1. Plant derived Anticancers
Mohammed N. Sabir
9/18/2018

2. Natural Products Approach Quick Facts Treatment Strategies
Plant derived Anticancers Pharmacognosy II
Definition
Introduction
Predisposing factors
Natural Products Approach
Quick Facts
Treatment Strategies
Screening Methods
Mechanisms of Action
Classification of Anticancers
Catharanthus roseus
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3. Benign tumors (Localized) Metastatic tumors
Plant derived Anticancers Pharmacognosy II
Cancer is a clinically large group of diseases that varies in their age of onset, invasiveness, their response to treatment and prognosis. It is characterized by rapid uncontrolled formation of abnormal cells which may mass together to form a grown tumor and almost lead to the death of the organism.
They are either:-
Benign tumors (Localized)
Metastatic tumors
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4. 10 billion USDs/Year spent for treatment protocols.
Plant derived Anticancers Pharmacognosy II
Cancer is one of the leading cause of death worldwide, WHO data reveals about 7.5millions of cases.
About 12% of these cases are curable (ex. Acute Lymphocytic Leukemia & Hodgkin Disease).
10 billion USDs/Year spent for treatment protocols.
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5. The main strategies for the treatment of cancer are:- Surgery
Plant derived Anticancers Pharmacognosy II
Over 50 clinically approved cytotoxic and antiproliferative anticancer agents are marketed in the USA.
The main strategies for the treatment of cancer are:-
Surgery
Radiation
Chemotherapy
Immunomodulators
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6. Drugs can often provide:- Temporary relief of symptoms
Plant derived Anticancers Pharmacognosy II
Drugs can often provide:-
Temporary relief of symptoms
Prolongation of life
Occasionally cures
Hundreds of chemical agents of known classes of chemotherapeutic agents have been synthesized, the activity of these compounds is based on their capacity for biological alkylation.
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7. Plant derived Anticancers Pharmacognosy II
The effectiveness of such alkylating agents is almost the same as the toxic dose.
These alkylating agents are highly reactive and this leads to side reactions with wide range of cell constituents.
A successful anticancer agent should kill or incapacitate cancer cells without causing excessive damage to normal cells (Selectivity & Efficacy). Such agent is difficult if not impossible to be existed.
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8. Plant derived Anticancers Pharmacognosy II
There is a continuous need for new prototypes. New templates to use in the design of potential chemotherapeutic agents;
Natural products are providing such templates. The chemical structures of many of these compounds are extremely complex and it is impossible to synthesize these compounds.
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9. Plant derived Anticancers Pharmacognosy II
Natural products approach to anticancer drug discovery has several advantages including:-
The potential of finding totally new and unique structural classes and activity type.
Among all natural sources, M.Os and plants represent a rich source of bioactive metabolites and templates that can be modified chemically to new drugs.
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10. Plant derived Anticancers Pharmacognosy II
Plant-derived compounds has played an important role in development of several clinically useful anticancer agents.
More than 3000 plant species have been reported to be used in treatment of cancer.
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11. Catharanthus alkaloids (Inhibiting enzymes that process DNA)
Plant derived Anticancers Pharmacognosy II
These include:-
Catharanthus alkaloids (Inhibiting enzymes that process DNA)
Vincristine (Natural)
Vinblastine (Natural)
Vindesine (Semisynthetic)
Vinorelbine (Semisynthetic)
Lignans (Inhibiting enzymes that process DNA)
Pdophyllotoxin (Natural)
Etoposide (Semisynthetic)
Teniposide (Semisynthetic)
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12. 3. Taxol (Terpenoids) (Interfere with tubulin polymerization)
Plant derived Anticancers Pharmacognosy II
3. Taxol (Terpenoids) (Interfere with tubulin polymerization)
4. Anthracyclins (Inhibiting enzymes that process DNA)
a) Daunorubicin (Natural)
b) Doxorubicin (Natural)
c) Epirubicin (Synthetic)
d) Idrarubicin (Synthetic)
Glycoproteins (Acting on DNA)
a) Dactinomycin
b) Bleomycin
c) Mitomycin
d) Plicamycin
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13. Plant derived Anticancers Pharmacognosy II
There are several promising new agents in clinical development based on selective activity against cancer-related molecular targets (CRMT) including (Flavopiridol and Combretastin Phosphate)
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14. Cancer is a leading cause of death 7.9 millions in 2007.
