically active natural products have been identified and are currently used as medical treatments.<\/span> Clinically useful examples include the anticancer agents<\/span> paclitaxel<\/a><\/span> and<\/span> vinblastine<\/a><\/span> (from<\/span> Taxus brevifolia<\/a><\/i><\/span> and <\/span>Catharanthus roseus<\/i><\/a>, respectively), the antimalarial agent<\/span> artemisinin<\/a><\/span> (from<\/span> Artemisia annua<\/a><\/i><\/span>),the opioid analgesic drug<\/span> morphine<\/a><\/span> (from Papaver somniferum<\/a><\/i><\/span>), and <\/span>galantamine<\/a><\/span> (from<\/span> Galanthus<\/a><\/i><\/span> spp<\/span>.), used to treat Alzheimer’s disease<\/a> (Fig 6.10)<\/span><\/span>. <\/span><\/sup><\/span><\/p>\n

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(Photo by:<\/span>Jason Hollinger<\/a>)<\/p>\n

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(Photo by:<\/span>Joydeep<\/a>)<\/p>\n

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(Photo by:<\/span>Kristian Peters<\/a>)<\/p>\n

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(Photo by:<\/span>Meneerke Bloem and Peter Coxhead<\/a>)<\/p>\n

Figure 6.10. Examples of biologically active metabolites from plants.<\/span><\/strong><\/p>\n<\/div>\n<\/div>\n

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Animals<\/span><\/em><\/strong><\/span><\/h5>\n
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Animals<\/strong><\/em> are multicellular, eukaryotic organisms of the kingdom Animalia. As described earlier, animals are heterotrophic organisms and are characterized by being mobile at some point in their lifetime.\u00a0\u00a0Animals can be divided broadly into vertebrates and invertebrates. Vertebrates<\/em><\/strong> have a backbone or spine (vertebral column), and amount to less than five percent of all described animal species. They include fish, amphibians, reptiles, birds and mammals. The remaining animals are the invertebrates<\/em><\/strong>, which lack a backbone. These include molluscs (clams, oysters, octopuses, squid, snails); arthropods (millipedes, centipedes, insects, spiders, scorpions, crabs, lobsters, shrimp); annelids (earthworms, leeches), nematodes (filarial worms, hookworms), flatworms (tapeworms, liver flukes), cnidarians (jellyfish, sea anemones, corals), ctenophores (comb jellies), and sponges. The study of animals is called zoology.<\/span><\/p>\n<\/div>\n<\/div>\n

Animals also represent a source of bioactive natural products. In particular, venomous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention. This is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with a macromolecular target in the body. As with plant feeding deterrents, this biological activity is attributed to natural selection, organisms capable of killing or paralyzing their prey and\/or defending themselves against predators being more likely to survive and reproduce. <\/span><\/p>\n

For example, Chlorotoxin<\/a> is a 36-amino acid<\/span> peptide<\/span> found in the venom<\/span> of the deathstalker scorpion<\/span> (Leiurus quinquestriatus<\/i><\/a>) which blocks small-conductance chloride channels (Fig. 6.11). It uses this toxin to immobilize it’s prey.<\/span><\/span><\/p>\n

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Figure 6.11 Chlorotoxin from the deathstalker scorpion (Leiurus quinquestriatus<\/i>).<\/span><\/strong>\u00a0 A ribbon diagram of the chlorotoxin protein is shown on the right<\/span>. Photo of the deathstalker scorpion by: Ester Inbar<\/a><\/span> and Ribbon diagram of chlorotoxin by: Lijealso<\/a><\/span>.<\/span><\/p>\n

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Remarkably, in humans\u00a0chlorotoxin binds preferentially to glioma brain cancer cells. A glioma<\/strong><\/em> is a type of tumor that forms in the brain or spinal chord.\u00a0 It can often become malignant<\/strong><\/em>, which is\u00a0a term used to describe\u00a0cancer that has poor prognosis and is prone to spreading to different areas of the body. Remarkably, chlorotoxin only binds with the tumor cells and not with normal brain\u00a0tissue. This feature\u00a0has allowed the development of new methods\u00a0to treat,\u00a0diagnosis, and remove several different\u00a0types of cancer. For example, TM-601 which is the synthetic version of chlorotoxin is currently under phase II clinical trial. Radioactive Iodine-131 can be attached to TM-601\u00a0and used to treat malignant glioma. TM-601 crosses blood-brain and tissue barriers and binds to the malignant brain tumor cells without affecting healthy tissue.\u00a0When TM-601\u00a0is\u00a0attached to the radioactive Iodine-131 the iodine will also be recruited specifically to the tumor where it can preferentially\u00a0kill the tumor cells. <\/span><\/p>\n

