anticancer part 1.pdf

Anticancer Agents Medicinal Chemistry III B Pharm Dr. Soha Telfah Assistant Professor, Pharmaceutical Medicinal Chemistry Faculty of Pharmacy, Philadelphia University-Jordan Em...

Anticancer Agents Medicinal Chemistry III B Pharm Dr. Soha Telfah Assistant Professor, Pharmaceutical Medicinal Chemistry Faculty of Pharmacy, Philadelphia University-Jordan Email: [email protected]  Learning Outcome ◼ At the end of this lesson students will be able to – Outline the current status, causes and treatment strategies of cancer – Explain the mechanism of action, SAR, therapeutic uses and side effects of following classes of anti-cancer agents: Alkylating Agents Heavy metal compounds (Metallating Agents) Anti-metabolite Antibiotics Plant Extracts Topoisomerase inhibitors Hormones Combination of chemotherapy with other treatments 2 Others First Examination= 20 Marks  The Status of Cancer Cancer is a leading cause of death worldwide, accounting for 12.6 million new cases and 7.6 million deaths every year. THIS IS EQUIVALENT TO ONE PERSON, EVERY 5 SECONDS OF EVERYDAY Source: GLOBOCAN 2008 By 2020 the World Health Organisation (WHO) 3 expects this rise to 16 million. Cancer A new growth of tissue in which multiplication of cells is uncontrolled and progressive (tumour). Abnormal cells can spread to other parts of the body (metastasise). 4 5 6  Cancer Types Cancer types are categorized based on the functions/locations of the cells from which they originate: Carcinoma: a tumor derived from epithelial cells, those cells that line the inner or outer surfaces of our skin and organs (80-90% of all cancer cases reported) Sarcoma: a tumor derived from muscle, bone, cartilage, fat or connective tissues. Leukemia: a cancer derived from white blood cells or their precursors. Lymphoma: a cancer of bone marrow derived cells that affects the lymphatic system. Myelomas: a cancer involving the white blood cells responsible 7 for the production of antibodies (B lymphocytes). 8 Causes of Cancer 9  What causes cells to divide out of control ??? Accumulation of faults in our DNA What causes DNA faults? 10 11 12 Biochemical Basis of Cancer: Mutation DNA mutations – Inborn mutations of cancer susceptibility genes – Acquired mutations Mutation: – Germline (Germline mutations are mutations that can be passed on to offspring) and – Somatic (Somatic mutations are mutations that happen in any other cell type and cannot be inherited by offspring) Genetic mutations within a single affected cell leads to monoclonal development. Genes affected can be those controlling cell cycle, DNA repair and/or differentiation, This leads to uncontrolled proliferation and tumour formation. 13  Cancer Treatment  Fourprimary modalities are employed in the approach to cancer treatment  Surgery (solid localized tumor): It often offers the greatest chance for cure, especially if the cancer has not spread to other parts of the body.  Radiation (solid localized tumor): Radiation therapy uses high-energy particles or waves to destroy or damage cancer cells. It is one of the most common treatments for cancer, either by itself or along with other forms of treatment.  Chemotherapy Chemotherapy (chemo) is the use of medicines or drugs to treat cancer. Accesses the systemic circulation and can theoretically treat the primary tumor and any metastatic disease.  Biologic therapy (immunotherapy or targeted therapies) Immunotherapy involves stimulating the host’s immune system to fight the cancer (Examples; interferons and interleukins) Targeted therapies include monoclonal antibodies such as tyrosine kinase inhibitors and proteosome inhibitors 14  The Classification of Anticancer Drugs ◼ According to chemical structure and resource of the drug: – Alkylating Agents – Heavy metal compounds (Metallating Agents) – Anti-metabolite – Antibiotics – Plant Extracts – Topoisomerase inhibitors – Hormones – Monoclonal antibodies – Others 15 History of Chemotherapy  Era of modern chemotherapy began in early 1940s  Goodman and Gilman first administered nitrogen mustard to patients with lymphoma  Nitrogen mustard was developed as a war gas rather than as a medicine  Toxic effects on the lymphatic system led to clinical trials Chemotherapy  Chemotherapy attacks tumors at the cellular level by interrupting processes or inhibiting substances necessary for cellular replication and life.  