The document discusses natural products taxanes and podophyllotoxins that have led to new anti-cancer drugs. It describes how over 60% of anti-cancer drugs originate from natural products. Taxanes such as paclitaxel and docetaxel stabilize microtubules, preventing cell division and causing cancer cell death. Podophyllotoxins like etoposide and teniposide inhibit topoisomerase and DNA synthesis in cancer cells. Both classes are effective against various cancer types with side effects like low blood counts and hair loss that require careful treatment. Natural products continue providing leads for developing new anti-cancer pharmaceuticals.

1. NATURAL PRODUCT A LEAD FOR NEW
PHARMACEUTICALS TAXANES &
PODOPHYLLOTOXINS
Presented by
ANBU DINESH.J
M.PHARM(SEMESTER-I)
DEPT OF PHARM.CHEMISTR
SRIPMS,COIMBATORE

2. CONTENTS
 DRUG DISCOVERY FROM NATURAL PRODUCTS
 NATURAL PRODUCTS FOR TREATMENT OF CANCER
 CANCER - INTRODUCTION
 ANTI-CANCER DRUG CLASSIFICATION
 TAXANES
a) PACILITAXEL
b) DOCETAXEL
 PODOPHYLLOTOXINS
a) ETOPOSIDE
b) TENIPOSIDE
 CONCLUSION
 REFERENCE
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3. DRUG DISCOVERY FROM NATURAL
PRODUCTS
 Natural products have been used for centuries for the treatment of several
ailments.
 Many bioactive compounds have been discovered from plants, animals and
microbes, such as natural products and secondary metabolites, developed into
drugs to treat diseases.
 Over 60% of the clinical use of anti-cancer drugs originate from natural products,
including plants, marine organisms, microbes, and more than 3,000 species of
plants can be used to treat cancer.
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4. NATURAL PRODUCTS FOR TREATMENT OF
CANCER
 Active ingredients such as alkaloids, flavonoids, terpenoids, polysaccharide and
saponin obtained from natural products have potent biological properties such
as anti-tumor, analgesia, anti-inflammatory, immunomodulation, anti-viral, etc.
 Most natural anti-neoplastic drugs often do not kill tumor cells directly, but
regulates the human immune function to achieve this purpose or both.
 DNA topoisomeraseⅠ (TopoⅠ) is an essential enzyme involved in cell growth.
 The inhibition of TopoⅠ 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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5. What is an cancer ?
 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 called a 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 tumor means the tumor can grow but will not spread.
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7. Cancer deaths in India
 Cancers are the leading types worldwide in terms of the number of new cases; for each
types, approximately 2.1 million diagnoses are estimated in 2018, contributing about 11.6% of
the total cancer incidence burden.
 Colorectal cancer (1.8 million cases, 10.2% of the total) is the third most commonly
diagnosed cancer, prostate cancer is the fourth (1.3 million cases, 7.1%), and stomach cancer
is the fifth (1.0 million cases, 5.7%).
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9. Anti-Cancer Drugs Classification:
 ALKLATING AGENTS
 Methyl Hydrazine : Procarbazine
 Ethylenimine: Thiotepa
 Nitrosourea: Carmustine , Lomustine
 Alkylsulfonate: Busulfan
 Nitrogen Mustard: Cyclophosphamide, Ifosphamide, Chlorambucil
 Triazine: Decarbazine, Temozolomide
 PLATINUM CO-ORDINATION COMPLEX
 Cisplatin, Oxaliplatin, Carboplatin
 ANTIMETABOLITES
 Purine Antagonist: 6-mercaptopurine ,6-thioguanine
 Pyrimidine Antagoinst: 5-flurouracil, cytarabine
 Folate Antagonist : Methotrexate, Premetexed
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10. MICROTUBULE DAMAGING AGENTS
 Vinca alkaloids : Vincristine,Vinblastin
 Taxanes: Paclitaxel, Docetaxel , Estramustine
MISCELLANEOUS
 Hydroxyurea,
 L-Asparaginase,
 Arsenic Trioxide.
