NATURAL PRODUCTS

1. NATURAL PRODUCTS

2. NATURAL PRODUCTS • Compounds that occur naturally in plants and animals • Ubiquitous compounds are usually not classified as natural products. Ubiquitous = occurs everywhere in nature, universal excludes amino acids, nucleic acids, all compounds found in major metabolic pathways. • Natural products are unique to only one species or family of organisms.

3. PRIMARY AND SECONDARY METABOLISM

4. A TYPICAL PLANT hn Glycolysis ENERGY Photosynthesis (daytime) CO2 Respiration H2O (nighttime) O2 N2 bacteria “N” TRACE METALS Na, Ca, K, Mg Fe, Cu, Co, Mo NO2-/NO3-/NH4+ H2O

5. PRIMARY METABOLISM Primary metabolism comprises the chemical processes that every plant must carry out every day in order to survive and reproduce its line. Photosynthesis Glycolysis Citric Acid Cycle Synthesis of amino acids Transamination Synthesis of proteins and enzymes Synthesis of coenzymes Synthesis of structural materials Duplication of genetic material Reproduction of cells (growth) Absorption of nutrients

6. SECONDARY METABOLISM Secondary metabolism comprises the chemical processes that are unique to a given plant, and are not universal. Secondary metabolism is the chemistry that leads to the formation of a naturalproduct. Sometimes portions of this chemistry are common to a number of different plants or plant families, but the actual chemical produced (natural product) is usually different in one plant than in another. Common chemical precursors can lead to different results. Secondary metabolites (in most cases) do not appear to be necessary to the survival of the plant, but they may give it a competitive advantage.

7. Three Principal Groups of Secondary Metabolites • Terpenes Lipid synthesized from acetyl CoA or from basic intermediates of glycolysis • Phenolic compounds Aromatic substances formed via the shikimic acid pathway or the malonic acid pathway • Nitrogen containing secondary products (alkaloids) Alkaloids which are synthesized primary from amino acids

8. CO2 + H2O PRIMARY METABOLISM hn Photosynthesis Glucose Carbohydrates SECONDARY METABOLISM SECONDARY METABOLISM GLYCOLYS IS Building Blocks Phenyl- propanoids Amno Acids Fatty Acids Lipids Flavonoids Proteins synthesis Alkaloids Acetyl CoA enzymes Acetogenins Terpenes Steroids regulation Nucleic Acids Citric Acid Cycle reproduction RNA DNA CO2 + H2O + ATP

9. hn CO2 polyketides acetogenins lipids fatty acids phenylpropanes citric acid cycle alkaloids Glucose (6 carbons) photosynthesis starch n glycolysis erythrose- 4-phosphate phosphoenol pyruvate (PEP) (3 carbons) shikimic acid anthanilic acid acetyl- coenzymeA (2 carbons) mevalonic acid lysine ornithine oxalo- acetate phenylalanine tyrosine energy (ATP) + CO2 + H2O tryptophan terpenes steroids carotenoids NH3 nicotinic acid aspartic acid glutamic acid

10. Terpene functions • Growth and development • carotenoid pigments are tetraterpenes • chlorophyll side chain is diterpene • giberellins (hormones) are diterpenes • abscissic acid (hormone) is a sesquiterpene C15 • sterols are triterpenes

11. Terpenes that act against vertebrate herbivores Triterpenes 1. Cardenolides (glycosides) - acutely toxic influence Na+/K+ ATPase of heart muscle medicinal application - digitalis (from foxglove), used to treat heart disease. Can slow and strengthen heart beat 2. Saponins (soaplike) - steroid, triterpenes glycosides have lipid and water soluble parts of molecule toxicity related to sterol binding, membrane disruption

12. Terpenes as human medicinal drugs • Limonene - monoterpenoid (C10) dietary anticarcinogen • Artemisnin - sesquiterpenoid (C15) antimalarial • Taxol - diterpenoid anticancer drug from Pacific yew (Taxus brevifolia)

13. Phenolics • Plants produce a variety of compounds that contain one or more phenol groups - called phenolics • Thousands of phenolics occur in plants

14. Phenolic Compounds • Secondary metabolites which contain a hydroxyl functional group on an aromatic ring • They are heterogenous group: Some are water soluble only in organic solvents Some are water soluble carboxylic acids and glycosides Some are insoluble polymer • Many serves as defense compounds against herbivores and pathogens • Other function in attracting pollinators and fruit dispensers

15. Types of Phenolic Compounds • Benzoic acid derivatives • Caffeic acid and other simple phenylpropanoids • Flavones • Isiplavones (Isoplavonoids) • Flavonoids • Lignin

16. N-containing secondary compounds • Those are encountered less commonly in plants than the phenolics and terpenoids • Those are important in view of their bioactivity as drugs and toxins • They are synthesized from aliphatic and aromatic amino acids • Aliphatics via TCA cycle • Aromatics via shikimic acid pathway

17. WHAT IS AN ALKALOID ? • Naturally-occurring compounds that contain nitrogen • Many have heterocyclic rings as a part of their structure • They are found mostly in plants • Many are physiologically active (often spectacularly) • Many are used by native peoples for religious or medicinal purposes. • Many are basic (“alkaline”, due to an unshared pair on N) • Those nitrogen compounds that are found in all organisms (i.e., amino acids, nucleic acids, etc.) are not considered alkaloids. • Alkaloids are “secondary metabolites”, they are not involved in primary metabolism.

18. How are Phytoalexins Formed? The “-noids” • Shikimic acid pathway (phenylpropanoids) • Hydroxycinnamic acids • Coumarins • Hydroxybenzoic acids • Mevalonic acid pathway (Isoprenoids) • Carotenoids • Terpenoids • Combination of Pathways Shikimic-Polymalonic) • Flavonoids and anthocyanins

19. TEXTS: • Manfred Hesse, Alkaloids - Nature’s Curse or Blessing?, Wiley-VCH (2002). (on reserve) • R.E. Schultes, A. Hofmann and C. Ratsch, Plants of the Gods, 2nd ed., Healing Arts Press (2001). (bookstore) • D. Pavia, Chemistry of Natural Products - Notes, WWU Chemistry Department (online) See web site for reserve book list GRADING: Two Hour Exams, occasional quizzes, Problem sets, Poster Presentation