Patrick An Introduction to Medicinal Chemistry 3/e Chapter 7 NUCLEIC ACIDS AS DRUG TARGETS

1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 7 NUCLEIC ACIDS AS DRUG TARGETS Part 2: Section 7.3 (Drugs acting on DNA)

2. Contents Part 2: Section 7.3 (Drugs acting on DNA) 3. Drugs acting on DNA 3.1. Intercalating agents - Topoisomerase II (6 slides) - Example – Proflavine (2 slides) - Examples - Examples – antimalarial agents 3.2. Alkylating agents (7 slides) 3.3. Chain cutters (3 slides) [21 slides]

3. 3. DRUGS ACTING ON DNA 3.1 Intercalating agents • Mechanism of action • Contain planar aromatic or heteroaromatic ring systems • Planar systems slip between the layers of nucleic acid pairs and disrupt the shape of the helix • Preference is often shown for the minor or major groove • Intercalation prevents replication and transcription • Intercalation inhibits topoisomerase II

4. 3. DRUGS ACTING ON DNA Topoisomerase II • Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand • Tyrosine residues in the enzyme are involved in the chain breaking process • The residues form covalent bonds to DNA

5. 3. DRUGS ACTING ON DNA Topoisomerase II • Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand Topo II • Tyrosine residues in the enzyme are involved in the chain breaking process • The residues form covalent bonds to DNA • The enzyme pulls the chains apart to create a gap

6. 3. DRUGS ACTING ON DNA Topoisomerase II • Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand • Tyrosine residues in the enzyme are involved in the chain breaking process • The residues form covalent bonds to DNA • The enzyme pulls the chains apart to create a gap • The intact strand of DNA is passed through the gap

7. 3. DRUGS ACTING ON DNA Topoisomerase II • Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand • Tyrosine residues in the enzyme are involved in the chain breaking process • The residues form covalent bonds to DNA • The enzyme pulls the chains apart to create a gap • The intact strand of DNA is passed through the gap • The break is resealed

8. 3. DRUGS ACTING ON DNA Topoisomerase II • Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand • Tyrosine residues in the enzyme are involved in the chain breaking process • The residues form covalent bonds to DNA • The enzyme pulls the chains apart to create a gap • The intact strand of DNA is passed through the gap • The break is resealed

9. 3. DRUGS ACTING ON DNA Topoisomerase II Mechanism of chain cutting

10. Example - Proflavine Proflavine 3. DRUGS ACTING ON DNA 3.1 Intercalating agents • Planar tricyclic system • The amino substituents are protonated and charged • Used as a topical antibacterial agent in the second world war • Targets bacterial DNA • Too toxic for systemic use

11. Proflavine G C A T T A T A G C G C T A T A T A A T A T A T C G G C T A T A G C G C G C T A A T C G T A van der Waals interactions T A Ionic interactions DNA DOUBLE HELIX 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Example - Proflavine

12. Planar rings Planar rings Doxorubicin(Adriamycin) Dactinomycin 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Examples Extra binding to sugar phosphate backbone by NH3 Extra binding to sugar phosphate backbone by cyclic peptide

13. Chloroquine Quinine 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Examples- antimalarial agents

14. 3. DRUGS ACTING ON DNA 3.2 Alkylating agents • Contain highly electrophilic groups • Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine) • Prevent replication and transcription • Useful anti-tumour agents • Toxic side effects (e.g. alkylation of proteins) Example Mechlorethamine (nitrogen mustard)

15. Intrastrand cross linking Interstrand cross linking 3. DRUGS ACTING ON DNA 3.2 Alkylating agents Cross linking

16. Aziridine ion Mechlorethamine 3. DRUGS ACTING ON DNA 3.2 Alkylating agents Mechanism of action Crosslinked DNA

17. 3. DRUGS ACTING ON DNA 3.2 Alkylating agents Mechlorethamine analogues Aromatic ring - e withdrawing effect N is less nucleophilic Less reactive alkylating agent Selective for stronger nucleophiles (e.g. guanine) Uracil mustard Used vs leukaemia Attached to a nucleic acid building block Concentrated in fast growing cells (tumours) Some selectivity

18. Cisplatin Mitomycin C 3. DRUGS ACTING ON DNA 3.2 Alkylating agents Binds to DNA in regions rich in guanine units Intrastrand links rather than interstrand Inhibits transcription Converted to alkylating agent in the body

19. -MeOH Reduction -H + Ring opening -CO2 -NH3 Alkylating agent Crosslinked DNA

20. Bleomycin Used vs skin cancer 3. DRUGS ACTING ON DNA 3.3 Chain cutters BLEOMYCIN A2 R = NHCH2CH2CH2SMe2 BLEOMYCIN B2 R = NHCH2CH2CH2CH2NHC(NH2)=NH • Abstracts H from DNA to generate radicals • Radicals react with oxygen resulting in chain cutting • Bleomycin also inhibits repair enzymes

21. Calicheamicin g1I Antitumour agent 3. DRUGS ACTING ON DNA 3.3 Chain cutters • Generates DNA diradical • DNA diradical reacts with oxygen • Results in chain cutting

22. Michael addition Cycloaromatisation O2 Oxidative cleavage 3. DRUGS ACTING ON DNA 3.3 Chain cutters