Plant derived Anticancers Pharmacognosy II
Quick facts (WHO 2011)
Cancer is a leading cause of death 7.9 millions in 2007.
Lungs, stomach, liver, colon and breast cancer are among the most frequent types.
The most frequent types of cancer differs between males and females.
About 30% of cancer can be prevented.
Tobacco usage is the single most important risk factors for CA.
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15. Deaths form CA will approaches 12 millions in 2030.
Plant derived Anticancers Pharmacognosy II
Quick facts (WHO 2011)
CA arises from a change in one cell, this change may be started by external agents and/or inherited genetic factors.
About 72% of all CA deaths occurred in low and middle income countries.
Deaths form CA will approaches 12 millions in 2030.
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16. Cytotoxic Antitumor Anticancer
Plant derived Anticancers Pharmacognosy II
Cytotoxic
Antitumor
Anticancer
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17. Method of investigation for anticancer drugs
Plant derived Anticancers Pharmacognosy II
Method of investigation for anticancer drugs
Goals: anticancer drug discovery and development of new anticancer agent with emphasis on solid tumor selectivity.
Effective anticancer agent exist in marine and other natural products sample.
The specific cellular based assays which will uncover leads which are active against our drug insensitive murine and human solid tumor models.
In vitro murine models are appropriate clinical analogues to study both activity and schedule optimization for translation to clinical protocols.
Analogue synthesis around a lead compound will yield further similar compounds with increased therapeutic activity.
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18. Indole (Vinca) alkaloids
Plant derived Anticancers Pharmacognosy II
Indole (Vinca) alkaloids
Isolated from Catharanthus roseus (Apocynaceae)
Found mainly in Madagascar.
The alkaloids are concentrated in the leaves and flowers.
Principal alkaloids are:-
1-Vincristine (Vinleukoblastine)
2-Vinblastine (Leurocristine)
Both are bisindoles
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19. Indole (Vinca) alkaloids
Plant derived Anticancers Pharmacognosy II
Indole (Vinca) alkaloids
Historically, the plant was used for the treatment of diabetes.
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20. Plant derived Anticancers Pharmacognosy II
Vincristine
Vinblastine
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21. Plant derived Anticancers Pharmacognosy II
Vincristine
Treatment of Hodgkin’s disease (a cancer affecting lymphatic glands, spleen and liver), small cell lung cancer, cervical and breast cancers.
Vinblastine
Clinically more important than vincristine and is used in the treatment protocols of childhood leukemia
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22. Plant derived Anticancers Pharmacognosy II
Vinblastine is structurally modified to yield desacetyl vinblastine amide (Vindesine) which has been introduced for clinical use in the treatment of acute lymphoid leukemia in children.
Vinorelbine is an anhydro derivative of 5’-norvinblastine, a semisynthetic derivative with broader anticancer activity and lower toxicities.
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23. (main S/E is meylosuppressive, neurotoxicities)
Plant derived Anticancers Pharmacognosy II
Vindesine
Used in acute lymphoid leukemia in children, Hodgkin’s and malignant lymphoma.
(main S/E is meylosuppressive, neurotoxicities)
Vinorelbine
Is a newer orally active semisynthetic analogue, used in
Breast cancer, non-small cell lung cancer).
(has lower S/E, less neurotoxicities)
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24. Vinblastine also inhibits angiogenesis…
Plant derived Anticancers Pharmacognosy II
Vinblastine also inhibits angiogenesis…
Angiogenesis is essential step in tumor’s transition to malignancy.
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25. Plant derived Anticancers Pharmacognosy II
Mechanism of action
Depolarization of microtubules (which is an important part of the cycloskeleton and mitotic spindle) by binding specifically to the microtubule protein tubulin in dimeric forms.
Drug-tubulin complex adds to the forming end of the microtubules to terminate assembly and deploymerization of the microtubules then occurs. This result in mitotic arrest at meta phase, dissolution of the mitotic spindle, and interference with chromosome segregation.
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26. Podophyllotoxin and its derivatives
Plant derived Anticancers Pharmacognosy II
Podophyllotoxin and its derivatives
Is the dried rhizome and roots of Podophyllum peltatum, P. hexandrun, P. emodi, (Berberidaceae).
