Anti-cancer drugs of natural origin.

1. NATURAL PRODUCTS AS LEAD FOR NEW PHARMACEUTICALS
ANTI-CANCER DRUGS
PRESENTED BY:
ANAM ILYAS
M.PHARM. (1ST YEAR)
PHARMACEUTICAL CHEMISTRY
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2. CONTENTS:
❑ DRUG DISCOVERY FROM NATURAL PRODUCTS.
❑ INTRODUCTION
❑ Anticancer drug from natural origin.
❑ Taxanes:
1. Introduction
2. Paclitaxel
3. Docetaxel
4. Sar of Paclitaxel
❑ Podophyllotoxin
1. Sar of podophyllotoxin
2. Etoposide
3. Teniposide
4. New analog of podophyllotoxin
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3. Drug discovery approach:
 Lead compound is a chemical compound obtained from a natural or synthetic sources that possess
a particular biological or pharmacological activity.
 FINDING A NEW DRUG INVOLVES:
➢ TARGET IDENTIFICATION AND VALIDATION:
At this stage a lot of compounds are tested Against the target protein or an enzyme. Compounds
showing chemical activity against the target are promoted to hits. Screening of library with e.g.
1,000,000 compounds may result in 100-500 hits.
➢ HITS TO LEAD:
the hits are further examinedin order to find some promising drug candidate. Typically 1-
3 lead compoundare found.
➢ LEAD OPTIMIZATION:
Prior to clinical trials a lead compound or compounds are modifiedstructurally to improve activity ,
lower toxicity, improvestability and safety.
In vitro cell-basedand In vivoanimal studies to collect data on toxicity and to understand the
metabolism of compounds in the body.
It Is Necessary To Optimize The Lead Properties That Is Toxicity,Potency, Binding Strength, Etc.
These modifications Result In 10-500 Lead Variations Sent For pre-clinical studies.
“Then, application to the FDA for pre-clinical studies and clinical trials
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4. WHAT IS CANCER???... 4
❖ Cells are the basic units that make up the human
body.
❖ Cells grow and divide to make new cells as the
body needs them.
❖ Usually, cells die when they get too old or
damaged and new cells growth take their place.
❖ Cancer begins when genetic changes occurs.
❖ Cells start to grow uncontrollably.These cells may
form a mass calleda tumor.
❖ A tumor can be cancerous or benign.
❖ A cancerous tumor is malignant, it can grow and
spread to other parts of the body.
❖ A benign tumour means the tumor can grow but
will not spread

5. NATURAL PRODUCT FOR THE
TREATMENT OF CANCER:
❖ Natural products have been used from centuries for the treatment of several ailments
❖ Active ingredients such as alkaloids, flavonoids, terpenoids, polysaccharide and saponin obtained from
natural products have potent biological properties such as anti-tumor, anti-inflammatory,
immunomodulation, anti-viral, etc.
❖ Most of the natural anti-neoplastic drugs often do not kill tumor cells directly, but regulates the human
immune function to achieve this purpose or both.
❖ DNA topoisomerase-Ⅰ (Topo-Ⅰ) is an essential enzyme involved in cell growth.
❖ The inhibition of Topo-Ⅰ is an important anti-cancer pathway.
❖ A large number of anti-cancer drugs combat cancers through cell cycle arrest, induction of apoptosis and
differentiation as well as through inhibition of cell growth and proliferation..
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6. Anticancer
Drugs from
natural
origin
 Taxanes:
Paclitaxel
Docetaxel
 Podophyllotoxins:
Etoposide
Teniposide
 Vinca alkaloids :
Vincristine
Vinblastine
Vinorelbine
➢ Camptothecins:
Irinotecan
Topotecan
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7. TAXANES:
 Taxanes are a class of diterpenes
 It is obtained from the bark of Pacific yew, Taxus brevifoliaBelonging to
the family (Taxaceae).
 Paclitaxel (Taxol) is discovered in the lab of the late Monrae.E.wall and of
Mansukh wani at reserch triangle institutein North Carolina.
 After being tested in the National Cancer Institute's (NCI) screening program
during the 1960s, was described as the most excitinganticancer compound
discovered in the previous 20 years.
 Paclitaxel is naturally obtained from the plant while Docetaxel is a semi-synthetic
analogue of paclitaxel.
 Taxanes are microtubule damaging agent which enhance stability of
microtubules, preventingthe separation of chromosomes during anaphase.
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8. PACLITAXEL
Mechanism of action
The drug reversiblybind to the
Beta-tubulin and results in
formationof stable non-
functioning microtubule by
promoting polymerization
and stabilization of the
microtubules.
Thus, it interferes with mitosis
causing the death of the cell.
PACLITAXEL
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9. DOCETAXEL
 MECHANISM OF ACTION:
 The cytotoxic activity of docetaxel is
exerted by promoting and stabilising
microtubule assembly, while
preventing physiological
microtubule depolymerisation/disass
embly in the absence of GTP.
 This leads to a significant decrease in
free tubulin, needed for microtubule
formation and results in inhibition of
mitotic cell division between
metaphase and anaphase,
preventing further cancer cell
progeny.
 Because microtubules do not
disassemble in the presence of
docetaxel, they accumulate inside
the cell and cause initiation of
apoptosis
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DOCETAXEL

