2. 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

3. 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

4. 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

5. 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 5- flourouracil not the opposite (Explain?)

6. DNA structure Purines and Pyrimidines

7. DNA structure Phosphodiester bond is relatively stable bond inside the body because of the negatively charged characterstics (HOW?)

8. Bonds formed in DNA structure Hydrophobic and London forces inside the same DNA strand H-bonding between the double helix

9. 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

10. Reversible DNA Binders Ideal DNA interactive agents better to be: Nonpeptide Targeted specific DNA sequence Targeted Specific site size

11. 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

13. 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

14. Minor Groove Binders

15. Netropsin and destamycin

16. SAR for Minor groove binders H-bond donors or acceptors Aromatic or heteroaromatic rings Crescent shape Moderate size structure