The document summarizes a presentation on the chemistry of prostaglandins, leukotrienes, and thromboxanes. Prostaglandins, leukotrienes, and thromboxanes are oxygen metabolites of arachidonic acid that form a family of lipid substances with intrinsic biological activities. They are involved in processes like inflammation, platelet aggregation, and vascular homeostasis. The presentation covers their biosynthesis from arachidonic acid, sub-families, properties, and biologically important examples like prostacyclin, thromboxane A2, and leukotriene B4. It also discusses the enzymes and pathways involved in their synthesis.

1. E V A L U A T I O N S E M I N A R O N
C H E M I S T R Y O F P R O S T A G L A N D I N S ,
L E U K O T R I E N E S A N D T H R O M B O X A N E S .
PRESENTED BY
ABHIMANYU AWASTHI
I M.PHARM (PHARMACEUTICAL CHEMISTRY)
DEPT. OF PHARMACEUTICAL CHEMISTRY
PRESENTED TO
DR. PRASHANTHA KUMAR B.R
ASSOCIATE PROFESSOR.
DEPT. OF PHARMACEUTICAL CHEMISTRY

2. CONTENTS
Introduction.
Eicosanoids.
Prostaglandins.
Leukotrienes.
Thromboxane's.
Prostaglandins.
Leukotrienes.
Thromboxanes.
Sub-Families of Prostaglandins.
SAR of Prostaglandins
Sub-Family of Leukotrienes.
Sub-Family of Thromboxanes.

3. BASIC ABBERVIATIONS
LT
COX
PTGS
LOX
PGI
TXA
PG
HETE
EETs
PGES
HpETE
BLT₁
BLT₂
Leukotrienes
Cyclooxygenase
Prostaglandin Endoperoxide Synthase
Lipooxygenase
Prostacyclin / Prostaglandin I₂
Thromboxanes
Prostaglandin
HydroxyEicosatetranoic Acid
Eicosatetranoic Acid
Prostaglandin E Synthase
HydroperoxyEicosatetranoic Acid
Leukotriene B4 Receptor₁ (Coupled GPCR)
Leukotriene B4 Receptor₂ (Coupled GPCR)
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4. PROSTAGLANDINS LEUKOTRINES
Prostaglandins are lipid
autacoids derived from
arachidonic acid.
They both sustain homeostatic
functions and mediate
pathogenic mechanisms,
including the inflammatory
response.
The leukotrienes are a family
of biologically active
molecules, formed by
leukocytes, mastocytoma
cells, macrophages, and other
tissues and cells in response
to immunological and
nonimmunological stimuli.
THROMBOXANES
Thromboxane A2 (TXA2),
together with prostacyclin
(PGI2), maintain vascular
homeostasis and platelet
aggregation.
PGI2 is a vasodilator and
platelet aggregation
inhibitor, and TXA2 is a
vasoconstriction and
platelet aggregation
promoter.
PROSTAGLANDINS, THROMBOXANES AND
LEUKOTRIENES ARE OXYGEN METABOLITES OF
ARACHIDONIC ACID FORMING A FAMILY OF LIPIDIC
SUBSTANCES WITH INTRINSIC BIOLOGICAL
ACTIVITIES.

5. EICOSANOIDS
Postaglandins & their related compounds prostacyclins (PGI), thromboxanes (TXA), leukotrienes (LT) &
lipoxins are collectively known as eicosaniods & acting as a paracrine hormones thus also called as
autocoids.
Structure of prostaglandins: Prostaglandins are derivatives of 20-carbon Poly unsaturated fatty acid (PUFA)-
prostanoic acid, hence known as prostanoids.
Arachidonate - most abundant precursor – derived from dietary linoleic acid or injested as a dietary
constituent. It is esterified to the phospholipids of cell membrane or other complex lipids.
Biosynthesis of Eicosanaoids depends mainly upon the availability of Arachidonate to Eicosanoids
synthesizing enzymes notably Phospholipase A₂.
NATURE
Oxidation & cyclization of arachidonic acid to PGG2
which is then converted to PGH2 by peroxidase.
PGH2 serves as the immediate precursor for the
synthesis of a number of prostaglandins, including
prostacyclins & thromboxane.
This is known as cyclic pathway of arachidonic acid.
Arachidonic Acid

6. Biosynthesis Of Prostaglandins,
Leukotrines & Thromboxanes Cascade
All the eicosanoids are metabolized
rapidly.
Degradation occur in lung & liver.
Two enzymes, namely 15-α-hydroxy PG
dehydrogenase & 13-PG reductase.
Convert hydroxyl group at C15 to keto
group & then to C13 and C14
dihydroderivative.

