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

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 9/18/2018

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 9/18/2018

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. 9/18/2018

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 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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) 9/18/2018

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 9/18/2018

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) 9/18/2018

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. 9/18/2018

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. 9/18/2018

Cytotoxic Antitumor Anticancer Plant derived Anticancers Pharmacognosy II Cytotoxic Antitumor Anticancer 9/18/2018

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. 9/18/2018

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 9/18/2018

Indole (Vinca) alkaloids Plant derived Anticancers Pharmacognosy II Indole (Vinca) alkaloids Historically, the plant was used for the treatment of diabetes. 9/18/2018

Plant derived Anticancers Pharmacognosy II Vincristine Vinblastine 9/18/2018

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 9/18/2018

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. 9/18/2018

(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) 9/18/2018

Vinblastine also inhibits angiogenesis… Plant derived Anticancers Pharmacognosy II Vinblastine also inhibits angiogenesis… Angiogenesis is essential step in tumor’s transition to malignancy. 9/18/2018

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. 9/18/2018

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. 9/18/2018

Podophyllotoxin and its derivatives Plant derived Anticancers Pharmacognosy II Podophyllotoxin and its derivatives 9/18/2018

Plant derived Anticancers Pharmacognosy II L-Phenyl Alanine Podophyllotoxin 9/18/2018

Plant derived Anticancers Pharmacognosy II Biosynthesis of Pdophyllotoxin 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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 9/18/2018

Plant derived Anticancers Pharmacognosy II Taxol 9/18/2018

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 (0.01-0.02%). Semisynthetic Docetaxel also produced by microbial culture of the fungi (Taxomyces adreanae) 9/18/2018

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. 9/18/2018

Anthracyclines Daunorubicin Doxorubicin Idrarubicin Epirubicin Plant derived Anticancers Pharmacognosy II Anthracyclines Daunorubicin Doxorubicin Idrarubicin Epirubicin Valrubicin Mitoxantrone -The anthracyclins are derived from Streptomyces spp. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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 9/18/2018

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. 9/18/2018

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 9/18/2018

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). 9/18/2018

Anthracyclines 2. Doxorubicin (Adriamycin®) (Hydroxydaunorubicin) Plant derived Anticancers Pharmacognosy II Anthracyclines 2. Doxorubicin (Adriamycin®) (Hydroxydaunorubicin) Pharmacokinetics:- Metabolic biotransformtion involves carbonyl reduction. 9/18/2018

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. 9/18/2018

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 9/18/2018

Anthracyclines 5. Idrarubicin Uses:- Leukemias Plant derived Anticancers Pharmacognosy II Anthracyclines 5. Idrarubicin Uses:- Leukemias AML in combination with Cytosine arabinoside. 9/18/2018

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. 9/18/2018

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. 9/18/2018

Camptotheca acuminata Plant derived Anticancers Pharmacognosy II Camptotheca acuminata 9/18/2018

-Physicochemical properties -SAR Pentacyclic planner Plant derived Anticancers Pharmacognosy II -Physicochemical properties -SAR Pentacyclic planner 9/18/2018

Ovarian and small cell-lung cancers Plant derived Anticancers Pharmacognosy II Analogues A. Topotecan Ovarian and small cell-lung cancers 9/18/2018

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. 9/18/2018

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 9/18/2018

Antitumor antibiotics Bleomycin Dactinomycin Mitomycin Plant derived Anticancers Pharmacognosy II Antitumor antibiotics Bleomycin Dactinomycin Mitomycin Plicamycin (Mithramycin) 9/18/2018

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 9/18/2018

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 9/18/2018

Antitumor antibiotics Bleomycin -Mechanism of action:- Plant derived Anticancers Pharmacognosy II Antitumor antibiotics Bleomycin -Mechanism of action:- 9/18/2018

Plant derived Anticancers Pharmacognosy II 9/18/2018

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. 9/18/2018

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. 9/18/2018

Antitumor antibiotics Dactinomycin (Actinomycin-D) Plant derived Anticancers Pharmacognosy II Antitumor antibiotics Dactinomycin (Actinomycin-D) -Derived from Streptomyces parvullus. Planer phenoxazinone 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

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. 9/18/2018

Antitumor antibiotics Mitomycin -Toxicities:- Hemolytic anemia. Plant derived Anticancers Pharmacognosy II Antitumor antibiotics Mitomycin -Toxicities:- Hemolytic anemia. Thrombocytopenia. Renal failure. Pneumonia. 9/18/2018

Plant derived Anticancers Pharmacognosy II Thank you 9/18/2018