STUDY OF NATURAL PRODUCTS- MORPHINE AND PACLITAXEL

UNDER THE GUIDANCE AND SUPERVISION OF

BY
Dr. SUMANA CHATTERJEE
SUBASISH DASH
DEEPT.PHARMACEUTICAL CHEMISTRY
M PHARM 1ST SEM
GURUNANAK INSTITUTE OF PHARMACEUTICAL SCIENCE
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
AND TECHNOLOGY
 INTRODUCTION

CONTENT STRUCTURE OF MORPHINE,COMPONENT ,USES

STRUCTURE OF PACLITAXEL ,COMPONENT,USES

INTODUCTION
•NATRURAL PRODUCT OBTAINED FROM
PLANT,ANIMAL,MARINE ORGANIGMS,OR MICRO-
ORGANIGMS ARE SHAPED BY EVALUATION .BY
EVOLUTIONARY TIME THE BYOSYNTHETIC ENGINE
OF NATURE HAS PRODUCED A MYRIAD OF NATURAL
PRODUCTS WITH HUGE CHEMICAL DIVERCITY AND
OFTEN DISTINCT BIOLOGICAL PROPERTY.
• More than half of currently
available drugs are natural compounds or are
related to them and only 36% of the 1073 small-
molecule approved drug for all disease are consider
as truly synthetic . Aproxmately 68%of anti-
infective are classified as a naturally derived or
inspired where as 79.8% of cancer compound in
cancer treatment fall in this category . Mostly new
structurally diverse natural compound isolated from
plant source have been considered as
prototype ,leads ,or head of the series and their
later structural modification has generated
compound with pharmacological activities and real
therapeutic potential.
 INTRODUCTION TO LEAD DISCOVERY
drug target is identified and validated, research now focuses on lead discovery, also known as lead
identification and screening, in which multiple drug candidates are developed. Leads must be shown to
reach the target and modulate its activity in vivo while acting within acceptable safety margins. At this
stage, high-throughput screening is typically used to identify promising candidates for a lead (hit-to-
lead)

Potential leads are evaluated for a range of properties that can include selectivity, binding
mechanism(s) and kinetic analysis, dose-response curves, tractability to modifications, potency, in
vitro toxicity, and orthogonal testing. Based on the results of this initial testing regimen, new lead-
related candidates are evaluated, for example, antibodies optimized by protein engineering for
increased efficacy and specificity or reduced immunogenicity. This stage is known as lead optimization
WAYS OF DRUG DISCOVERY
In four different ways , medicinal plants having good therapeutic properties are valuable for
modern system of herbal and natural drug discovery.
•They are used as direct sources of therapeutic and bioactive agents.
•Bioactive fractions serve as raw material base for the elaboration and development of herbal-
based more complex semi-synthetic chemical compounds.
•The isolated structures derived from herbal plant species can be used as lead for new drug
discovery in developing herbal compounds.
•Lastly, plants can be used as bioactive markers for the spectroscopic and chromatographic
analysis along with the discovery of new compounds.
 AS EARLY AS 1806 A GERMAN
PHARMACIST FRIEDRICH
WILHELM ADAM SERTURNER
REPORTED ISOLATION OF
MORPHINE1.NAMED AFTER
MORPHEUS THE GREEK GOD OF
DREAMS . THIS WORK PRAVED
THE WAY FOR THE DISCOVERY
OF NATURAL PRODUCT LIKE
FOLLOWING
MORPHINE

Synonyms;
C17H19NO3
morphine
Morphia
Morphinum
Morphium IUPAC NOMENCLATURE: (4R,4aR,7S,7aR,12bS)-3-Methyl-2,3,4,4a,7,7a-
Morphin hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol
MORPHINE is one of several important alkaloids derived from the poppy plant, Papaver
somniferum. Morphine is a very efficacious drug for the relief of moderate to severe pain and
is the standard by which all other agents are measured. Morphine is also used preoperatively
to reduce anxiety, cause sedation and reduce the dose of anesthetic. Its vasodilatory and
bradycardic effects make it a useful agent in the treatment of myocardial infarction. It is also
used in the treatment of pulmonary edema. Morphine produces respiratory depression and
gastrointestinal effects at therapeutic doses. In addition, tolerance develops to the repeated
use of this drug and physical dependence occurs . 

BIOLOGICAL SOURCE MORPHINE-The latex is collected from unripe capsules

upon incision of papaver somniferum Linn.

