MEDCHEM E CHEM BIO LECTURE 3 Active ingredients from plants

• Historically, plants have played an important role in medicine
• For early peoples, plants were intricately connected to diet and healing
• Animals seem to have an instinct for medicinal plants
• Phytochemicals


  Secondary metabolites such as tannins and alkaloids that often have antiviral, antibacterial, antifungal and antihelminthic (vermifuges) properties
• Phytochemicals


  • Nicotine
  • Bufotenin
  • Tannic acid
• Tannins


  Polyphenolic biomolecules
• Alkaloids


  Low molecular weight nitrogen-containing compounds
• Alkaloids


  • Cocaine
  • Atropine
• As late as the 1970s, 25% of drugs in use in North America and Europe had some plant extract or plant derivative
• Now that number has decreased due to the onset of so many synthetics, but plants are still extremely valuable sources for some of our most powerful anticancer substances and relaxants
• Taxol


  A drug that targets tubulin (a protein that is a major component of the eukaryotic cytoskeleton), causing defects in cell division
• Taxol is currently used to treat various types of cancer such as ovarian, lung and breast cancer
• Problems related to Taxol production


  • It accumulates in the bark at a very low concentration and with a prohibitively high cost of extraction
  • The extraction implies the destruction of the yew trees
  • The process of total chemical synthesis is not commercially viable
• Semisynthetic production of Taxol


  1. Conversion of precursors (i.e.10-deacethylbaccatin III) found in Taxus needles

  2. Cost and difficulty of the extraction process of the precursors are also high
• Taxol production from an abundant analogue


  1. One-pot reaction system contained a specific 7-β-xlyosidase, the improved 10-β-acetyltransferase, the substrate 7-β-xylosyl-10-deacetyltaxol (XDT) and the acetyl group donor acetyl-CoA

  2. The catalytic efficiency of this enzyme was improved by mutagenesis

  
• Taxol from nursery cultivated Taxus

  • Twigs and/or needles are harvested for the extraction of Taxol or its precursor 10-deacetylbaccatin III to keep the plant alive
  • This method avoids the destruction of the wild Taxus resource and permits its sustainable utilization
  • Plant biotechnology can provide an alternative system for taxol production
• Elicitors


  Chemical substances that are involved in plant stress response and can increase plant secondary metabolism
• Atropine


  Used in ophthalmology as a cycloplegic, to temporarily paralyze the ciliary muscle of the eye; and as a mydriatic, to dilate the pupils
• Atropine


  An antagonist of acetylcholine, the only neurotransmitter of the parasympathetic nervous system
• Atropine


  Lowers the "rest and digest" activity of all muscles and glands regulated by the parasympathetic nervous system, causing for example an acceleration of the heart-beat
• Valerian


  Used as a medicinal herb as a sedative, anti-convulsant, migraine treatment and pain reliever
• Mechanism of action of valerian


  Not completely clarified, may be due to the variety of molecules found in the plant. It includes alkaloids, GABA, and valerenic acid
• Long term ingestion of the dried root of valerian in large, chronic doses can result in depression
• GABA receptors

  Channel receptors that allow negatively charged chloride ions to enter the neuron, thus reducing its excitability and inhibiting the firing of a new action potential
• Valerenic acid


  Binds to GABA receptor at a different position than GABA, helping to reduce the transmission of the neural message
• The terms medicines, drugs, and poisons can all apply to a single plant chemical, which at one concentration is curative, at another a potentially addictive substance, and at a higher concentration a harmful or lethal poison
• Unlike modern drugs, the active plant chemical is NOT PURE and its potency could be either enhanced or reduced by the presence of other metabolites produced by the plant
• The possibility that the plant may be growing on polluted soil adds extra risks: heavy metals can prove to be very toxic to human body and some pesticides have been linked to neurological disorders and cancer
• The first antiseptics were plants and spices
• The first very effective antipyretics and anti-inflammatory agents were plants such as willow (Salix) and quinine (Cinchona)
• Cocaine and then atropine were the earliest local anaesthetics for delicate eye surgery
• Taxol is a secondary metabolite
• To increase the natural synthesis of taxol, chemical substances called elicitors are added to plant cell cultures
• Atropa belladonna (deadly nightshade) is one of the most toxic plants
• Atropine is an enantiomeric mixture of (+)- and (-)-hyoscyamine