10. STRUCTURAL ACTIVITY RELEATIONSHIP OF
TAXANES: 10

11. THERAPEUTIC
USES OF
TAXANES:
The approved indications of paclitaxel are:
 Metastaticovarian and breast carcinoma
after failure of first line chemotherapy and
relapse cases.
 It has also shown efficacy in advanced cases
of head and neck cancer
 Used in lung cancer
 Oesophageal adenocarcinoma
 Prostate cancer
 In Kaposi's sarcoma(causes lesions in the soft
tissues).
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12. PODOPHYLLOTOXIN
 It Is Obtained From The Dried
Rhizomes And Roots Of
Podophyllum hexandrum Royal Or
Podophyllum emodi Well, Belonging
TO FAMILY (Berberidaceae).
 Rhizome of P. hexandrum contains
several lignans which possess
antitumor activity.
 Podophyllotoxin(podophyllin) is the
most active cytotoxic natural
product.
 It is used as starting compound for
the synthesis of anticancer drug
etoposide and teniposide.
 Podophyllotoxin acts by inhibiting
microtubule assembly.
 Podophyllotoxin is used for its Emetic,
cathartic, And Anthelminthic effects.
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13. SAR OF PODOPHYLLOTOXINS ANALOGS 13

14. ETOPOSIDE
 Etoposide also known as
epipodophyllotoxin.
 Due to the lack of water solubility of
etoposide its prodrug etoposide
phosphate is used.
 It is usually prescribed in multiple
chemotherapy protocols .
 It is a highly active and widely used
antineoplastic agent .
 It is active against many tumour
types and used primarily as part of
combination treatment for testicular
tumours and leucopenia.
 This is most active single agent for
small cell lung cancer
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15. ➢ MECHANISM OF ACTION OF ETOPOSIDE:
▪ Etoposide is most active in late S & G2 phase of cell cycle.
▪ Etoposide forms a tertiary complexwith DNA and the topoisomerase II enzyme (which
aids in DNA unwinding), preventsre-ligation of the DNA strands, and by doing so causes
DNA strands to break.
▪ Cancer cells rely on this enzyme more than healthy cells, since they divide more
rapidly. Therefore, this causes errors in DNA synthesis and promotes apoptosis of the
cancer cell.
➢ THERAPEUTIC USES:
 It is used in testicularcancer and prostatic cancer.
 In small cell lung cancer.
 Hodgkin's and other lymphomas.
➢ SIDE EFFECTS:
 Gastrointestinal distress(Nausea, Vomiting, Diarrhoea, Anorexia).
 Myelosuppression.
 At high doses, Etoposide is hepatotoxic.
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16. TENIPOSIDE
 It is in a class of drugs known as podophyllotoxin derivatives and slows the growth
of cancer cells in the body.
 Teniposide is more potent, more highly protein bound than etoposide ,and its uptake
and binding to cells is also greater than Etoposide.
 Teniposide is injected for the treatment of acute nonlymphocytic leukaemia,
Hodgkin's disease and other lymphomas, Kaposi's sarcoma, neuroblastoma, and
other less thoroughly validated tumor situations.
 It can be used in single drug therapy for induction of remission.
➢ MECHANISM OF ACTION OF TENIPOSIDE:
 Teniposide causes dose-dependent single- and double-stranded breaks in DNA and
DNA-protein cross-links.
 The substance has been found to act as an inhibitor of topoisomerase II (an enzyme
that aids in DNA unwinding),since it does not intercalate into DNA or bind strongly to
DNA.
 The cytotoxic effects of teniposide are related to the relative number of double-
stranded DNA breaks produced in cells, which are a reflection of the stabilization of a
topoisomerase II-DNA intermediate
 Its action is most prominent in the late S or early G-2 cell-cycle phases; thus cells do
not enter the M-phase.
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18. New analogue of
podophyllotoxin:
 GL-331 is a new analogue
which is more potent than
teniposideand etoposide in
vitro and in vivo and retained
cytotoxicity against resistant
cells.
 It is currently under phase 2
clinical evaluation.
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19. THANK YOU...
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