TOPOISOMERASE -1-INHIBITOR :
 Topotecan ,
 Irinotecan.
TOPOISOMERASE-2-INHIBITOR : Etoposide
ANTIBIOTICS: Actinomycin D , Doxorubicin , Daunorubicin , Mitomycin C
TARGETED DRUGS: Imatinib , Nilotinnib ,Sunitinib
HORMONAL DRUGS : Prednisolone , Anastrozole , Letrozole
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11. TAXANES
 Taxanes are a class of diterpenes
 The prototype taxane is the natural product paclitaxel , originally known as Taxol and
first derived from the bark of the Pacific Yew tree.
 Docetaxel is a semi-synthetic analogue of paclitaxel.
 Taxanes enhance stability of microtubules, preventing the separation of
chromosomes during anaphase.
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TAXANES
PACLITAXEL
DOCETAXEL

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14. PACLITAXEL
 A cyclo decane isolated from the bark of the Pacific yewtree ,Taxus brevifolia
 It stabilizes microtubules in their polymerized form leading to cell death.
 Abraxane is the latest attempt to improve upon paclitaxel, one of the leading chemotherapy
treatments.
 It’s brand name is Abraxane , Abraxis ,Bioscience, Epitaxol, Onxol ,Paxceed,Paxene
,Taxol ,Taxol A , Vascular Wrap , Xorane.
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15. MECHANISM OF ACTION
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16. ADVERSE EFFECTS
 Common side effects include
 nausea and vomiting,
 loss of appetite,
 change in taste,
 thinned or brittle hair,
 Joint pains more than 3days,
 colour changes in nails,
 tingling in the hands or toes.
 More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at
the injection site, change in normal bowel habits for more than two days, fever,
chills,cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe
exhaustion, skin rash, facial flushing , female infertility by ovarian damage
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17. USES
 Paclitaxel is approved in the UK for ovarian, breast and lung cancers and Kaposi's sarcoma.
 Paclitaxel should be available for the treatment of advanced breast cancer after the failure
of anthracyclic chemotherapy, but that its first-line use should be limited to clinical trials
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18. DOCETAXEL
 Docetaxel (as generic or under the trade name Taxotere) is a clinically well-
established anti-mitotic chemotherapy medication (that is, it interferes with cell
division).
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19. MECHANISM OF ACTION
The cytotoxic activity of docetaxel is exerted by promoting and stabilising
microtubule assembly, while preventing physiological microtubule
depolymerisation/disassembly 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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20. ADVERSE EFFECTS
 Common chemotherapy side effects such as alopecia occur; sometimes this can be
permanent.
 Haematological adverse effects include Neutropenia (95.5%), Anaemia (90.4%), Febrile
neutropenia (11.0%) an Thrombocytopenia (8.0%).
ALOPECIA
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21. USES
 The main use of docetaxel is the treatment of a variety of cancers after the
failure of anthracycline-based chemotherapy
 Docetaxel has cytotoxic activity against breast, colorectal, lung, ovarian,
prostate, liver, renal, gastric, head and neck cancers, and melanoma.
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22. PODOPHYLLOTOXINS
 Podophyllum hexandrum Royle of family Berberidaceae is an endangered medicinal plant.
 Rhizome of P. hexandrum contains several lignans which posses antitumor activity.
 Podophyllotoxin is the most active cytotoxicnatural product.
 It is used as starting compound for the synthesis of anticancer drug etoposide and teniposide.
 Podophyllotoxin acts by inhibiting microtubule assembly.
 These drugs are used for lung cancer, testicular cancer, neuroblastoma, hepatoma and other tumors.
 Availability of podophyllotoxin from plants is rare because of lack of organized cultivation.
 The chemical synthesis of podophyllotoxin is complicated .
 The production of podophyllotoxin using cell cultures, organ cultures, and biotransformation route or
by manipulating biosynthetic pathway is an attractive alternative for production of podophyllotoxin.
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 Podophyllotoxin bears four consecutive chiral centers, C-1 to C-4 .
 The molecule also contains four planar fused rings.
