Medical ChemistryLecture 12 2007 (J.S.)

Eicosanoids

IsoprenoidsTerpenes and steroids

Lipids II

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Eicosanoidsare a family of polyunsaturated C20 fatty acid derivatives,

(Greek eikosi – “twenty”),

which act as local hormones and have a wide range of biological functions.

All are derived from essential polyunsaturated fatty acids

– arachidonic acid (eicosatetraenoic, abbr. ETE)20:4 (5,8,11,14) from the n-6 series, and

– eicosapentaenoic acid (abbr. EPE) 20:5 (5,8,11,14,17) from the n-3 series.

COO–

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There are two major types of eicosanoids:

– cyclic prostanoids, which can be held as derivatives of an unnatural 20-carbon fatty acid containing a 5-carbon (cyclopentane) ring called prostanoic acid:

prostaglandins, prostacyclins, and related thromboxanes;

– acyclic leukotrienes and lipoxins

COO–

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Cyclic eicosanoids - prostanoids:

Prostaglandins

Although prostaglandins are synthesized in nearly all cell types, the name denotes the tissue from which they were isolated for the first time (the prostate gland)..

The major classes differing in the structure of the ring (as well as in its desaturation) are designated by letters (PGH, PGE, PGF, PGA, PGB),the numerical subscript denotes the number of carbon-carbon double bonds outside the ring of all eicosanoids, i.e. of both prostanoids and leukotrienes.

Prostanoids with the subscript 2 (two double bonds in the side chains) are members of the second (or diene) series that is synthesized from arachidonate 20:4 (n-6), the other two double bonds of the precursor are lost in forming a ring.Those with the subscript 3 - the third (or triene) series are synthesized from eicosapentaenoic acid 20:5 (n-3).

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Inactivated "secondary" prostaglandins PGA and PGB are produced by dehydration (A – dehydration catalysed by an acid, B – dehydration catalysed by a base)

PGE PGF

PGH (an endoperoxide) in the intermediate in biosynthesis of all prostanoids.

The most significant "primary" prostaglandins are PGE and PGF exhibiting very high biological activity. (E – ether extractable, less polar than F – extractable into phosphate buffer)

PGA PGB

PGH

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Prostaglandin E2 PGE2

Prostaglandin F2α PGF2α

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(abbreviation PGI) are the derivatives of PGH, in which C-6 of the short side chain closes the five-membered heterocycle fused with the cyclopentane ring:

Prostacyclins

Prostacyclin PGI2

6

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Thromboxanes

originate through transformation of the common precursor of all prostanoids – endoperoxide PGH. Instead of cyclopentane ring, those compounds contain a six-membered heterocycle oxane.The name denotes that they are specific products of thrombocytes (blood platelets).

Thromboxane TXA2

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Acyclic eicosanoids:

LeukotrienesThe characteristic feature of these acyclic 20-carbon compounds produced primarily in leukocytes and mast cells is the presence ofthree conjugated double bonds (trienes), the position of which may be different and the configuration either trans or cis.

The classes are designated by letters (LTA, LTB – LTE), the subscript denotes the total number of double bonds.

COO–O

LTA4

LTB4

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Peptidoleukotrienes (leukotrienes class C, D, E) – carbon atom 6 binds the sulfur atom

of glutathione (-GluCys Gly) in the class LTC,of cysteinyl-glycine in the class LTD, andof only cysteine in the class LTE.

Leukotrienes are the most effective eicosanoids, e.g. their vasodilating effectis about 5 000 times more intensive than that of the same amount of histamine.

OH

S

CysGly LTD4

Slow-reacting substanceof anaphylaxis (SRS-A)

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are hydroxylated derivatives of arachidonic acid (ETE) and eicosapentaenoic acid (EPE)

produced by combined effect of lipoxygenases catalysing hydroxylation of carbons 5, 12, or 15.

The term lipoxin is derived from "lipoxygenase interaction products“.

Lipoxins

LXA4

5-Hydroxytetraenoic acid (5-HETE)

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Examples Structural group Synthesized inThe most remarkable

effect:

PGE2 prostaglandin E nearly all cell typesinflammatory reaction,

vasodilatation

PGF2α prostaglandin F nearly all cell types vasoconstriction

PGI2 prostacyclinendothelial cells,

smooth muscle cellsof blood vessels

vasodilatation,inhibition of platelet

aggregation

TXA2 thromboxane blood plateletsplatelet aggregation,

vasoconstriction

LTD4 leukotriene leukocytes, mast cellsbronchoconstriction,

vasoconstriction

LXA4 lipoxin various cell typesbronchoconstriction,

vasodilatations

Eicosanoids

Isoprenoids

Isoprenoidsare a family of natural products whose structures are composed of five-carbon isoprene units. The unit consists of a four-carbon chainwith a one-carbon branch at carbon 2.