8. Sub-Families of

9. PROPERTIES
This has a cyclopentane ring & two side
chains with 8 to 12 C, with carboxyl group on
one side.
Prostaglandins differ in their structure due
to substituent group & double bond on
cyclopentane ring.
Most important prostaglandins (PGF2 &
PGF2α), prostacyclins (PGI2), thromboxanes
(TXA2) & leukotrienes (LTA4).
SYNTHESIS
Arachidonic acid (5,8,11,14 - eicosatetraenoic acid) is the
precursor for most of the prostaglandins in humans.
It occurs in the endoplasmic reticulum. Release of
arachidonic acid from membrane bound phospholipids by
phospholipase A2. It occurs due to a specific stimuli by
hormones – epinephrine or bradykinin.
Cyclooxygenase – a suicide enzyme.
Prostaglandin synthesis can be partly
controlled by suicidal activity of the
enzyme cyclooxygenase.
This enzyme is capable of undergoing self-
catalysed destruction to regulate a key
step in prostaglandin and thromboxane
synthesis and are the targets of
nonsteroidal antiinflammatory drugs
(NSAIDs).
COX / PROSTAGLANDIN-
ENDOPEROXIDE SYNTHASE
Figure 1 : Fused COX Enzyme

10. SAR OF PROSTAGLANDINS
In the upper chain : Methyl Esters (misoprostol) ,sulphonamide (sulprostone) and hydroxyl group (rioprost) posses
greater activity than natural PGs.
In the cyclopentane ring : Variation in the cyclopentane ring results in a reduction in the PG activity.
Enlargement of the ring or reduction of the ring leads to inactive compounds. Replacement of the carbon atom of
cyclopentane ring by O, S, and N also leads to inactive compounds, Replacement of 9-keto group with =CH2 group gives
active (metenprost) PG.
In the lower chain : C-15 hydroxyl group is protected from metabolism by the introduction of methyl group at C-15 and
gem dimethyl group at C-16, The shifting of C-15 hydroxyl group to C-16 position increases the metabolic stability of
alkoxy, phenoxy analogues, and they are more active than natural PGs.

11. The leukotrienes are the chemical messenger that are
potent inflammatory mediators which may have a role
in inflammatory diseases such as allergic rhinitis,
inflammatory bowel disease and asthma. The clinically
important leukotrienes are LTB4 and the cysteinyl
leukotrienes (CysLTs). .
They have 3 conjugated double bonds (triene). They
have also been similarly designated A,B,C……F and given
subscripts 1,2,3,4.
Leukotrienes have Separate receptors for LTB₄(BLT₁ and
BLT₂) and for the cysteinyl LTs (LTC₄,LTD₄) have been
defined. Two subtypes, cysLT₁ and cysLT₂.
To make leukotrienes, cells need 5-lipoxygenase and a
protein co-factor, 5-lipoxygenase activating protein
(FLAP).
All LT receptors couple with Gq protein and function
through the IP₃/DAG transducer mechanism. The BLT
receptors are chemotactic and primarily expressed in
leukocytes and spleen. BLT₁ receptor has high affinity
while BLT₂ receptor has lower affinity for LTB₄.
LEUKOTRINES
trienes

12. RATE
LIMITING
STEP
LEUKOTRINES LOX BIOSYNTHESIS
CASCADE
The first steps in the
generation of
leukotrienes are
catalysed by the
calcium and ATP-
dependent enzyme 5-
lipoxygenase.
Each enzyme catalyses
the insertion of an
oxygen moiety at a
specific position in the
arachidonic acid
backbone. 5-
lipoxygenase forms 5-
HPETE, the precursor of
the leukotrienes.

