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Alkylating anticancers
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Alkylating anticancers






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    Alkylating anticancers Alkylating anticancers Presentation Transcript

    • AlkylatingAnticancers
    • What is Cancer ?
    • Cancer is uncontrolled growth of abnormal cells in the body. (cancer cells don’t die)
      There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected.
      Cancer cells are also called malignant cells.
    • Normal cells in the body follow an orderly path of growth, division, and death.
      Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form.
      Unlike normal cells, cancer cells do not experience apoptosis and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.
    • The basic differences between cancer cells and normal cells is that cancer cells characterized by :
      Uncontrolled cell proliferation.
      Decreased cellular differentiation
      Ability to invade surrounding tissues and
      Ability to establish new growth at ectopic site “metastasis”
    • Difference between benign and malignant (cancer) tumors that :
      Malignant tumors metastasize while Benign tumors don’t metastasize
      Metastasis: is a secondary growth originating from the primary tumor and growing elsewhere in the body.
    • Causes of cancer
      Environmental factors 90-95 %
      Smoking and alcohol
      Genetic factors 5-10%
    • Carcinogenesis
    • Treatment
    • Types of cancer treatment
      Used in conjugation with all types of treatment
      Radiation therapy
      Monoclonal antibodies
      Hormonal therapy
    • Immunotherapy
      It used as a follow-up therapy and it postpones the spread or recurrence of cancer
      Types of immunotherapy :
      Interluekin -2
    • Chemotherapy
      Chemotherapy in cancer is mostly palliative (not curative) except for certain types of cancer e.g. Hodgking’s disease , lymphosarcoma , rhapdomyosarcoma
      Chemotherapeutic drugs are better at killing cycling cells “i.e. cells during DNA Synthesis” (s phase) and active division, that is more active against cycling than non-cycling cells.
    • Chemotherapeutic drugs have many side effects as :
      Bone marrow toxicity
      Nausea and vomiting
      Loss of hair
      Increased susceptibility to infection
      Teratogenic in pregnant women
    • Mechanism of action of chemotherapeutic agents divide into three mechanisms
      Stop the synthesis of pre DNA molecule building blocks e.g. folic acid and nucleotides
      Directly damage the DNA in the nucleus of the cell
      Effect on the synthesis or breakdown of the mitotic spindles
    • Stop the synthesis of pre DNA molecule building blocks e.g. folic acid and nucleotides
      These agents work to block some step in the formation of deoxyribonucleotides or nucleotides which are necessary in making of RNA & DNA . So When these steps are blocked , the nucleotides cannot be synthesized and these cells cannot replicate .
      Examples : methotrexate , fluorouracil and Mercaptopurine
    • Directly damage the DNA in the nucleus of the cell
      These agents chemically damage DNA and RNA. They disrupt replication of the DNA and either totally halts replication or cause the manufacture of nonsense DNA or RNA i.e. the new DNA or RNA does not code
      Examples : alkylating agents (e.g. Cisplatin) , daunorubicin and doxorubicin .
    • Effect on the synthesis or breakdown of the mitotic spindles
      Mitotic spindles help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division.
      Examples :Vinblastine and Vincristine
    • Alkylating agents
    • Alkylating agents are compounds that are capable of introducing an alkyl group into nucleophilic sites on DNA , RNA or any enzyme through covalent bond .
      These agents are thought to react with the 7 position of guanine ( or any other nitrogen base) in each of the double strands of DNA, causing cross-linking that interferes with separation of the strands and prevents mitosis.
    • The effects of base alkylation include misreading of the DNA codon and single strand breakage of the DNA chain. However, the longtime effects are mutation and cell death.
      The favored site on DNA is at the N7 position of guanine, adenine, cytosine, and even the sugar phosphate groups .
    • Alkylating agents
    • Platinum based alkylating like agents
    • Nitrogen Mustards
      The nitrogen mustards are cytotoxic chemotherapeutic agents similar to mustard gas which was used in WWI and WWII
    • Nitrogen mustards contain
      BIS(2-chloroethyl) group
      Modification of this group
      Change stability , reactivity
      and lipophilicity
    • Mechanism of Alkylation byNitrogen Mustards
    • Methclorethamine (2-chloro-N-(2-chloroethyl)-N-methyl-ethanamine)
      a strong vesicant and is
      taken By IV infusion and It used
      to treat prostate cancer .
      A major disadvantage of
      mechlorethamine is that it has mutagenic and carcinogenic effect on bone marrow stem cells.
    • Cyclophpsphamide (Cytoxan®)
    • Cyclophosphamide (N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide)
      This most widely used
      Alkylating agent
      It is inactive in vitro but
      When it administered it is
      Metabolized by liver into phosphoramide Mustard (active compound)
    • SAR of Cyclophosphamide
      Bis-2-chloroethylamino group is essential
      Chloro atom provides maximum activity
      Levo-isomer is inactive
      Triethylene derivative is inactive
    • CyclophosphamideActivation/Metabolism
    • phosphoramide Mustard is cytotoxic to cancer cells while acrolein is toxic to the bladder
      Cyclophosphamide may given orally but its absorption incomplete So it is better to be given I.V
      It used to treat many types of cancer such as
      lymphosarcomas , breast, ovarian, and lung cancer.
    • Nitroureas
      They are compounds that have nitroso (R-NO) group and a urea. They have little cross-resistance with other alkylating agents
      They cross blood-brain barrier So they used against brain tumors
    • Carmustine(N,N'-bis(2-chloroethyl)-N-nitroso-urea )
      It cause alkylation of DNA
      At O-6 position of guanine
      It mainly used to treat brain
      cancer and lymphoma
      It cause pulmonary toxicity and nephrotoxicity
    • Alkyl sulphonates
      Busulfan (butane-1,4-diyl dimethanesulfonate)
      It is used for treatment of
      chronic myelogenous leukemia
      (CML) in bone marrow
      Transplantation patients
      Main side effect is seizure
    • Platinum based alkylating like agents
      These agents do not have an alkyl group, but They also damage DNA.They permanently coordinate to DNA to interfere with DNA repair (They trigger apoptosis)
      Platin is the only heavy metal compound in common use as a cancer chemotherapeutic agent
    • Cisplatin(diamminedichloroplatinum)
      It acts against cells that are
      actively synthesizing nucleic
      acids (S phase) and against
      cells in mitosis (M phase)
      the preferred site of binding
      is the N7 position of guanidine
    • Because it’s bifunctional (having two leaving groups) Cisplatin can form inter-strand DNA cross links which cause cytotoxicity
      It used in treatment of man-seminomatous testicular cancer and in ovarian cancer
      It is nephrotoxic agent
    • Methylhydrazines
      It must be converted into an azo derivative in vivo to become active against tumor cells.
      Alkylation of DNA or possible transmethylation may be the mode of action.
    • It is a component of the MOPP (Mechlorethamine, vincristine , procarbazine and predinsone) combination that is so effective in treatment of Hodgkins disease.
      It has monamineoxidase inhibition properties (MAOI) ,So it should not be taken with most antidepressants and certain migraine medications.
    • Refrences
      *Foy’s Principles of Medicinal Chemistry, chapter 42, sixth edition.
      **Foy’s Principles of Medicinal Chemistry, chapter 6, sixth edition
      Goodman & Gilman's The Pharmacological Basis of Therapeutics , eleventh edition
      Cancer chemotherapy--the first twenty-five yearsby R. B. Scott
      Handbook of Cancer Chemotherapy (6th edition)