In addition, researchers at Fred Hutchinson Cancer Research Center\u00a0<\/a>have also created a chlorotoxin derivative called BLZ-100 that is attached to a fluorescent dye.\u00a0 This provides a long lasting signal that makes the tumor glow, almost as if all the parts of the tumor have been painted.\u00a0 It can be used in real time to help a surgeon determine where the edges of the tumor are or where the tumor has spread, so that in can be removed completely. Animal trials with this ‘tumor paint’ have shown positive results with many types of cancer.\u00a0Figure\u00a06.12\u00a0shows a tumor that has been\u00a0removed from a dog that has breast cancer \u2014 it\u2019s called mammary carcinoma in a dog \u2014 and the surgeons knew about that big spot down in the bottom right, that was cancer, but really that\u2019s all they were able to tell from the clinical exam and the scans that were done in advance. This dog received a dose of tumor paint the day before surgery, and\u00a0in the\u00a0right panel of Figure 6.12\u00a0is what the surgeons were able to see. Not only could they see the main tumor, but they could see additional areas of cancer that were not visible to the naked eye. <\/span><\/p>\n

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Figure 6.12 Making Cancer Visible.\u00a0<\/strong> On the left is a photo of a mammary tumor that has been removed from dog.\u00a0 On the right, is the same mammary tumor exposed to BLZ-100.\u00a0 The fluorescent areas are where the cancer tissue is present.\u00a0 Photo by<\/span> Todd Bishop at Geekwire<\/a>.<\/p>\n

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All\u00a0across America everyday, women\u00a0who have had breast cancer surgery\u00a0are told, “you have clean margins, everything looks good, we\u2019ll follow it with some scans”, and then six to nine months later they start to get some bad news.\u00a0\u00a0Unfortunately, the surgeons can\u2019t always see exactly where the cancer is, and sometimes cancer isn\u2019t contiguous. It jumps around into some spots a little ways away from the primary, and tumor paint is helping making cancer much more visible. To hear more about this and other related drug developments, listen to Jim Olson’s Geekwire Talk <\/a>posted below. <\/span><\/p>\n

https:\/\/wou.edu\/chemistry\/files\/2017\/01\/Jim-Olson-Geekwire-Talk.mp4<\/a><\/video><\/div>\n

Other novel drugs that have arisen from\u00a0animal venoms include,\u00a0teprotide, a peptide isolated from the venom of the Brazilian pit viper Bothrops jararaca <\/em>(Fig 6.13). <\/em>Teprotide <\/em>was found to have activity as an antihypertensive agent and provided an initial lead compound for the development of blood pressure lowering medications. It was\u00a0not a good drug candidate on its own, due to\u00a0the expense in isolating it\u00a0and the lack of oral availability.\u00a0 However the structure was used as\u00a0a lead compound and many derivative structures were made to try and find smaller, more soluble, orally active compounds that had the same biological activity. This has resulted\u00a0in the development of the currently presecribed antihypertensive agents, cilazapril and captopril (Fig 6.13). <\/span><\/p>\n

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6.13 Teprotide and Its Synthetic Derivatives Cilazapril and Captoprial.\u00a0 <\/strong>Teprotide (B)\u00a0is a toxin produced by the pit viper, Bothrops jararaca <\/i>(A).\u00a0 Due to poor oral availability and expense teprotide was not a good drug compound, however, its biological activity lead to the development of the synthetic antihypertensive drugs, Cilazapril (C) and Captopril (D).<\/span><\/p>\n

Photo of Bothrops jararaca<\/em> by:<\/span> Felipe S\u00fcssekind\u00a0,<\/a>\u00a0Structure of Teprotide by:<\/span> Yikrazuul<\/a>, Structure of Cilazapril by:<\/span> Vaccinationist,<\/a> and Structure of Captorpril by:<\/span> Vaccinationist.<\/a><\/p>\n

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In addition to the terrestrial animals described above, many marine animals have been examined for pharmacologically active natural products, with corals<\/a>, sponges<\/a>, tunicates<\/a>, sea snails<\/a>, and bryozoans<\/a> yielding chemicals with interesting analgesic, antiviral, and anticancer activities. Two examples developed for clinical use include \u03c9-conotoxin <\/a>(from the marine snail Conus magus<\/em><\/a>) and ecteinascidin 743 (from the tunicate Ecteinascidia turbinata<\/em>) (Figure 6.14). The former, \u03c9-conotoxin, is used to relieve severe and chronic pain, <\/span><\/sup>while the latter, ecteinascidin 743 is used to treat cancer. <\/span><\/p>\n

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6.14 Medicines from the Sea.\u00a0<\/strong> In the upper panel the marine snail, Conus magnus<\/em> and it’s\u00a0active metabolite, \u03c9-conotoxin, are shown.\u00a0 Note that \u03c9-conotoxin is a protein.\u00a0 Thus, it’s structure is much to large to show all the organic bonds.\u00a0 Proteins are often depicted in ribbon diagrams to give you a sense of the 3-dimensional folding patterns. In the lower panel the tunicate Ecteinascidia turbinate <\/em>and its metabolite, ecteinascidin 743 (ET-743) are shown.\u00a0 Photo of Conus magnus provided by:<\/span> Richard Parker.<\/a> Ribbon diagram of \u03c9-conotoxin provided by: Fvasconcellos<\/a>. Photo of the tunicate, Ecteinascidia turbinate provided by: Sean Nash<\/a>.<\/span><\/span><\/p>\n