Also known as May apple or American mandrake. Originally found in N. America, India and China.
The plant contains 14-18% Lignans, the podophyllotoxin accounts for 0.45%.
These lignans are biosynthesized from L-phenyl alanine.
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27. Podophyllotoxin and its derivatives
Plant derived Anticancers Pharmacognosy II
Podophyllotoxin and its derivatives
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28. Plant derived Anticancers Pharmacognosy II
L-Phenyl Alanine
Podophyllotoxin
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29. Plant derived Anticancers Pharmacognosy II
Biosynthesis of Pdophyllotoxin
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30. Podophyllotoxin and its derivatives
Plant derived Anticancers Pharmacognosy II
Podophyllotoxin and its derivatives
Podophyllotoxin is used in the treatment of venereal warts, Vaginal warts and available as tincture for external use.
It act as antimitotic (prevent formation of mitotic spindle from tubulins through binding to tubulin).
Not used as anticancer because of high toxicities.
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31. Podophyllotoxin and its derivatives
Plant derived Anticancers Pharmacognosy II
Podophyllotoxin and its derivatives
Semisynthetic derivatives (Etoposide).
Is a semisynthetic derivative, through addition
Of sugars.
Used in the treatment of:-
-Small Cell lung cancer
-Testicular cancer
-Lymphomas
In combination with other anticancers.
Given orally and as i.v.
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32. Podophyllotoxin and its derivatives
Plant derived Anticancers Pharmacognosy II
Podophyllotoxin and its derivatives
Semisynthetic derivatives (Teniposide).
Used in the treatment of:-
-Pediatric neuroblastoma.
Both inhibits Topoisomerase II, thus preventing DNA synthesis and replication.
Their activity is based on the trans-fused 5’-member lactone ring.
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33. Podophyllotoxin and its derivatives
Plant derived Anticancers Pharmacognosy II
Podophyllotoxin and its derivatives
Side effects:
Decreased blood pressure
Alopecia
Metallic taste
Nausea
Rash
Fever
Bone marrow suppression
Decrease WBC count
Decrease RBC count
Decrease Platelets count
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34. Plant derived Anticancers Pharmacognosy II
Taxol
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35. Plant derived Anticancers Pharmacognosy II
Taxol
Derived from Taxus brevifolia (Taxaceae), the bark of the plant contains the highest concentration of the terpenes. It is a slow growing tree that found in N. America (Canada forests in British Colombia) and USA. Taxol was first isolated in 1971.
The metabolite needs 100 Years until maturation, yielding 2gm of the drug, which counts ( %).
Semisynthetic Docetaxel also produced by microbial culture of the fungi (Taxomyces adreanae)
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36. Taxol Clinical uses:- Ovarian cancer Metastatic breast cancer
Plant derived Anticancers Pharmacognosy II
Taxol
Clinical uses:-
Ovarian cancer
Metastatic breast cancer
Lung cancer
Head and neck cancer
They are antimitotic through binding to microtubules promotive their assembly from tubulin and stabilizing them against depolarization during cell division.
The resulting abnormal tubulin microtubules disrupts the normal mitotic spindle and inhibit cell-proliferation.
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37. Anthracyclines Daunorubicin Doxorubicin Idrarubicin Epirubicin
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Daunorubicin
Doxorubicin
Idrarubicin
Epirubicin
Valrubicin
Mitoxantrone
-The anthracyclins are derived from Streptomyces spp.
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38. Anthracyclines -They are used to treat many cancers:- Leukemia
Plant derived Anticancers Pharmacognosy II
Anthracyclines
-They are used to treat many cancers:-
Leukemia
Breast cancer
Uterine cancer
Ovarian cancer
Lung cancer
They are the most effective anticancers developed.
-The major S/E is the cardiotoxicity.
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39. Anthracyclines Mechanism of action
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Mechanism of action
(Intercalating red quinone-based drugs)
Inhibit DNA synthesis by intercalating between base pairs of the DNA strands, thus preventing replication of rapidly-growing cancer cells.
Inhibition of topoisomerase II enzyme. Thus preventing the relaxing of supercoiled DNA and blocking DNA transcription.
