Transcript D. DNA interactive agents

Introduction
 Drugs 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 agents
 Are 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 interactions
 Overlapping 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 5flourouracil not the opposite (Explain?)
DNA structure
 Purines and Pyrimidines
DNA structure
 Phosphodiester bond is
relatively stable bond
inside the body because
of the negatively charged
characterstics (HOW?)
Bonds formed in DNA structure
 Hydrophobic and London forces inside the same DNA
strand
 H-bonding between the double helix
Three types of DNA interactive
agents
 Reversible binders
 Alkylators: covalently bind to DNA double helix
 DNA strand breakers: generates radicals that will
cleave polynucleotide strands
Reversible DNA Binders
 Ideal DNA interactive agents better to be:
 Nonpeptide
 Targeted specific DNA sequence
 Targeted Specific site size
Reversible DNA Binders
 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
External Electrostatic Binders
 Polycationic 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 binders
 H-bond donors or acceptors
 Aromatic or heteroaromatic rings
 Crescent shape
 Moderate size structure