FAMILY- Papaveraceae

GEOGRAPHICALSOURCE-
India,Pakistan,Afghanistan,China,Russia,Turkey
METHOD OF PRODUCTION
Opium plants are crushed and diluted in the sulfuric acids. This helps in the extraction of opioids from poppy plants.
Extract is collected in the form of precipitate by reacting it with ammonium hydroxide solution
THERAPEUTIC USES:
•For the reduction of both, acute and chronic pain
•In reducing the symptoms of shortness of breath.
•Also used as an opiate substitution therapy.
SIDE EFFECTS
•Constipation
•Hormone imbalance
•Impairment of human performance
•Addiction
•Development of tolerance of the opioids in the brain cells
•Person become dependent on the Morphine
STRUCTURAL SIMPLIFICATION OF MORPHINE
•.     Morphine Type: Morphine, codeine, neopine, pseudo or oxymorphine, thebaine
and porphyroxine. Morphine consists of alkaloids which has phenanthrene nucleus
whereas those of the papaverine group has benzyliso-quinoline structure. Protopine
and hydrocotamine are of different structural types. The morphine molecule has
both a phenolic and an alcoholic hydroxyl group and acetylated form is diacetyl
morphine or heroin. Codeine is ether of morphine (methyl-morphine). Other
morphine ethers which are used medicinally are ethylmorphine and pholcodine.
Simplification products
1) Butorphanol : Butorphanol is to 3 times more potent than morphine and has a shorter duration
of action (0.5 to 3 hours), with minimal sedation . Cardiovascular and respiratory side effects are
minimal compared with mu receptor agonists, and butorphanol produces antitussive and antiemetic
effects. It is k- opioid receptor agonist.
2) Pentazocine : Pentazocine is classified as an opioid with mixed actions, having an analgesic
potency estimated at one-half that of morphine . Like morphine, pentazocine may cause sedation,
respiratory depression, and constipation with prolonged use, but advantages include decreased
dysphoric side effects, and it is a a synthetic opioid.
the equivalent potency of pentazocine and morphine requires dosages of pentazocine
which surpass the analgesic effect of morphine, as well as dosages which provide less pain relief than
morphine.
It work by activating κ-opioid receptors and μ-opioid receptors.
3) Pethidine:Pethidine is a synthetic opioid, which is about one tenth as potent as morphine.
 doses of intravenous morphine and pethidine give an equivalence ratio of 1:7.5 to 1:12.5. We used a
ratio of 1:10 in this trial.
pethidine is preferred over morphine-Because of its short duration of action (1–2 h at the most),
pethidine is of more practical use as a preanesthetic medication than as a postoperative analgesic.
Vomiting is less common than with morphine when used as a premedicant.
4) Methadone:Methadone did not produce superior analgesic efficiency or overall tolerability at 4
weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain. :
Methadone is a synthetic opioid agonist and for chronic pain .
 Opium :- 
1. Opium extract + FeCl3→ Reddish purple color (Due to presence of
meconic acid )
2. Morphine + HNO3 →Orange red color while codeine donot respond
3. Morphine + K3 Fe (CN6) →Bluish green while codeine do not respond
4. Papaverine + HCl + K3 Fe (CN6) →lemon yellow colour
Special Test For Cocaine :-  Cocaine + H2SO4 → Characteristics smell of
methyl benzoate
 Molecular
Formula C47H51NO14