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40. Anthracyclines Mechanism of action
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Mechanism of action
(Intercalating red quinone-based drugs)
3. Creates iron-mediated free oxygen radicals that damage the DNA and cell membrane.
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41. Anthracyclines Daunorubicin (DaunoXome® (Liposomal))
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Daunorubicin (DaunoXome® (Liposomal))
Isolated from Streptomyces peucetius
Used for the treatment protocols of:-
-Acute myeloid leukemia (AML)
-Acute lymphocytic leukemia (ALL)
(Used in combination with Cytarabine).
-Neuroblastoma (NB)
-Chronic ML.
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42. Anthracyclines Daunorubicin (DaunoXome® (Liposomal))
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Daunorubicin (DaunoXome® (Liposomal))
Route of administration: (I.V.), (I.M/S.C. causes sever tissue damage)
*Never to be administered intrathecally because of tissue necrosis.
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43. Anthracyclines Toxicities:-
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Toxicities:-
Cardiotoxicity (enhanced by Cyclophosphamide)
Severe myelosuppression
BM suppression
Renal/hepatic failure
Teratogenicity
Alopecia
S kin Rash
Contact dermatitis
Nausea
Vomiting
Diarrhea
Fever
Chills
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44. Anthracyclines Pharmacokinetics:- -Do not enter CNS
Plant derived Anticancers Pharmacognosy II
Anthracyclines
Pharmacokinetics:-
-Do not enter CNS
-Metabolism involves, removal of the sugar moiety and attached oxygen, demethylation, glucouronidation
-The metabolites it not biologically active.
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45. Anthracyclines 2. Doxorubicin (Adriamycin®) (Hydroxydaunorubicin)
Plant derived Anticancers Pharmacognosy II
Anthracyclines
2. Doxorubicin (Adriamycin®)
(Hydroxydaunorubicin)
Uses:-
Hematological malignancies
Soft tissue carcinomas
Bladder carcinoma
Stomach
Lung
Ovaries
Thyroid
Multiple myeloma NB
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46. Anthracyclines 2. Doxorubicin (Adriamycin®) (Hydroxydaunorubicin)
Plant derived Anticancers Pharmacognosy II
Anthracyclines
2. Doxorubicin (Adriamycin®)
(Hydroxydaunorubicin)
Used as I.V. infusion
Toxicities:-
Myelosuppression HF
Arrythmias
Nausea
Rash (related to the accumulation of the drug in the plasma).
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47. Anthracyclines 2. Doxorubicin (Adriamycin®) (Hydroxydaunorubicin)
Plant derived Anticancers Pharmacognosy II
Anthracyclines
2. Doxorubicin (Adriamycin®)
(Hydroxydaunorubicin)
Pharmacokinetics:-
Metabolic biotransformtion involves carbonyl reduction.
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48. Anthracyclines 3. Epirubicin Is a diasteroisomer of doxorubicin.
Plant derived Anticancers Pharmacognosy II
Anthracyclines
3. Epirubicin
Is a diasteroisomer of doxorubicin.
Uses:-
-Breast Cancer/ after surgery.
Same toxicities.
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49. Anthracyclines 4. Valrubicin Used only in Bladder Cancer Toxicities:-
Plant derived Anticancers Pharmacognosy II
Anthracyclines
4. Valrubicin
Used only in Bladder Cancer
Toxicities:-
Hematurea
Incontinence
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50. Anthracyclines 5. Idrarubicin Uses:- Leukemias
Plant derived Anticancers Pharmacognosy II
Anthracyclines
5. Idrarubicin
Uses:-
Leukemias
AML in combination with Cytosine arabinoside.
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51. Anthracyclines 6. Mitoxantrone Uses:- -Non Hodgkin’s disease
Plant derived Anticancers Pharmacognosy II
Anthracyclines
6. Mitoxantrone
Uses:-
-Non Hodgkin’s disease
-Metastatic Breast Cancer
-ALL
-Prostate cancer in combination with Prednisone.
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52. Plant derived Anticancers Pharmacognosy II
Camptothecins
Cytotoxic quinoline that inhibit DNA topoisomerase I. isolated from the bark and stem of (Camptotheca acuminata (happy tree, Cancer tree, tree of life), Cornaceae, Nyssaceae). The tree is native to China and Tibet.
Was used traditionally in Chinese Medicine as Anticancer agent.