Goals of Cancer Chemotherapy:  Cure  Prolong survival  Palliation  Radiosensitive 16 The Cell Cycle  G1 phase: cell prepares for DNA synthesis S phase: cell generates complete copy of genetic material  G2 phase: cell prepares for mitosis M phase: replicated DNA is condensed and segregated into chromosomes https://www.youtube.com/watch?v=Q6ucKWIIFmg  G0 phase: resting state Chemotherapy  Cell cycle phase – specific  Agents with major activity in a particular phase of cell cycle  Schedule dependent  Cell cycle phase – nonspecific  Agents with significant activity in multiple phases  Dose dependent 17 How Cells Divide and How Chemotherapy Works https://www.youtube.com/watch?v=VRhz3DhjG5M 18  CHEMOTHERAPY Backbone of cancer chemotherapy regimens Cytotoxicity is not selective 19 Problems with chemotherapy Treatments are non-specific, attack healthy cells as well as normal cells since cancer cells are derived from normal cells. Cancers can develop resistance: for example with platinum-drugs, cancer cells became resistant by many ways: – Decreased drug uptake/increased efflux – Enhanced tolerance of DNA adducts – Enhanced repair of DNA adducts – Increased drug deactivation by intracellular glutathione Ideal cytotoxic drugs should: – Selectively target cancer cells without causing damage to normal cells. – Reduce size of tumors + minimize risks of metastases. Unfortunately, most of the available agents are not selective, they also affect rapidly-proliferating normal tissues (bone marrow, gastro intestinal epithelium, hair cells etc.) causing serious side-effects (bone 20 marrow suppression, nausea, vomiting etc.).  Treatment Side effects - Terminology Neutropenia (is a hematological disorder characterised by an abnormally low number of neutrophil granulocytes (a type of white blood cell). Myelosuppression is a decrease in the production of blood cells. (Red blood cells and platelets). Ototoxicity is damage of the ear, specifically the cochlea or auditory nerve. Nephrotoxicity is kidney damage. Results in decreased kidney function. Hepatotoxicity is liver damage. Results in decreases liver function. Neuropathy is usually short for peripheral neuropathy, and means a damage to peripheral nerve(s). Hypomagnesaemia is an abnormally low level of magnesium in blood 21 serum. Extravasation: a dreaded complication of chemotherapy Most chemotherapeutic agents are given by intravenous (IV) administration, which cause few side-effects at the site of injection. A tissue reaction varying from irritation to necrosis. Extravasation is defined either as the escape of a chemotherapeutic agent from a vessel into the surrounding tissues by leakage or as an involuntary injection of a drug into the tissues. The severity of tissue injury is dependent on the type and concentration of the chemotherapeutic agent and the quantity injected. Cytotoxic agents may be classified as IRRITANTS or VESICANTS Irritants are drugs that can cause an inflammatory reaction, aching, swelling, pain or phlebitis, hyperpigmentation at the injection site or along the vein. These symptoms are self-limiting and there are no long-term sequelae. Vesicants are drugs that may cause severe and lasting tissue injury and necrosis. Symptoms may arise immediately after extravasation or appear 22 after several days or weeks.  