NATPROD

• Terpenoids


  Also known as isoprenoids, form a large and structurally diverse family of natural products derived from C5 isoprene units joined in a head-to-tail fashion
• Typical terpenoid structures


  • Hemiterpenes (C5)
  • Monoterpenes (C10)
  • Sesquiterpenes (C15)
  • Diterpenes (C20)
  • Sesterterpenes (C25)
  • Triterpenes (C30)
  • Tetraterpenes (C40)
• Isoprene was known as a decomposition product, and had been suggested as the fundamental building block for these compounds, also referred to as "isoprenoids"
• Isoprene is produced naturally but is not involved in the formation of isoprenoids
• Isoprene


  A volatile compound which is released in huge amounts by many species of plants (e.g. woody trees such as oaks, willows, poplars, and spruce)
• Biochemically active isoprene units


  Dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP)
• Relatively few of the natural terpenoids conform exactly to the simple concept of a linear head-to-tail combination of isoprene units
• Geraniol (C10), Farnesol (C15), Geranylgeraniol (C20), Squalene (C30) and phytoene (C40), although formed entirely of isoprene units, display a tail-to-tail linkage at the center of the molecules
• Most terpenoids are modified further by cyclization reactions (such as menthol, bisabolene, and taxadiene)
• Many other natural products contain terpenoid elements such as the acetate and shikimate pathways
• Meroterpenoids


  Secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate
• Pathways for biochemical isoprene units


  • Mevalonic acid (MVA)
  • Methylerythritol phosphate (MEP) or (2-C-methyl-d-erythritol 4-phosphate)
• Mevalonic acid (MVA)


  Precursor in the biosynthetic pathway known as the mevalonate pathway that produces terpenes (in plants) and steroids (in animals)
• Methylerythritol phosphate (MEP)


  Also referred to as the mevalonate-independent pathway or the deoxyxylulose phosphate pathway, is an alternative pathway to IPP and DMAPP, and this pathway is probably more widely utilized in nature than is the mevalonate pathway
• Hemiterpenes


  The simplest terpenes, consisting of a single C5 isoprene unit. Relatively few true hemiterpenes are produced in nature, but IPP and DMAPP are reactive hemiterpene intermediates in the pathways leading to more complex terpenoid structures
• Monoterpenes


  Class of terpenes that consists of two isoprene units (C10). Comprising hydrocarbons, they are the largest class of plant secondary metabolites. Found in the essential oils extracted from many plants, including fruits, vegetables, spices and herbs
• Monoterpene biosynthesis


  1. Enzyme-catalysed combination of DMAPP and IPP yields Geranyl Diphosphate (GPP)

  2. Linalyl PP and Neryl PP are isomers of GPP, formed from GPP by ionization to the allylic cation, allowing a change in attachment of the diphosphate group or change in stereochemistry at the double bond
• Cyclization of monoterpenes


  Precursors like Neryl PP or Linalyl PP have favorable stereochemistry, making them suitable for forming monocyclic menthane systems. The process involves the formation of a carbocation, termed Menthyl or α-Terpinyl, which has the menthane skeleton
• Most monoterpenes are optically active, with enantiomeric forms isolated from different sources or even the same organism
• Irregular monoterpenes


  Natural compounds derived from two isoprene units, but do not follow the typical head-to-tail coupling mechanism. Found mainly in the Compositae/Asteraceae plant family, examples include chrysanthemic acid and pyrethric acid
• Pyrethrins

  Derived from pyrethrum flowers (Chrysanthemum cinerariaefolium), used in insect sprays for household and post-harvest insecticides. Biodegradable, non-toxic to mammals but toxic to fish and amphibians, with rapid action on insect nervous systems
• Iridoids


  Monoterpenoid compounds containing an iridane skeleton, typically featuring a cyclopentane ring fused to a six-membered oxygen heterocycle. Derived from geraniol through a unique folding mechanism
• Iridoids


  • Loganin, nepetalactone, ligstroside, oleuropin, harpagide, harpagoside
• Devil's claw


  Perennial tuberous plant with long creeping stems found in southern Africa, commonly used as an anti-inflammatory and antirheumatic agent
• Sesquiterpenes


  Derived from three C5 units, synthesized primarily via the mevalonate pathway, unlike monoterpenes which are often synthesized from the MEP pathway. Formation involves addition of a C5 IPP unit to GPP, resulting in the precursor farnesyl diphosphate (FPP)
• Sesquiterpenes


  • γ-bisabolene, α-bisabolol, zingiberene, β-sesquiphellandrene
• Feverfew


  Perennial aromatic herb of the Compositae/Asteraceae family, effective prophylactic treatment for migraine in about 70% of sufferers, reducing frequency, severity, and associated vomiting
• Diterpenes


  Originate from GGPP, synthesized through the addition of an Isopentenyl Pyrophosphate (IPP) molecule to Farnesyl Pyrophosphate (FPP). GGPP undergoes cyclization mediated by carbocation formation, yielding diverse diterpenoid structures
• Phytol


  A reduced form of geranylgeraniol, which forms the lipophilic side-chain of the chlorophylls, e.g. chlorophyll a
• Taxol (paclitaxel)


  From Pacific yew, exhibits significant anticancer properties and is a widely used chemotherapy agent
• Phorbol


  Present in Euphorbia plants, phorbol esters activate protein kinase C, contributing to tumorigenesis. 12-O-myristoylphorbol 13-acetate is one of the most potent tumour promoters known
• Copalyl PP synthesis


  Protonation of GGPP leads to (-)-copalyl PP. Alternative folding leads to (+)-copalyl PP (labdadienyl PP). Kaurene synthase catalyzes cyclizations, leading to ent-kaurene
• Stevioside


  An intensely sweet compound produced in Stevia rebaudiana (Compositae/Asteraceae) via oxidation, hydroxylation, and glucosylation of the ent-kaurene precursor
• Abietic acid synthesis


  Tricyclic system built similarly to ent-kaurene pathway, generating enantiomeric compounds. Methyl migration occurs, leading to the formation of the diene abietadiene
• Ginkgolides


  Highly oxidized diterpene trilactones responsible for Ginkgo biloba's medicinal properties, formed through extensive modification of the copalyl diterpene skeleton
• Forskolin


  Isolated from Coleus forskohlii (Plectranthus barbatus), used in traditional Indian medicine. Lowers blood pressure, cardioprotective, stimulates adenylate cyclase activity
• Salvinorin A


  A neoclerodane diterpene from Salvia divinorum, exhibits hallucinogenic properties and acts as a selective kappa-opioid receptor agonist
• Sesterterpenes


  Predominantly found in fungi and marine organisms, derived from cyclization of geranylfarnesyl PP (GFPP)
• Triterpenes


  Synthesized differently from typical terpenes, formed by joining two molecules of FPP to yield squalene. Cyclization of squalene occurs via the intermediate 2,3-oxidosqualene, catalyzed by squalene epoxidase
• Triterpene acids


  Frequently derived from triterpene hydrocarbons through oxidative modifications, examples include oleanolic acid and betulinic acid