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The main differences between normal and cancer cells The rapid, abnormal and uncontrolled cell division that needs rapid DNA production DNA damage is defective in cancer cells: the cell cycle arrest or apoptosis is switched-off
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DNA Interactive agents
IntroductionDrugs that interact with DNA are generally
very toxic to normal cells
The major use is in cancer
Little are selective agents against abnormal DNA
Few differences have been recognized between cancer cell and normal cell
The main differences between normal and cancer cells
The rapid, abnormal and uncontrolled cell division that needs rapid DNA production
DNA damage is defective in cancer cells: the cell cycle arrest or apoptosis is switched-off
Anticancer agentsAre more active on rapidly dividing cells such
as Leukemia and Lymphoma
Unfortunately, most of cancer types are solid tumors
Anticancer agents affects more rapidly dividing normal cells such as bone marrow, GIT mucosa and hair
Possible drug-drug interactionsOverlapping toxicity:
is the most important to concern about.Example: drugs that cause renal toxicity should
not be used with drugs normally excreted in urine
The order of administration:Example: Methotrexate should be given before
5-flourouracil not the opposite (Explain?)
DNA structurePurines and Pyrimidines
N
NNH
N
NH2
NH
NNH
N
O
NH2Adenine Guanine
N
NH
NH2
O
NH
NH
O
O
Cytosine Thymine
DNA structurePhosphodiester bond
is relatively stable bond inside the body because of the negatively charged characterstics (HOW?)
Bonds formed in DNA structureHydrophobic and London forces inside the
same DNA strandH-bonding between the double helix
Three types of DNA interactive agentsReversible binders
Alkylators: covalently bind to DNA double helix
DNA strand breakers: generates radicals that will cleave polynucleotide strands
Reversible DNA BindersIdeal DNA interactive agents better to be:
NonpeptideTargeted specific DNA sequenceTargeted Specific site size
Three ways of binding to double helix by these agents:
Electrostatic binding along exterior of the helix
Interaction with the edges of the base pairs (Minor and Major groove)
Intercalation between base pairs
Reversible DNA Binders
External Electrostatic BindersPolycationic compounds that will bind to the
external DNA negatively charged sugar phosphate backbone
This binding will lead to disruption of the DNA structure
Minor Groove Binders
Netropsin and destamycin
SAR for Minor groove bindersH-bond donors or acceptorsAromatic or heteroaromatic ringsCrescent shapeModerate size structure