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