Introduction

1. Introduction Natural products, especially those derived from plants, have been used for medicinal purposes since ancient times Clay tablets of the Babylonian, Assyrian, and Sumerian eras dated 2600 - 4000 BC are thought to be the earliest recordings of plant usage as herbal remedies Egyptians also had many paintings of medicinal plants on their tomb walls dated around 2200 – 2700 BC The Ebers papyrus, which dates from around 1550 BC, is the most famous medical document of ancient Egypt and contains more than 800 medicinal recipes using medicinal plants This centuries-old usage of natural products certainly continues into the present, as half of prescription drugs in the market today contain plant-derived ingredients

2. Some important natural products 1785:William Withering used foxglove extract to treat heart patients, and he published this application. Digoxin was discovered due to this treatment; Glaxo Smith Kline markets this drug as Lanoxin, and it is used to treat arrhythmia and congestive heart failure 1803: Sertϋrner isolated morphine from opium 1817: Isolation of strychnine 1820: Isolation of caffeine and quinine 1828: Isolation of nicotine 1833: Isolation of atropine 1855: Isolation of cocaine 1868: Isolation of digitaline 1897: Arthur Eichengrün and Felix Hoffmann at Bayer Company created aspirin . Aspirin was the first synthetic drug synthesized from a natural product, salicylic acid, extracted from the willow bark 1928: Alexander Fleming discovered Penicillin from penicillium mold, and this discovery changed modern medicine and the treatment and understanding of infectious disease

3. Pharmacognosy Greek = Pharmakon + gnosis (Drug) (Knowledge) The study of starting material intended for therapeutic and biological origin. In other words from plants, animals or by fermentation from micro-organisms Deals with natural products used as drugs or for preparation of drugs

4. Phytochemistry • The study of chemicals involved in the activity of medicinal plants which are usually secondary metabolites. Many are known to provide protection against biological attacks and plant diseases. They also exhibit a number of protective functions for human consumers. • Techniques commonly used in the field of phytochemistry include extraction, isolation, structural determination using different spectroscopic methods (MS, UV, IR, 1D & 2D NMR) as well as various chromatography techniques (HPLC, LC-MS)

5. Natural Products: -Entire organisms such as a plant or an animal which has not been subjected to any treatment except to a simple process of preservation, i.e. drying -Part of an organism, i.e. leaf or an isolated gland/exudate or other organ of an animal or microorganism • Crude drugs: A term used to describe natural products which are not pure compounds but are whole/ parts of plants, extracts and exudates • Ethnopharmacology: A branch of science concerned with the study of plants in traditional medicine with emphasis on pharmacological aspects of culture’s medical treatment as well as its social appeal, including taste, symbology and religious context

6. How drugs of natural origin can be used?Industrial feasibility? Isolated and purified natural products: Cardiac glycosides, morphine, antibiotics,… Derivatives of natural products : Steroids (sex hormones, contraceptives, corticosteroids,…) Total chemical synthesis of natural products: Tubocurarine, caffeine,…. Partial synthesized / modified natural products Different anticancer drugs (vinblastine, taxol,…) New natural products or new natural product like small molecules

7. Production of drugs based on natural products Ethnopharmacology/ethnobotany/traditional medicine Isolation from natural resources (cost, limited access to raw materials) Total synthesis (complex structures) Combination enzymatic and chemical synthesis (advances in molecular biology) Transgenic plants Cell and tissue culture (expensive and tedious) HTS (High Throughput Screening)

8. Some reasons for the interest in natural compounds in the 20th /21st century • Search for chemicals from natural sources as curative agents, especially for chronic diseases (diabetes, hyperlipidemia, hypertension) or for diseases the synthetic chemistry was not successful (cancer) • Increased interest in the chemical compounds from the viewpoint of pure science • Worldwide interest in the different traditional medicines (“back to the nature”-trends) • Interest in the use of chemical constituents as an aid in plant taxonomy (chemotaxonomy)

9. Plants and their metabolites Primary metabolites: Compounds produced during the fundamental pathways; essential for the plant life (H2O, CO2 → Photosynthesis): carbohydrates, fats, proteins, nucleic acids →primary activity of green plants Secondary metabolites:Not necessarily involved in the essential metabolism of the cell, but exert physiologic activity for the plant, its environment and human ( phyto-hormons, plant-protection, plant-insect-, plant-animal interactions, source of drugs); produced through specific pathways with a limited distribution in nature; condition and species sensitive; most pharmacologically active natural products are 2ry metabolites

10. Classification of natural products Based on: • Chemical structures: e.g. carbohydrates, steroids, alkaloids,… • Physiological effect(s)/Pharmacological activity: e.g. vitamins, antibiotics, anticoagulant, hypotensive,… • Taxonomic: part used e.g. flower, family , genus, species,… • Biosynthetic Pathway: e.g. shikimic acid derivatives, mevalonic acid derivatives, acetate-malonate derived

11. The biosynthesis of the secondary metabolites • Acetate-malonate pathway • Acetate-mevalonate pathway (mevalonic acid pathway) • Shikimic acid pathway • “Amino acid “pathway

12. Acetate malonate pathway A-Non-aroamtic derivatives (polyacetylenes, polyynes) B-Aromatic polyacetates (polyketides) B1-Monocyclic compounds: -Lichen compounds -Phloroglucinol derivatives of male fern -Bitter principles of hops -Cannabinoids -Phenylchroman derivatives (Flavonoids) B2-Polycyclic compounds: -Anthracenes -Chromones -Antibiotics from acetate metabolism

13. Acetate mevalonate pathway • Isoprenoid compounds • Terpenes (mono-, sesqui-, di-, tri-, tetra-, poly-terpenes( • Cardiac glycosides • Saponin glycosides • Steroids • Vitamin D

14. Acetate-derived Natural Products Acetate formed from carbohydrate via pyruvic acid Produce large no. of imp. natural products (flavonoids, anthraquinones, macrolides, terpenes & steroids) 2 main routes originate with acetate pathway: Acylpolymalonate pathway leading to FA & polyketides Mevalonic acid pathway producing terpenes & steroids

15. Shikimic acid pathway • Aromatic biosynthesis: • Phenols • Phenolic glycosides • Phenyl-propane-derivatives • Lignins • Lignans • Aromatic amino acids

16. “Amino acid” pathway Includes all biogenetic drugs containing “N”.: -Alkaloids -Cyanogenic glycosides -Glucosinolates -Alliines -Antibiotics from amino acid metabolism -Anticancer drugs from amino acid metabolism

17. General Biosynthesis Pathway

18. Most important building blocks