Isoprene unit C5

regular tail-to-head attachment(the head is usually directed to thefree end of a molecule, the tail tothe inner part)

irregular attachment tail-to-tail(tail-to-tail and head-to-head linkagesare less frequent)

"head""tail"

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Isoprene2-methylbuta-1,3-diene

Isoprene unit of polymers

Terpenesare isoprenoids mainly of plant origin that can be isolated from essential oils of plants. Some terpenes play also an important role in metabolism of animals.Numerous terpenes contain various functional group (mostly alcoholic or phenolic hydroxyl, carbonyl), may be saturated or unsaturated, acyclic or cyclic.

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According to the number of isoprene units comprising themolecules, terpenes are classified as

monoterpenes with two isoprene units, C10,

sesquiterpenes C15 – three isoprene units,

diterpenes C20 – four isoprene units,

triterpenes C30 – six units,

tetraterpenes C40 – eight units,

and polyterpenes, which comprise more isoprene units.

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Isopentenyl diphosphate Dimethylallyl diphosphate

All isoprenoids are synthesized from acetyl-CoA by way of an importantintermediate isopentenyl diphosphate and its isomer dimethylallyl diphosphate.

Dimethylallyl diphosphate and isopentenyl diphosphate are basal units forpolymerization. They join together to give a monoterpene geranyl diphosphate:

A sesquiterpene farnesyl diphosphate originates by joining the third basal unit:

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occurs in oil of geranium but also constitutes about 50 % of rose oil extracted from rose petals.

Geraniol

Examples of monoterpenes (C10) with open chain

Citral (aldehyde)

Volatile monoterpenes provide plants and flowers with much of theirfragrance. Some of them are constituents of perfumes and flavours.

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Menthol(peppermint oil)

Thymol

-Pinene(turpintine)

2-Bornanone(camphora)

Examples of cyclic monoterpenes (C10)that may be taken as derivatives of menthane, a hydrocarbon:

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Phytol is a diterpene (C20) alcohol, three of its four isoprene units are fully

hydrogenated (saturated):

Phytyl occurs as a side-chain attached to 1,4-naphtoquinone in phylloquinone (vitamin K1):

Squalene is a triterpene (C30), a symmetrical hydrocarbon - the intermediate in the biosynthesis of cholesterol and other steroids:

extended conformation folded conformer

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Carotenoidsare tetraterpenes (C40) – natural pigments, present in leaves of all green

plants. Unlike other terpenes their molecules comprise an extensivesystem of conjugated double bonds.

-Ionone – a natural ketone (C13) is a cause of a fragrantscent of the violet.

-ionone ring

Oxidative splitting in the middle of -carotene molecule produces retinol (vitamin A).

Other types of carotenes differ from -carotene in different structures of their ends.

Oxygenous derivatives of carotenes are named xanthophylls.

β-Caroteneis the most important carotene that contains two β-ionone rings at both ends of the molecule (this hydrocarbon is symmetrical).

Lycopene is a red aliphatic hydrocarbon (without any ring), e.g., in tomato

and red pepper.

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Retinol (vitamin A)originates by oxidative splitting of carotenes which contain a -ionone ring.

In the body, retinol gives retinalby reversible oxidation, or it isoxidized irreversibly to retinoate(retinoic acid).

all-trans-retinal

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11-cis-retinal

Retinalis the photosensitive component of visual purple – rhodopsin.After absorption of photon(s), all-trans-retinal undergoes isomerization to11-cis-retinal, which initiates the cascade of reactions that result invisual percept.

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In the biosynthesis of plasma type glycoproteins, dolichol diphosphate is anchoredin the membrane of endoplasmic reticulum and glycosyls are added stepwise to itsdiphosphate group. After the oligosaccharide is built up, it is transferred to theprotein and linked through N-glycosidic bond to the side chain of asparaginyl residue).

Dolicholis a long-chain polyprenol that contains about 20 isoprene units (about 100 carbonatoms). Double bonds in cis-configuration, the last isoprene unit (α-unit) is saturated.

Dolichol diphosphate (Dol-P-P)

n = 10nH

Ubiquinone(coenzyme Q)

Steroids

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Steroids The biological precursor of steroids is a 30-carbon linear branched

hydrocarbon (triterpene) squalene.

From squalene, steroidal alcohols are synthesized through a complex process that, in its final stages, involves the loss of several carbon atoms.