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53. Camptotheca acuminata
Plant derived Anticancers Pharmacognosy II
Camptotheca acuminata
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54. -Physicochemical properties -SAR Pentacyclic planner
Plant derived Anticancers Pharmacognosy II
-Physicochemical properties
-SAR
Pentacyclic planner
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55. Ovarian and small cell-lung cancers
Plant derived Anticancers Pharmacognosy II
Analogues
A. Topotecan
Ovarian and small cell-lung cancers
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56. Used with 5FU in metastatic carcinomas of colon and rectum.
Plant derived Anticancers Pharmacognosy II
Analogues
B. Irrinotecan
Used with 5FU in metastatic carcinomas of colon and rectum.
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57. Orthostatic hypertension Dizziness Alopecia Rash Anorexia Anemia
Plant derived Anticancers Pharmacognosy II
Toxicities
Emesis
Immune suppression.
Neutropenia
Diarrhea
Myelosuppression
Orthostatic hypertension
Dizziness
Alopecia
Rash
Anorexia
Anemia
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58. Antitumor antibiotics Bleomycin Dactinomycin Mitomycin
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Bleomycin
Dactinomycin
Mitomycin
Plicamycin (Mithramycin)
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59. Antitumor antibiotics Bleomycin
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Bleomycin
-Glycopeptide mixture related to Vancomycin isolated from:
Streptomyces verticillus
The major components of the mixture are:-
Bleomycin A2
Bleomycin B2
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60. Antitumor antibiotics Bleomycin
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Bleomycin
-Various bleomycins varies in their terminal amine functions.
-The parent compound (bleomycinic acid) is inactive and composed from
–Pyrimidine
-Sugars
-Unusual amines
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61. Antitumor antibiotics Bleomycin -Mechanism of action:-
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Bleomycin
-Mechanism of action:-
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62. Plant derived Anticancers Pharmacognosy II
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63. Antitumor antibiotics Bleomycin -Clinical uses:-
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Bleomycin
-Clinical uses:-
Squamous cell carcinomas of the skin and cervix.
Lymphomas.
Solid tumors.
Head and neck cancer.
Germ cell tumor.
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64. Antitumor antibiotics Bleomycin -Toxicities:-
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Bleomycin
-Toxicities:-
Lung toxicities (Pneumonia with cough), increases with age.
Allergic reactions.
Fever.
Hypotension.
Used S.c., I.V., and I.M.
Elimination through renal excretion.
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65. Antitumor antibiotics Dactinomycin (Actinomycin-D)
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Dactinomycin (Actinomycin-D)
-Derived from Streptomyces parvullus.
Planer phenoxazinone
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66. Antitumor antibiotics -Mechanism of action:-
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
-Mechanism of action:-
Inhibitor of DNA-dependant, RNA polymerase.
-Clinical uses:-
Pediatric cancer (Wilm’s tumor).
Germ cell cancer.
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67. Antitumor antibiotics -Toxicities:- Nausea. Vomiting. Sever pain.
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
-Toxicities:-
Nausea.
Vomiting.
Sever pain.
Alopecia.
BM suppression.
Stomatitis.
Because of the selective inhibition of DNA-dependent RNA polymerase (reversetranscription), it gain important research tool in microbiology.
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68. Antitumor antibiotics Mitomycin Isolated from Streptomyces caespitosus
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Mitomycin
Isolated from Streptomyces caespitosus
Undergoes metabolic activation
through an enzyme-mediated
reduction to generate the
alkylating agent which cross-link
DNA in hypotoxic tumor cell.
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69. Antitumor antibiotics Mitomycin -Clinical Uses:-
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Mitomycin
-Clinical Uses:-
Hypoxic tumor stem cells of solid tumors.
Squamous cell cancer of the anus and cervix.
Adenocarcinomas of the stomach, pancreas and lung.
Bladder cancer (superficial type), because it isn’t absorbed to systemic circulation, so no systemic toxicities.
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70. Antitumor antibiotics Mitomycin -Toxicities:- Hemolytic anemia.
Plant derived Anticancers Pharmacognosy II
Antitumor antibiotics
Mitomycin
-Toxicities:-
Hemolytic anemia.
Thrombocytopenia.
Renal failure.
Pneumonia.
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71. Plant derived Anticancers Pharmacognosy II
Thank you
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