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)