Basic terpene (isoprenoid) skeletons & precursors – Resource: Chapter 5, Dewick

Formation of isoprene units by the mevalonate pathway

An alternative route to isoprenes: The mevalonate-independent pathway utilizes deoxyxylulose phosphate as its carbon source

Biosynthesis of monoterpenes begins with isomerization of IPP to DMAPP

IPP adds to a second dimethylallyl cation, forming a 10 C chain

Loss of H+ produces GPP

further isomerization andformation of monoterpenes

Some common open-chain monoterpene skeletons

Cilantro & coriander(Coriandrum sativum)

Primarily monoterpenes: linalool, -terpinene, -pinene, borneol & camphor, cineole, cymene

Cyclization and rearrangements produce a variety of monoterpene

skeletons

OPP

Many monoterpene skeletons from one C10

precursor

Once the skeleton forms,enzymes and cofactors facilitatecation formation, enabling • rearrangements• cyclizations• isomerizations• hydrations to addOH groups• oxidation to ketoor acid groups

loss of OPP- givesallylic cation

cycliz.

deprot. hydration

Stereochemistry affects properties: Limonene exists as (+)-R or (-)-S stereoisomers, which are found as minor constituents of many essential oils of spices, fruitsThese are precursors to the (+)-S and (-)-R carvones

(+)-R has an orange smellwhile (-)-S smells like lemonBoth are minor constituents inpeppermint (Mentha x piperita)

allylic hydroxylationoxidation

(+)-S-carvone ismajor constituent of oil of caraway(Carum carvi)

(-)-R-carvone ismajor constituent of spearmint oilMentha spicata

Putting the “nip” in catnip: iridoid monoterpenes

oxidation

Compound in cranberry fruit & leaveshas oxidized iridoid skeleton esterified with a hydroxycinnamoyl unit + a sugar

oxidations

Catnip (Nepeta cataria)Labitae = Mint family

Active ingredient: nepetalactone affects cats through vomeronasal organ(cats vary in susceptibility to catnip)

An isoprene unit (prenyl group) may attach to a larger skeleton forming a “prenylated” structure,by the action of prenyl transferase enzymes – increases lipid-solubility of the molecule

Xanthohumol (hops) has a chalconeskeleton prenylated on the A ring

Hyperforin (St. John’s Wort) has a multi-prenylated central ring derived from phloroglucinol

Attachment of larger isoprenoid groups is also common, as found in Vitamins E & K

Bafilomycin (Streptomyces griseus)antibacterial, antifungal

H

OH H

OH

O

O

O

O

AcO

Epicochlioquinone from fungus Stachbotrys bisbyi

Terpene or polyketide?

Biosynthesis of farnesyl pyrophosphate stereoisomers, which are the precursors to C15 sesquiterpene skeletons

further isomerization andformation of monoterpenes

…or addition of another isoprene, leading to sesquiterpenes throughfolding of farnesyl cation

(E,E)-FPP formsgermacryl cationhumulyl,guiaylcaryophyllyleudesmyl

isomerizes

(E,Z)-FPP formsbisabolyl cationcis-germacryl carotylcadinyl

Sesquiterpenes: farnesyl cation can isomerize, fold and cyclize in several differentpatterns leading to a variety of skeletons

Caryophyllene is in cloves (Syzigium aromaticum) & black pepper (Piper nigrum)

see chamomile

from Artemesia

ginger, chamomile

sandalwood

Ginger (Zingiber officinale): flavor comes from sesquiterpenes differing only in pattern ofunsaturation: zingiberene, -bisabolene, -sesquiphellandrene, curcumene Phenylpropanoids – gingerols – contribute to aroma

German chamomile (Matricaria) - Compositae/Asteraceae or daisy family--dried aerial parts used in chamomile tea, thought to promote calming effect--antibacterial/antifungal/wound healing(bisabolenes, bisabolol)--antiinflammatory, taken to control gastriculcers (-bisabolol & chamazulene)

FPP

oxidationsdehydrationsloss of CO2

chamazulene(anti-inflammatory)

Valerian (Valeriana officianalis)Valerian is prepared from the carefully dried roots of a perennial herb found throughout Europe. Valerian preparations are widely used as herbal tranquillizers to relieve nervous tension, anxiety, and insomnia. Valerian was used during WW1 to treat shell-shock. The drug does possess mild sedative and tranquillizing properties, but for maximum activity the roots need to be freshly harvested and carefully dried. The major active principles are believed to be epoxyiridoid esters called valepotriates, the major one being valtrate. Many researchers believe the sedative activity of valerian cannot be due to the valepotriates, which are very unstable and not water soluble. Some of the sedative activity is said to arise from sesquiterpene derivatives such as valerenic acid and valeranone which have been shown to be physiologically active. (Dewick, Ch. 4)

Feverfew(Tanacetum parthenium)

used to treat migraines; contains sesquiterpene parthenolide

Parthenolide: active principle in Feverfew (Tanacetum parthenium)--can reduce incidence and severity of migraine headaches, inhibitshistamine release, platelet aggregation--dried leaves contain up to 1% parthenolide by weight--thought to work by alkylation of thiols, irreversibly binding to Cys residues

Artemisia annua (Qinghao)Active compounds against malaria: artemesinins, sesquiterpene-derived

skeleton with peroxy functional group

The quinoline alkaloids were used against malaria for many years, but resistant strains have emerged

Artemesins• Used to treat fevers, especially malaria; active principle is artemesinin, which also kills the protozoan (Plasmodium falciparum) carried by malarial mosquitoes.• Active site: peroxide linkage –complexes with haemin, iron-containing soluble derivative of hemoglobin produced through proteolytic digestion by the parasite• Attempts by parasitic enzymes to detox the haemin result in cleavage of the peroxide, generating ROS that kill the parasite. •Synthetic derivatives retain this linkage

Diterpenes can be nasty…Phorbols are tumor promotors—activate protein kinase Cand cell proliferation. Often used in bioactivity studies to cause inflammation

From sap of Euphorbia species

Diterpenes: C20 derived from GGPP precursor

or nice…taxadiene forms basis of taxol,used in breast, ovarian cancer treatment

Labdane diterpenes: chair-controlled folding resembles that of higher terpenoids

Terpenes…why the diversity?--Enzymes controlling folding vary among species, genera, families--Alkyl migrations and oxidation patterns vary--Environmental factors also may influence rxn pathways

Diterpenes: Folding is key!

Ginkgo biloba —improvement of cerebrovascular circulation, cognitive memoryActive constituents: flavonoids and diterpene lactones derived from labdane skeletonGinkgolides inhibit platelet-activating factor (PAF) involved in inflammation, allergic rxn***More about Ginkgo in a separate slideshow!