13. SUB-FAMILIES OF
LEUKOTRINES
When cells are activated,
cytosolic 5-lipoxygenase is
translocated to the nuclear
membrane.
A nuclear membrane protein,
5-lipoxygenase activating
protein (FLAP), is required
before 5-lipoxygenase can
synthesise 5-HPETE from
arachidonic acid.

14. BIOLOGICAL FUNCTIONS
Prostaglandins play a role in
various reproductive functions:
It has also been proposed that
Prostaglandin A may be the
natriuretic hormone, the
circulating hormone which
controls sodium reabsorption by
the kidney.
1) conception; 2) luteolysis;
3) menstruation; 4) parturition.
Leukotrienes (LTs) are lipid
mediators that play pivotal roles
in acute and chronic inflammation
and allergic diseases.
They exert their biological effects
by binding to specific G-protein-
coupled receptors.
Each LT receptor subtype exhibits
unique functions and expression
patterns
Thromboxane activates the
GIIb/IIIa receptors on platelets
and initiates platelet aggregation.
ADP binds to the P2Y12 G-
protein-coupled receptor that, in
turn, increases the platelet
cytosolic calcium (Ca2+) level
and induces platelet activation.
PROSTAGLANDINS LEUKOTRINES THROMBOXANES

15. THROMBOXANES
Thromboxane A2 (TxA2) is in the family of lipids known as
eicosanoids, which are metabolites of arachidonic acid generated by
the sequential action of three enzymes – phospholipase A2, COX-
1/COX-2 and TxA2 Synthase (TXAS).
TxA2 was originally described as being released from platelets and is
now known to be released by a variety of other cells including
macrophages, neutrophils, and endothelial cells.
Named after its role in thrombosis, TxA2 has prothrombotic
properties, as it stimulates the activation of platelets and platelet
aggregation.
TxA2 is also a known vasoconstrictor and gets activated during times
of tissue injury and inflammation.
They are basic nucleus of chromane ring with a endoperoxide bridge.

16. SUB-FAMILY OF THROMBOXANES
THROMBOXANE A2 THROMBOXANE B2
Thromboxane A2 (TXA2) is a short-
lived, lipid mediator synthesized by
platelets from arachidonic acid and
released from the phospholipid
membrane upon platelet activation.
Its main role is in amplification of
platelet activation and recruitment of
additional platelets to the site of injury
Thromboxane B2 is an inactive
metabolite/product of
thromboxane A2. It is almost
completely cleared in the urine
Thromboxane B2 is a potent
vasoconstrictor and platelet
aggregating agent

17. DRUGS DEVELOPED FROM THESE MOLECULES
PROSTAGLANDINS LEUKOTRINES THROMBOXANES
Bimatoprost
Carboprost
(Hemabate).
Dinoprostone
(Cervidil).
Misoprostol
(Cytotec).
Latanoprost
(Xalatan).
Montelukast
Zafirlukast
Zileuton.
Clopidogrel
(Plavix)
Prasugrel (Effient)
Ticagrelor
(Brilinta)
Acetylsalicylic
acid (Aspirin)

19. William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry.
Proteopedia.org/wiki/index.php/Cyclooxygenase.
Basicmedicalkey.com/22-lipids-the-eicosanoids-prostaglandins-leukotrienes-and-thromboxanes
Carroll, R. G. (2007). Endocrine System. Elsevier's Integrated Physiology, 157-176.
O'Donnell SR. Leukotrienes - biosynthesis and mechanisms of action. Aust Prescr 1999;22:55-7.
Leukotriene receptors. In: Alexander SP, Peters JA, editors. TIPS 1998 receptor and ion channel nomenclature
supplement. 9th ed. Amsterdam: Elsevier; 1998. pg. 50-1.
Thromboxane, In Wikipedia. https://en.wikipedia.org/wiki/Thromboxane
.
REFERENCES

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