Chemotherapeutic Agents IRRITANTS or VESICANTS 23  Part – I Alkylating agents Nitrogen mustard Nitrosoureas: Carmustine, Lomustine Busulfan Aziridines: Thiotepa Methylhydrazines: Dacarbazine and Procarbazine Mitomycin C Cisplatin and Cisplatin Analogues 24  Alkylating agent  The alkylating agents are among the oldest and most useful of antineoplastic drugs.  Evolved from the observation of bone marrow suppression and lymph node shrinkage in soldiers exposed to sulfur mustard gas warfare during World War I Cl Cl Cl Cl S S R R N N Cl Cl Cl Cl SulfurSulfur Mustard Mustard Nitrogen Nitrogen AnalogAna (chemical (chemical weapon) weapon) not not used clinically used clinically  Less-reactive derivatives were synthesized to treat cancerous overgrowths of lymphoid tissues  The nitrogen mustards were the first alkylating agents used medically, as well as the first modern cancer chemotherapies. 25  Alkylating agents Contain highly electrophilic groups Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine) Prevent replication of DNA and transcription Useful anti-tumour agents Toxic side effects (e.g. alkylation of proteins) Can cause interstrand and intrastrand cross-linking of DNA if two electrophilic groups are present Alkylation of nucleic acid bases can result in miscoding X X X X Nu Nu Nu Nu Nu Nu Nu Nu Intrastrand cross linking Interstrand cross linking 26  Alkylating agents Nucleophilic groups on nucleic acid bases nucleophilic groups NH2 O NH2 7 N N 3 1 N HN N nucleophilic 3 N N H2N N O groups N N R R R Adenine Guanine Cytosine Miscoding resulting from alkylated nucleic acid bases Thymine Alkylated guanine Cytosine Guanine DRUG NH2 O N Me O HO N N HN N N NH N R N N N N R R O H2N R H2N O Normal base pairing Abnormal base pairing Guanine prefers keto tautomer Alkylated guanine prefers enol tautomer 27  Alkylating Agents Mechanism of Action of nitrogen mustard Nitrogen mustards inhibit cell reproduction by formation of irreversible covalent binding with the nucleic acids (DNA). The specific type of chemical bonding involved is alkylation. After alkylation, DNA is unable to replicate and therefore unable to synthesize proteins and other essential cell metabolites. Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions. 28 Alkylating agents Chlormethine (Mechlorethamine) - Cl Nucleophile + H 3C N Electrophilic carbon Used medicinally in 1942 Cl MOA: Causes intrastrand and interstrand cross-linking Prevents replication of DNA Monalkylation of guanine also possible Used mainly to treat Hodgkin's disease and non-Hodgkin's lymphoma. Prevention of extravasation: 0.16 M sodium thiosulfate and ice packs Analogues 29 with better properties have been prepared  Mechanism of Action of Chlormethine Generation of highly reactive “aziridinium ions” that act as alkylating agents to cross-link DNA producing defective DNA and abnormal cellular function and eventually cell death. DNA DNA H G = Guanine O N NH2 H Cl O N NH2 N N + N CH3 N CH3 N N N CH3 N N G Cl Cl Cl Mechlorethamine Aziridinium ion N NH2 N N NH2 highly reactive N NH alkylating agent N NH G N O O DNA DNA H O N NH2 H O N NH2 N N N N N Crosslinked DNA CH3 N + N N N N NH2 N N NH2 NH NH CH3 N 30 N O O  Rationales used to improve nitrogen mustards Substituting an aromatic ring for methyl group can be predicted to increase chemical stability and thereby decrease the rate of alkylation because of electron-withdrawing effect. This also, will lead to good oral bioavailability, tissue distribution, before alkylation is widespread. E.g. Chlorambucil, and melphalan. Cl Cl COOH Cl NH2 N CH3 N N COOH H Cl Cl Cl Mechlorethmine Chlorambucil Melphalan 31  R R NuH Fast N N Cl..N Cl Cl Cl Nu R Moderate + HCl R=Alkyl Aziridinium ion Ph NuH Slow N N Cl..N Cl Cl Cl Nu Ph Moderate + HCl Lone pair delocalized Less nucleophilic NuH Slow S S Cl..S Cl Cl Cl Nu Moderate + HCl 32 less stable than N-aanalog  Rationales used to improve nitrogen mustards Attachment of amino acid, nucleic acid base or hormone to nitrogen mustards improve their uptake by using the carrier protein. Melphalan Cl Uracil Mustard C H3 N O Estramustine H 2N OH N C H3 HN H H C OOH Cl H C H3 O N O H H H L-phenylalanine Cl N O (amino acid) Uracil (nucleic base) Cl Estradiol (sex hormone) 33  Estramustine phosphate: Estracyt® Prodrug ❖ To increase selectivity, nitrogen mustards was bonded with natural carrier e.g. Estramustine which is active against prostate cancer. 