The typical steroidal alcohol in animals is cholesterol, from which allother steroids of biological importance originate.

Cholesterol has 27 carbon atoms, most of its derivatives even less.Steroids are therefore not strictlyterpenes, but they are related toterpenes in the sense that they arebiosynthesized by a similar route.

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Cyclopentanoperhydrophenanthrene(also the name sterane is used)

Phenanthrene(fused aromatic benzene rings)

Perhydrophenanthrene(fused cyclohexane rings)

There are eight stereoisomers of sterane which differ in cis and trans configurations of A/B, B/C, and C/D ring fusions.

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The rings in steroids are denoted by the letters A, B, C, and D:

Carbon atoms in steroids are numbered in a specific manner:

1102

34

5

9

67

8

11

1514

16

171312

A B

C D

Carbons outside the rings:

17

2223

27

2625

2120

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18

24

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The two fused cyclohexane rings in chair conformations:

trans fusion cis fusion

A trans fusion yields a nearly planar structure,whereas a cis fusion gives a buckled structure.

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5-Gonane

From the eight stereoisomers of sterane, two are named gonanes:The fusion of the steroid rings B ands C as well as C and D is trans, the fusion of the rings A and B is either trans (so called 5α-)or cis (5β-configuration). In nearly all natural steroids the atoms attached to C-10, C-8, C-13 lie above the plane containing the four rings – they are β oriented.The atoms (substituents) that are below the plane are α oriented.

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5-Gonane

The cis fusion of the rings A and B (characteristic for the bile acids,with the buckled structure of the steroid skeleton) occurs rarely.

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Substituents:

C17 Gonane (none)

C18 Estrane 13-methyl

C19 Androstane 10,13-dimethyl

C21 Pregnane 10,13-dimethyl-17β-ethyl

C24 Cholane 10,13-dimethyl-17β-(2-pentyl)

C27 Cholestane 10,13-dimethyl-17β-[2-(6-methyl)heptyl]

(C28 Ergostane C29 Stigmastane)

The nomenclature of steroid hydrocarbons

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5α-Estrane

C18

Estra-1,3,5(10)-triene(ring A is aromatic)

13β-methyl-5α-gonane C-18

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10,13-Dimethyl-5α-gonane

5α-AndrostaneC19

C-19

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17β-Ethyl-5α-androstane

5α-PregnaneC21

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17β-(2-pentyl)-5β-androstane

5β-CholaneC24

Five-carbon side chain at C-17

C-24

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5α-CholestaneC27

Eight-carbon branched side chain at C-17

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Ergostane C28 The 3β-hydroxyderivative is a phytosterol from which in plants

ercalciol (ergocalciferol, vitamin D2) is synthesized.

Stigmastane C29

CH3

CH2

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C27

C24

C21

C19

C18

Cholesterol is the precursor for other important steroids:

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CholesterolCholest-5-ene-3β-ol

C27

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Calciol (cholecalciferol, vitamin D3) is synthesizedfrom 7-dehydrocholesterol by photolysis that is a cause of opening of the ring B:

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Bile acids are various hydroxy derivatives of 5β-cholan-24-oic acid

C24

Cholic acid3α,7α,12α-Trihydroxy-5β-cholan-24-oic acid

Example:

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Progesterone is a progestin (gestagen): it prepares the lining of the uterus for implantationof an ovum and is also essential for the maintenanceof pregnancy.

C21

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Corticoids are hormones produced in theadrenal cortex.

Glucocorticoids (such as cortisol) promote gluconeogenesis and the formation of glycogen, enhance the degradation of proteins and fat, and inhibit the inflammatory response. They enable animals to respond to stress.

Mineralocorticoids (primarily aldosterone) act on the kidney to increase the reabsorption of Na+ and the excretion of K+, which leads to an increase in blood volume and blood pressure.

C21

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Mineralocorticoids

Corticosterone11β,21-Dihydroxypregn-4-ene-3,20-dione

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Aldosterone

(hemiacetal form)

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Cortisol, the major glucocorticoid, is synthesized from progesterone by hydroxylations at C-17, C-21, and C-11.

Cortisol (hydrocortisone)

11β,17α,21-Trihydroxypregn-4-ene-3,20-dione

Glucocorticoid

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Testosterone17β-Hydroxyandrost-4-ene-3-one

C19Androgens are responsible for the development of male secondary sex characteristics.

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EstradiolEstra-1,3,5(10)-triene-3,17β-diol

C18Estrogens are required for the development offemale secondary sex characteristics and, alongwith progesterone, also participate in the ovariancycle.