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6.6 Foundations of organic and natural product chemistry<\/span><\/strong><\/h3>\n<\/div>\n<\/div>\n

The concept of natural products dates back to the early 19th century, when the foundations of organic chemistry were laid. Organic chemistry was regarded at that time as the chemistry of substances\u00a0derived from\u00a0plants and animals. It was a relatively complex form of chemistry and stood in stark contrast to inorganic chemistry, the principles of which had been established in 1789 by the Frenchman Antoine Lavoisier in his work Trait\u00e9 \u00c9l\u00e9mentaire de Chimie.<\/i><\/span><\/p>\n

Early Investigations<\/span><\/strong><\/h4>\n

During the first half of the nineteenth century, some of the first systematic studies of organic compounds were reported. Around 1816 Michel Chevreul<\/span> started a study of soaps<\/span> made from various fats<\/span> and alkalis<\/span>. This process is called saponification.\u00a0 You will notice that the\u00a0ester bonds in the triacylglycerides (fats and oils) are broken down during the saponification process into the salts\u00a0of the fatty acids and glycerol.\u00a0He separated the different salts of the fatty acids that, in combination with the alkali, produced the soap. Since these were all individual compounds, he demonstrated that it was possible to make a chemical change in various fats (which traditionally come from organic sources), producing new compounds. This was an important discovery because up until that point, chemists believed that it was not possible to alter or synthesize organic compounds.\u00a0 <\/span><\/p>\n

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In 1828 Friedrich W\u00f6hler<\/span> produced the organic<\/i> chemical urea<\/span> (carbamide), a constituent of urine<\/span>, from inorganic<\/i> starting materials (the salts potassium cyanate<\/span> and ammonium sulfate<\/span>), in what is now called the W\u00f6hler synthesis<\/span>. These types of foundational studies\u00a0marked the birth of synthetic organic chemistry.<\/span><\/p>\n

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6.15 Model of W\u00f6hler<\/span> Synthesis.\u00a0\u00a0<\/strong>Created By:<\/span> Bensaccount<\/a><\/p>\n

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Structural Theories<\/span><\/strong><\/h4>\n

In addition to being able to synthesize organic molecules, another critical aspect during the development of organic chemistry\u00a0was the isolation and structural elucidation of organic substances: although the elemental composition of pure organic substances (irrespective of whether they were of natural or synthetic origin) could be determined fairly accurately, the molecular structure was still a problem. The urge to do structural elucidation resulted from a dispute between Friedrich W\u00f6hler and Justus von Liebig, who both studied a silver salt of the same composition but had different properties. W\u00f6hler studied silver cyanate, a harmless substance, while von Liebig investigated silver fulminate, a salt with explosive properties. The elemental analysis shows that both salts contain equal quantities of silver, carbon, oxygen and nitrogen. According to the prevailing ideas, both substances should possess the same properties, but this was not the case. This apparent contradiction was later solved by Berzelius’s theory of isomers, whereby not only the number and type of elements are of importance to the properties and chemical reactivity, but also the position of atoms in space\u00a0within a compound. <\/span><\/p>\n

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This was a direct cause for the development of structure theories, such as the radical theory of Jean-Baptiste Dumas and the substitution theory of Auguste Laurent. However, it took until 1858 before by August Kekul\u00e9 formulated a definite structure theory. He posited that carbon was tetravalent and can bind with other carbon atoms to form organic molecules. Archibald Scott Couper independently arrived at the idea of self-linking of carbon atoms (his paper appeared in June 1858), and provided the first molecular formulas where lines symbolized bonds connecting the atoms. For organic chemists, the theory of structure provided dramatic new clarity of understanding, and a reliable guide to both analytic and especially synthetic work. As a consequence, the field of organic chemistry developed\u00a0rapidly from this point.<\/span><\/p>\n

Expanding the concept<\/span><\/strong><\/h4>\n

The concept of natural products chemistry, which was initially based on organic compounds that could be isolated from plants, was extended to include animal material in the middle of the 19th century by the German Justus von Liebig<\/a><\/span>. In 1884, Hermann Emil Fischer<\/a><\/span>, turned his attention to the study of carbohydrates and purines, work for which he was awarded the Nobel Prize in 1902. He also succeeded to make a variety of carbohydrates synthetically in the laboratory, including<\/span> glucose<\/a><\/span> and<\/span> mannose<\/a><\/span>. After the discovery of<\/span> penicillin<\/a><\/span> by<\/span> Alexander Fleming<\/a><\/span> in 1928, fungi and other micro-organisms were added to the arsenal of sources of natural products.<\/span><\/p>\n

Milestones<\/span><\/strong><\/h4>\n

By the 1930s, several large classes of natural products were known. Important milestones in natural products research have\u00a0included several notable Nobel Prize awards:<\/span><\/p>\n