EVALUATION SEMINAR ON

CHEMISTRY OF PROSTAGLANDINS,
LEUKOTRIENES AND THROMBOXANES.

PRESENTED TO PRESENTED BY
DR. PRASHANTHA KUMAR B.R ABHIMANYU AWASTHI
ASSOCIATE PROFESSOR. I M.PHARM (PHARMACEUTICAL CHEMISTRY)
DEPT. OF PHARMACEUTICAL CHEMISTRY DEPT. OF PHARMACEUTICAL CHEMISTRY
CONTENTS

Introduction.
Eicosanoids.

Prostaglandins.

Leukotrienes.

Thromboxanes.

Prostaglandins.

Sub-Families of Prostaglandins.

SAR of Prostaglandins

Leukotrienes.

Sub-Family of Leukotrienes.

Thromboxane's.

Sub-Family of Thromboxanes.
BASIC ABBERVIATIONS

LT - Leukotrienes
COX - Cyclooxygenase
PTGS - Prostaglandin Endoperoxide Synthase
LOX - Lipooxygenase
PGI - Prostacyclin / Prostaglandin I₂
TXA - Thromboxanes
PG - Prostaglandin
HETE - HydroxyEicosatetranoic Acid
EETs - Eicosatetranoic Acid
PGES - Prostaglandin E Synthase
HpETE - HydroperoxyEicosatetranoic Acid
BLT₁ - Leukotriene B4 Receptor₁ (Coupled GPCR)
BLT₂ - Leukotriene B4 Receptor₂ (Coupled GPCR)
 PROSTAGLANDINS, THROMBOXANES AND
LEUKOTRIENES ARE OXYGEN METABOLITES OF
ARACHIDONIC ACID FORMING A FAMILY OF LIPIDIC
SUBSTANCES WITH INTRINSIC BIOLOGICAL
ACTIVITIES.

PROSTAGLANDINS LEUKOTRINES THROMBOXANES

Prostaglandins are lipid The leukotrienes are a family Thromboxane A2 (TXA2),

autacoids derived from
arachidonic acid.
They both sustain homeostatic
functions and mediate
pathogenic mechanisms,
including the inflammatory
response.
of biologically active
molecules, formed by
leukocytes, mastocytoma
cells, macrophages, and other
tissues and cells in response
to immunological and
nonimmunological stimuli.
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.
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

Arachidonic Acid synthesis of a number of prostaglandins, including
prostacyclins & thromboxane.

This is known as cyclic pathway of arachidonic acid.

 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.
Sub-Families of
 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.
Figure 1 : Fused COX Enzyme
COX / PROSTAGLANDIN-
ENDOPEROXIDE SYNTHASE
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).
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).
 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.
LEUKOTRINES
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). .
trienes
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 LOX BIOSYNTHESIS
CASCADE
The first steps in the
generation of
leukotrienes are
catalysed by the
calcium and ATP-
dependent enzyme 5-
lipoxygenase. RATE
LIMITING
STEP
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.
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.

SUB-FAMILIES OF
LEUKOTRINES
 BIOLOGICAL FUNCTIONS
PROSTAGLANDINS
Prostaglandins play a role in
various reproductive functions:
1) conception; 2) luteolysis;
3) menstruation; 4) parturition.
It has also been proposed that
Prostaglandin A may be the
natriuretic hormone, the
circulating hormone which
controls sodium reabsorption by
the kidney.
LEUKOTRINES
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
THROMBOXANES
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.
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.

SUB-FAMILY OF THROMBOXANES
THROMBOXANE A2
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
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
DRUGS DEVELOPED FROM THESE MOLECULES

PROSTAGLANDINS LEUKOTRINES THROMBOXANES

Bimatoprost Montelukast Clopidogrel
Carboprost Zafirlukast (Plavix)
(Hemabate). Zileuton. Prasugrel (Effient)
Dinoprostone Ticagrelor
(Cervidil). (Brilinta)
Misoprostol Acetylsalicylic
(Cytotec). acid (Aspirin)
Latanoprost
(Xalatan).
 REFERENCES

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

THANK YOU!

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