34  Synthesis of Chlorambucil CH3 HO Nitration CH3 (CH2)3-COOH O2 N (CH2)3-COOH 4-Phenylbutyric acid CH3 CH3 2 O O2 N (CH2)3-COO- H2N (CH2)3-COO- CH3 CH3 Ethylene oxide (oxirane) HO Cl CH3 POCl 3 CH3 N (CH2)3-COO- N (CH2)3-COO- CH3 Phosphoryl chloride CH3 HO Cl Cl Hydrolysis Chlorambucil N (CH2) 3-COOH 35 Cl Alkylating agents Chlormethine analogues HOOC Cl ❖ Aromatic ring is electron-withdrawing N ❖ Lowers nucleophilic strength of nitrogen Cl ❖ Less reactive alkylating agent Chlorambucil ❖ Less side reactions and less toxic Cl NH2 Aromatic ring is present HOOC N H Less reactive alkylating agent Cl Mimics phenylalanine Melphalan Transported into cells by transport proteins Cl O ❑ Uracil ring is electron-withdrawing N HN ❑ Less reactive alkylating agent O N Cl ❑ Mimics a nucleic acid base H ❑ Concentrated in fast growing cells 36 Uracil mustard  Alkylating agents OH Me H Urethane H O H H Urethane group is electron-withdrawing Cl N O Lowers nucleophilic strength of nitrogen Estramustine Alkylating group is attached to oestradiol Cl Steroid is hydrophobic Capable of crossing cell membranes 37 Cyclophosphamide Cyclophosphamide is the most commonly used alkylating agent Non-toxic prodrug (Orally active) and requires CYP450 for activation Acrolein is toxic metabolite responsible for hemorragic cystitis Mechanism of action H+ HO O H H2N O NH O NH O P P P Cytochrome H O NR2 O NR2 O NR2 P450 enzymes Cyclophosphamide Indications: Malignant lymphomas, mycosis fungoides and leukemias; several non- H2N O Cl toxic O malignant diseases: severe rheumatoid P HO N arthritis and systemic lupus erythematosus. H Cl Other Toxicity: Myelosuppression, Alopecia, Alkylating agent Acrolein Cardiotoxicity, immunosuppressive Acrolein toxicity can be avoided by co-administration with 38 N-acetylcysteine, or mercaptoethanesulfonate.  Micheal acceptor 39 Synthesis of Cyclophosphamide H2N Cl Cl Cl Cl Cl H -HCl HO N O P Cl HN O P N O P N Cl Cl (C2H5)2NH O Cl Cl Dioxane (20-30 0C) Cl bis(2-chloroethyl)amine Cyclophosphamide Ifosfamide It is closely related in structure, clinical use, toxicity with Cyclophosphamide Prodrug: requires CYP450 for activation Acrolein is toxic metabolite Indications: Germ cell testicular cancer Side40effects: Hemorrhagic cystitis, CNS problems such as confusion and coma  Alkylating agents: Nitrosoureas O O Cl Cl Cl N N N N H H N N O O Lomustine Carmustine Carmustine Indications: Palliative treatment for brain tumors, multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphomas Non-vesicant, I.V. or topical Highly lipid soluble (may cross BBB) Long delay in bone marrow suppression (6 weeks) - do not give more often than every 6 weeks Lomustine Indications: Brain tumors and Hodgkin’s disease Bone marrow toxicity is cumulative - delayed for 6 weeks Capsule: take on empty stomach to avoid N/V 41 Highly lipid soluble allows 50% higher CNS levels Nitrosoureas Decompose in the body to form an alkylating agent and a carbamoylating agent Alkylating agent causes interstrand cross-linking between G-G or G-C Carbamoylating agent reacts with lysine residues on proteins May inactivate DNA repair enzymes O C N R Isocyanate O (carbamoylating Cl R agent) N N + N2 + HO N H Cl N Cl O H O N OH Alkylating agent Cl DNA Cl X Y X Y Alkylation Cross- Alkylating linking agent DNA DNA Protein-Lys-NH2 O O C N R Protein-Lys-NH 42 Isocyanate Carbamoylation HN R Other Alkylating Agents Busulfan: Myleran®, Busulfex ® O O S O Me Me O S O Notes O Synthetic agent used as an anticancer agent Sulfonate Causes interstrand cross-linking (good leaving group) Very well tolerated drug but severe myelosuppression Discontinue