Biogenesis of natural acetylenes• Biogenetic precursor of the acetylenic substances is oleic acid

H3C-(CH2)7-CH=CH-(CH2)7-COOH Oleic acid [18:1(9c)]

↓-2H H3C-(CH2)4-CH=CH-CH2 CH=CH-(CH2)7-COOH Linoleic acid [18:2 ] → Linolenic acid [18:3]

↓-2H H3C-(CH2)4-CΞC-CH2 CH=CH-(CH2)7-COOH Crepenynic acid (12-13 dehydrolinoleic acid)

↓-2H H3C-CH2- CH2- CH2- CH= CH -CΞC-CH2 CH=CH-(CH2)7-COOH Dehydrocrepenynic acid

↓-2H ↓-2H ↓-2H

Further modifications: Shortening of the side chain, oxidation, reduction, decarboxylation, ester formation,

addition of “O” or “S”, elimination of the methyl group, hydrogenation,…….

Classification of the acetylenic substances

Depending on the functional group in addition to the presence of triple bond:

• Straight chain hydrocarbons• Fatty acids• Alcohols• Ketones• Esters• Aromatics• Furans• Thiophens• Acetylenes with spiroketals

Echinacea spp. [coneflowers] Fam. Asteraceae

• North American origin;• Medicinally used three species are: E. angustifolia

E. purpurea

E. pallida

Constituents and uses

• High MW CH/PS [echinacin, inulin,…• Phenolic compounds: Caffeic acid derivatives; some as glycosides• Pyrrolizidine alkaloids• Terpenoids: sesquiterpene lactones• Polyynes, some as amides

H3C-CO-(CH2)5- CH=CH- CH2 – CΞC- CΞCH

HCΞC-CΞC- C H2- C H2- CH=CH= CH- CO-NH-CH2-CH- (CH3)2

• Immunostimulating effect; prevention and treatment of common cold, flu, respiratory disorders,…

• Antibacterial activity against: E.coli, S. aureus, P. aeruginosa• Commercially available: Echimmune Tablets, syrup

Toxic polyalkyne containing plants of Apiaceae

1-Cicuta virosa European water hemlock• All parts of the plant are toxic; roots very rich in acetylenic

compounds• Major compound is cicutoxin, a reversible potassium channel

blocker; other compounds: cicutol, cicudiol,..• Signs of toxicity: Profuse salivation, abdominal pain,

prolonged vomiting and violent convulsions

HO- C H2- (CH2)2 - (CΞC)2 - (CH=CH)3- CHOH- (CH2)2 -CH3

Cicutoxin

2-Oenanthus crocata Water dropwort; oenanthotoxin3-Aethusa cynapium Dog parsley; aethusin

Acetylenes from microorganism

• Mycomycine isolated from Nocardia acidophilus

• Very thermolabile• Complete retention of activity by storage at

temp. -40o or lower• Soluble in alcohol, ether, DCM• Forms water-soluble Na-salts

Acylpolymalonate Pathway• Complex reaction catalysed by enzymes containing co-

enzyme A• Acylcoenzyme A, CH3CO-SCoA, formed on oxidative

degradation of sugar is the basic unit for the biosynthesis of many comps. e.g. fatty acids

(RCO-(CH2CO)nOH • Aldol / Claisen condensation, alkylation, reduction,

dehydration & oxidation produce polyketide derivatives

RCO-SCoA + n COOH-CH2CO-SCoA R COOHn-1

O O

Acyl CoA Malonyl CoA Polyketides

Condensation of polyketomethylenic acid products

• Condensation of acetate units gives long chains or ring structures producing poly-ketomethylenic acid condensed further to aromatic substances

R COOH

O O O

R

O

COOH

OHHO

R

HO OH

OH

R

OH

O

O

Aromatic Polyketides

• Condensation of acetate-derived C2 units produce polyketo-acid (poly-keto-methylene-chain)

• Following dehydration, a chain of polyketo-acid contains 4 or more acetate units, cyclize in 5 different ways producing benzene or pyrone rings

• Important ones are: Orsellinic acid type and phloroacetophenone type monocyclic compounds, which in turn are further modified

Formation of monocyclic aromatic compounds

Formation of orsellinic acid

“Depsides” are esters formed between the carboxyl group of one and a phenolic OH group of another OH-benzoic acid and “Depsidones” are esters and cyclic ethers formed of di- or tri-OH-benzoic acids

+

Constituents of some lichens:Cetraria islandica (Fam. Parmeliaceae) Iceland moos

• Formation of depsides and depsidones using orsellinic acid :

O

OH

CH3

COOH

OHO

CH3

OH

OCH3

COOH

OHO

CH3

OH

O

DepsideLecanoric acid

Depsidone

Usnic acid

C-methylation and condensation

Chemistry and metabolism of the cannabinoidsCannabis sativa (Cannabidaceae)

Cannabis, Indian hemp, marihuana, hashish, charas, dagga,..Flowering tops (glandular hair) of the pistillate (female) plants from which no resin has

been removed3 genetic types: hemp (=fiber type),the drug and intermediate (less common) typesDrug type is rich in Δ9or Δ1THCActivities: from inactive to hallucinogenic, psychotropic Transformation may occur also during smokingEuphoric narcotic: feeling of wellbeing, exaltation, inner joy may be alternate with

panic, depression, fear of death; ideas are disrupted, hallucinations; time/space/sound

Effective dose on smoking 200-250μg/kg , ingestion 300-480 μ; Δ1THC is lipophilic, is rapidly absorbed and binds to plasma and cellular proteins, peak plasma conc. after inhalation 7-8 min.; half life: 8 days; metabolites accumulate in the brain (head and neck carcinoma!), CNS (altering the turnover rate of neurotransmitters; chromosomal damage; mimic hormones (impotence, temporary sterility), low birth weight of the off-springs

Personality changes…….deteriaration of “good mental health”

Metabolism and possible uses of the cannabinoids

Metabolized in the liver to hydroxylated compounds (11-OH derivatives)Possible medicinal uses: treatment of glaucoma bronchodilator hypotensive antiemetic [Marinol, FDA]; syn. Nabilone antiepileptic/anticonvulsant antibacterial/antiviral analgesicLimitations: euphoria/depression most effective route : inhalation tolerance

Nomenclature of the cannabinoids

Cannabinoids