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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)

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Presentation on theme: "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)"— Presentation transcript:

1 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 1 © Contents 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 1 © 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Mechanism of action Contain planar aromatic or heteroaromatic ring systemsContain planar aromatic or heteroaromatic ring systems Planar systems slip between the layers of nucleic acid pairs and disrupt the shape of the helixPlanar 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 groovePreference is often shown for the minor or major groove Intercalation prevents replication and transcriptionIntercalation prevents replication and transcription Intercalation inhibits topoisomerase IIIntercalation inhibits topoisomerase II

4 1 © Topoisomerase II Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strandRelieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand 3. DRUGS ACTING ON DNA Tyrosine residues in the enzyme are involved in the chain breaking processTyrosine residues in the enzyme are involved in the chain breaking process The residues form covalent bonds to DNAThe residues form covalent bonds to DNA

5 1 © Topoisomerase II Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strandRelieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand 3. DRUGS ACTING ON DNA Tyrosine residues in the enzyme are involved in the chain breaking processTyrosine residues in the enzyme are involved in the chain breaking process The residues form covalent bonds to DNAThe residues form covalent bonds to DNA The enzyme pulls the chains apart to create a gapThe enzyme pulls the chains apart to create a gap Topo II

6 1 © Topoisomerase II Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strandRelieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand 3. DRUGS ACTING ON DNA Tyrosine residues in the enzyme are involved in the chain breaking processTyrosine residues in the enzyme are involved in the chain breaking process The residues form covalent bonds to DNAThe residues form covalent bonds to DNA The intact strand of DNA is passed through the gapThe intact strand of DNA is passed through the gap The enzyme pulls the chains apart to create a gapThe enzyme pulls the chains apart to create a gap

7 1 © Topoisomerase II Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strandRelieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand 3. DRUGS ACTING ON DNA Tyrosine residues in the enzyme are involved in the chain breaking processTyrosine residues in the enzyme are involved in the chain breaking process The residues form covalent bonds to DNAThe residues form covalent bonds to DNA The break is resealedThe break is resealed The intact strand of DNA is passed through the gapThe intact strand of DNA is passed through the gap The enzyme pulls the chains apart to create a gapThe enzyme pulls the chains apart to create a gap

8 1 © Topoisomerase II Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strandRelieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand 3. DRUGS ACTING ON DNA Tyrosine residues in the enzyme are involved in the chain breaking processTyrosine residues in the enzyme are involved in the chain breaking process The residues form covalent bonds to DNAThe residues form covalent bonds to DNA The break is resealedThe break is resealed The intact strand of DNA is passed through the gapThe intact strand of DNA is passed through the gap The enzyme pulls the chains apart to create a gapThe enzyme pulls the chains apart to create a gap

9 1 © Mechanism of chain cutting 3. DRUGS ACTING ON DNA Topoisomerase II

10 1 © 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Example - Proflavine Proflavine Planar tricyclic systemPlanar tricyclic system The amino substituents are protonated and chargedThe amino substituents are protonated and charged Used as a topical antibacterial agent in the second world warUsed as a topical antibacterial agent in the second world war Targets bacterial DNATargets bacterial DNA Too toxic for systemic useToo toxic for systemic use

11 1 © Proflavine van der Waals interactions Ionic interactions 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Example - Proflavine

12 1 © Planar rings Extra binding to sugar phosphate backbone by NH 3 Doxorubicin (Adriamycin) Dactinomycin Extra binding to sugar phosphate backbone by cyclic peptide 3. DRUGS ACTING ON DNA 3.1 Intercalating agents Examples

13 1 © Examples- antimalarial agents Chloroquine Quinine 3. DRUGS ACTING ON DNA 3.1 Intercalating agents

14 1 © 3.2 Alkylating agents Contain highly electrophilic groupsContain highly electrophilic groups Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine)Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine) Prevent replication and transcriptionPrevent replication and transcription Useful anti-tumour agentsUseful anti-tumour agents Toxic side effects (e.g. alkylation of proteins)Toxic side effects (e.g. alkylation of proteins) Example Mechlorethamine (nitrogen mustard) 3. DRUGS ACTING ON DNA

15 1 © Interstrand cross linking Intrastrand cross linking Cross linking 3.2 Alkylating agents 3. DRUGS ACTING ON DNA

16 1 © Mechlorethamine Aziridine ion Crosslinked DNA 3.2 Alkylating agents 3. DRUGS ACTING ON DNA Mechanism of action

17 1 © Aromatic ring - e withdrawing effect N is less nucleophilic Less reactive alkylating agent Selective for stronger nucleophiles (e.g. guanine) Mechlorethamine analogues Uracil mustard Used vs leukaemia Attached to a nucleic acid building block Concentrated in fast growing cells (tumours) Some selectivity 3.2 Alkylating agents 3. DRUGS ACTING ON DNA

18 1 © Binds to DNA in regions rich in guanine units Intrastrand links rather than interstrand Inhibits transcription Converted to alkylating agent in the bodyCisplatin Mitomycin C 3.2 Alkylating agents 3. DRUGS ACTING ON DNA

19 1 © -MeOH Ring opening -H + Alkylating agent -CO 2 -NH 3 Crosslinked DNA Reduction

20 1 © Abstracts H from DNA to generate radicalsAbstracts H from DNA to generate radicals Radicals react with oxygen resulting in chain cuttingRadicals react with oxygen resulting in chain cutting Bleomycin also inhibits repair enzymesBleomycin also inhibits repair enzymes BLEOMYCIN A2 R = NHCH 2 CH 2 CH 2 SMe 2 BLEOMYCIN B2 R = NHCH 2 CH 2 CH 2 CH 2 NHC(NH 2 )=NH Bleomycin Used vs skin cancer 3.3 Chain cutters 3. DRUGS ACTING ON DNA

21 1 © Generates DNA diradicalGenerates DNA diradical DNA diradical reacts with oxygenDNA diradical reacts with oxygen Results in chain cuttingResults in chain cutting Calicheamicin  1 I Antitumour agent 3.3 Chain cutters 3. DRUGS ACTING ON DNA

22 1 © Cycloaromatisation O2O2 Oxidative cleavage Michael addition 3.3 Chain cutters 3. DRUGS ACTING ON DNA


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