at first sign of bone marrow abnormalities Can cause hyperuricemia—use allopurinol to avoid Mechanism of Action O O S O Me OSO2Me Me O S O O O N -MeSO3- N N -MeSO3- N HN N Guanine N N N N H2N N N 43 DNA DNA DNA DNA DNA Other Alkylating Agents: Aziridines Thiotepa: Thioplex® N Indications: Adenocarcinoma of the N P N breast or ovary, urinary bladder papillary carcinoma, lymphomas S IV use only Thiotepa - Thioplex® Tris-1-aziridinylphosphine sulfide MOA: Alkylates by ethyleneimine radical disrupting DNA Monitor renal and hepatic function - decrease dosage as appropriate Monitor blood counts for at least three weeks following cessation of therapy - very highly toxic to bone marrow - discontinue if sharp drop in WBC’s or platelets 44 Other Alkylating Agents: Methylhydrazines Procarbazine HCl: Matulane® H N N CH3 H H H 3C N Indications: Hodgkin’s disease CH3 O MOA: Free radical methylation of DNA: results in cessation of protein, Procarbazine HCl - Matulane® DNA and RNA synthesis Caution Initial treatment should be considered via hospitalization due to hepatic and renal impairment - metabolism in liver and kidneys produce cytotoxic metabolites. Capsules, warn patients of ethanol-disulfiram like reactions, avoid sympathomimetics such as cold-cough preps and tyramine containing foods due to possibility of hypertensive crisis. 45  Procarbazine Mechanism of Action 46 Other Alkylating Agents: Methylhydrazines Dacarbazine: HN N Prodrug activated by demethylation in liver N N CONH2 Decomposes to form a methyldiazonium ion H3C N Alkylates guanine groups CH3 Mechanism of Action AIC HN N Cyt P-450 HN N HN N HN N -CH2O liver N N CONH2 N N CONH2 N NH CONH2 H2N CONH2 H3C N N N H H CH3 H O CH3 CH3 N N CH3 Methyldiazonium ion N2 + CH3 DNA 47 O6-Methylguanine-DNA Other Alkylating Agents Mitomycin C O CH2OCONH2 H2N OMe Me N NH O ❑ Prodrug activated in the body to form an alkylating agent ❑ One of the most toxic anticancer drugs in clinical use 48  H O OH O CH2OCONH 2 CH2OCONH2 CH2OCONH2 H2N OMe H2N OMe H2N -MeOH N NH Reduction N NH N NH Me Me Me H O OH OH Mitomycin C O H C NH2 H O O CH2OCONH 2 OH CH2 H2N H2N H2 N-DNA -H + Ring H2 N-DNA NH-DNA opening Me N N Me NH2 NH2 OH OH Alkylating agent O Guanine HN N N N NH NH-DNA OH OH CH2 O Guanine CH2 H 2N N H2N HN NH NH-DNA N -CO2 N Me N -NH3 N Me NH2 NH2 OH OH 49 Crosslinked DNA  H3 N Cl Metallating agents Pt Cisplatin: Platinol® H3 N Cl Cisplatin Diamminedichloroplatinum Neutral inactive molecule acting as a prodrug Platinum covalently linked to chloro substituents Ammonia molecules act as ligands that bound irreversibly by coordinate covalent bonds MOA Activated in cells with low chloride ion concentration Chloro substituents are replaced with neutral water ligands Produces positively charged species that react with DNA Cl NH3 H2O H2O NH3 + H2O NH3 2+ DNA DNA NH3 Pt Pt Pt Pt + Cl NH3 Cl NH3 H2O NH3 DNA NH3 50 Cisplatin Metallating agents Cisplatin Cl NH3 Pt Cl NH3 Binds to DNA in regions rich in guanine units Intrastrand links are formed rather than interstrand link It binds to N-7 and O-6 positions of adjacent guanine molecules Hydrogen bond involved in base-paring guanine to cytosine are disrupted by the cross-links Causes localised unwinding of the DNA double helix O 1 7 Inhibits transcription HN 6 5 N 8 H2N 2 N 4 N 9 3 CH3 51 https://www.youtube.com/watch?v=Wq_up2uQRDo Guanine  Cisplatin Mechanism of Action (Video Presentation) 52 https://www.youtube.com/watch?v=Wq_up2uQRDo Metallating agents Cisplatin analogues O H2 Cl NH3 OAc N O O Pt H3N O H3N Pt Cl Cl N Pt N Cl Pt H3N H2 O OAc N O O Me H2 O Carboplatin JM216 Oxaliplatin Picoplatin Less side effects First orally Approved in 1999 active analogue Comparative adverse effect profiles of platinum drugs Adverse effects Cisplatin Carboplatin Oxaliplatin Nephrotoxicity ++ + - GI toxicity +++ + + Peripheral neurotoxicity +++ - ++ Ototoxicity + - - Hematologic toxicity + ++ + 53 Hypersensitivity - + -