 The podophyllotoxin molecule includes a number of oxygen
containing functional groups: an alcohol , a lactone , three methoxy
groups, and an acetal
 Derivatives of podophyllotoxin are synthesized as properties of the
rings and carbon 1 through 4 are diversified.
 For example,
 Ring A is not essential to antimitotic activity.
 Aromatization of ring C leads to loss of activity,
 Possibly from ring E no longer being placed on the axial position.
 In addition, the stereochemistry at C-2 and C-3 configures a trans-
lactone, which has more activity than the cis counterpart.
 Chirality at C-1 is also important as it implies an axial position for
ring E.
PODOPHYLLOTOXINS

24. ETOPOSIDE
 Etoposide(Demethylepipodophyllotoxinethylideneglucopyranoside,
EPE, epipodophyllotoxin).
 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 .
 The product is available as an injectable solution to be administered
by infusion or it is administered orally as liquid capsules .
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25.  Combination of chemotherapy (etoposide + cisplatin) and concomitant
radiotherapy followed by removal of tumour is highly effective in the
treatment of pediatric patients with primary intracranial yolk sac tumour and
embryonal carcinoma .
MECHANISM OFACTION:
 Etoposide forms a tertinary complex with DNA and the topoisomerase II enzyme (which
aids in DNA unwinding), prevents re-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
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26. ADVERSE EFFECTS
 Major side effects include hair loss, nausea, anorexia, diarrhoea and low leucocyte
and platelet counts.
 Etoposide is known to cause fetal damage and birth defects, so pregnant or nursing
women should not use it
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27. TENIPOSIDE
Teniposide is used for the treatment of lymphomas of
acute refractory leukemia and that of brain and
bladder tumors.
 It can be used in single drug therapy for induction of
remission.
It is in a class of drugs known as podophyllotoxin
derivatives and slows the growth of cancer cells in the
body
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28. MECHANISM OF ACTION
 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
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29. SIDE EFFECTS
 Teniposide, when used with other chemotherapeutic agents for the treatment
of ALL, results in severe bone marrow suppression.
 Other common side effects include gastrointestinal toxicity, hypersensitivity
reactions, and reversible alopecia.
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30. MEDICINAL USES
 Teniposide is used for the treatment of a number of cancer types in children.
 In the US, it is approved for the second-line therapy of acute lymphocytic
leukemia (ALL) in combination with other antineoplastic drugs.
 In Europe, it is also approved for the treatment of Hodgkin's lymphoma,
generalized malignant lymphoma, reticulocyte sarcoma, acute leukaemia,
primary brain tumours (glioblastoma, ependymoma, astrocytoma), bladder
cancer, neuroblastoma and other solid tumours in children
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31. CONCLUSION
 “Taxanes” a 7 letter word which means a lot in the field of cancer treatment,
though their mechanism of action is clear to us in numerous cancers but there
still remains several facets of them to be unveiled.
 All those who contributed in the field of cancer in relation to taxanes are to be
endlessly thanked including our patients who have helped researchers, doctors,
pharmaceutical companies seen light at the end of the tunnel.
 But there are still miles to go before curative treatment for cancer patients are
delineated; encouragement and faith is thereto continue with those eternal
“oncological explorations” which represent a blessing in cancer treatment.
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32. REFERENCE
 Production of podophyllotoxin from Podophyllum hexandrum: a potential natural
product for clinically useful anticancer drugs by Archana Giri & M. Lakshmi
NarasuSchool of Biotechnology, Jawaharlal Nehru Technological University, Mahaveer
marg, Hyderabad 500028, India
 Ardalani H, Avan A, Ghayour-Mobarhan M. Podophyllotoxin: a novel potential natural
anticancer agent. Avicenna J Phytomed, 2017; 7 (4): 285-294
 Taxanes: Promising Anti-Cancer Drugs Nilufer Jasmine Selimah Fauzee, Zhi Dong, Ya-
lan Wang
 From lab to pharmacy shelves: the story of a plant derived Anticancer drug,
“PACLITAXEL”Maira Junjua*, Sana Jafar, Fazeelat Karamat1 Faheem Ahmed.
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