paclitaxel
TAXOL
Synonyms
Taxol A
Abraxane
Paclitaxel is an antineoplastic agent which acts by
inhibitor of cellular mitosis and which currently plays a
central role in the therapy of ovarian, breast, and lung
cancer. Therapy with paclitaxel has been associated
with a low rate of serum enzyme elevations, but has not Paclitaxel
been clearly linked to cases of clinically apparent acute
liver injury.
•Paclitaxel is a compound extracted from the Pacific
yew tree Taxus brevifolia with antineoplastic activity.
Paclitaxel binds to tubulin and inhibits the disassembly
of microtubules, thereby resulting in the inhibition of cell
division. This agent also induces apoptosis by binding
to and blocking the function of the apoptosis inhibitor
protein Bcl-2 (B-cell Leukemia 2).
 •Paclitaxel is a tetracyclic diterpenoid isolated
originally from the bark of the Pacific yew tree,
Taxus brevifolia. It is a mitotic inhibitor used in
cancer chemotherapy. Note that the use of the
former generic name 'taxol' is now limited, as Taxol
 is a registered trade mark. It has a role as a
microtubule-stabilizing agent, a metabolite, a
human metabolite and an antineoplastic agent. It is
a tetracyclic diterpenoid and a taxane diterpenoid. It
derives from a baccatin III
•Biological Source It is obtained from the bark of
the Pacific Yew tree, Taxus brevifolia Nutt belonging
to the family Taxaceae. Geographical Source The
plant is a native to the northwest United States. It
is a small, not so growing evergreen tree.
IUPAC Name;-
[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl]oxy-1,9-
dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
•Classification
•Paclitaxel falls under the category of taxanes.
•Physiochemical Properties
The discovery of paclitaxel began in
1962 as a result of a NCI-funded screening
program. A number of years later it was isolated
from the bark of the Pacific yew, Taxus brevifolia,
hence its name "taxol". The discovery was made
by Monroe E. Wall and Mansukh C.
S. NO. PHYSICAL AND CHEMICAL PROPERTIES

1 Molecular weight 853.9 g/mol

2 Appearance Fine white powder

3 Melting point 213-216 °C

4 Solubility Insoluble in water

5 Octanol water partition 3

coefficient

6 Presence of ring Taxane ring

TYPES OF DERIVATIVE
1- lorataxel;-A semi-synthetic derivative of the taxane 10-
deacetylbaccatin III with potential antineoplastic
activities Larotaxel penetrates the blood brain barrier.

2) Ortataxel:-Ortataxel,a new-generation taxane, is not a

substrate for the Pgp efflux pump. It is active in tumor
models resistant to paclitaxel and docetaxel and elicits
responses in taxane-resistant non-small cell lung cancer
3) Tesetaxel: Tesetaxel is an orally administered taxane being investigated as a chemotherapy agent.
mainly used for various types of cancer like breast cancer, gastric cancer.
•Methods of
Synthesis                                                         
              
•i. 7-OSiEt2(OCH2CF3)-baccatin-III is coupled
with ((3R-cis)-1-Benzoyl-3-(1-methoxy-1-
methylethoxy)-4-phen-yl-2-azetidinone)
(BMOP) in anhydrous THF at -55°C to form an
MOP intermediate.
•ii. The formed MOP intermediate is then
hydrolyzed with TFA/AcOH/Water for 17 hours.
•iii. Paclitaxel can be obtained finally through
chromatography.
 •Therapeutic Uses
•Paclitaxel is used for the treatments of:
•Breast cancers
•Ovarian cancers
•Lung cancers
•Bladder cancers
•Prostate cancers
•Melanomas
•Esophageal cancers

Paclitaxel
•Other solid tumor cancers
•Kaposi’s sarcoma
•Side Effects
•Common side effects includes low blood counts,
hair loss, arthralgias, myalgias, periphery
neuropathy, nausea, vomiting, diarrhea, mouth
sores and hypersensitivity reactions.
•Some people may suffer from side effects like
edema, increase in blood test liver function, low
blood pressure, darkening of the skin and changes
in the color of the nails.
 •Paclitaxel has been associated with serum
aminotransferase elevations in 7% to 26% of patients, but
values greater than 5 times the upper limit of normal
(ULN) in only 2% of those receiving the highest doses.
Similar rates of alkaline phosphatase elevations and
occasional mild bilirubin elevations also occur. The
abnormalities are usually asymptomatic, mild and self-
limited, rarely requiring dose modification or

Toxicity
discontinuation. Paclitaxel has not been linked
convincingly to instances of delayed, idiosyncratic
clinically apparent liver injury with jaundice. However,
the hypersensitivity reactions that occur with infusions of 
paclitaxel can be severe and accompanied by acute
hepatic necrosis. The liver injury may be relatively mild
and anicteric , but can also be severe with rapid onset of
multiorgan failure and death
 Morphine is class of drugs called opioid which
potentially cause change in mood, physical
dependence, tolerance and rewarding
effects which would eventually cause drug
dependence. Opoid drugs have effect on both the
central and peripheral nervous systems. In central
nervous system opioids have effects on spinal
cord and other parts of CNS.
Paclitaxel is a microtubule-targeting drug of the
CONCLUSION taxane family. It is widely used for the treatment of
a range of cancers, namely breast, ovarian and
lung. Its most commonly documented cardiac
adverse effects have been bradycardia and heart
block.
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THANK YOU