1. Patrick: An Introduction to Medicinal Chemistry 6e
Chapter 9
DRUGS TARGETING
NUCLEIC ACIDS
DNA & RNA
modified

2. 1. DRUGS ACTING ON DNA
Intercalating agents
Topoisomerase poisons
Alkylating agents
Metallating agents
Chain cutters
Chain terminators
Control of gene transcription

3. 1. DRUGS ACTING ON DNA 1.1 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 can inhibit topoisomerases

4. 1. DRUGS ACTING ON DNA 1.1 Intercalating agents
Proflavine
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
Prflavine structure not shown

5. Sugar phosphate backbone
1. DRUGS ACTING ON DNA
1.1 Intercalating agents
Example - Proflavine
Proflavine T
DNA DOUBLE HELIX A G C
Sugar phosphate backbone
Proflavine R
van der Waals interactions
Ionic interactions
Prflavine structure not shown

6. 1. DRUGS ACTING ON DNA 1.1 Intercalating agents
Examples - anticancer agents
Planar rings
Doxorubicin (Adriamycin)
Dactinomycin
Doxorubicin (Adriamycin)
Dactinomycin
Planar rings
Doxorubicin (Adriamycin)
Dactinomycin
Planar rings
Doxorubicin (Adriamycin)
Dactinomycin
Extra binding to sugar phosphate backbone by cyclic peptides
Extra binding to sugar phosphate backbone by NH3

7. 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Notes on dactinomycin
Intercalates via minor groove of DNA double helix
Prevents unwinding of DNA double helix
Blocks transcription by blocking DNA-dependent RNA polymerase
Notes on doxorubicin
Intercalates via the major groove of DNA double helix
Blocks the action of topoisomerase II by stabilising the DNA-enzyme complex
Acts as a topoisomerase poison

8. 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Examples - Bleomycins
Primary amine
Primary amide
Bithiazole
intercalating
region
Pyrimidine
ring
Primary amine
Imidazole
ring
Structure refreshed B l e o m y c i n A 2 R = N H C S M ( ) +

9. 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Notes on bleomycins
Used as anticancer agents
Intercalate DNA by means of bithiazole ring system
Ferrous ion then chelated by nitrogens of the primary amines, amide, and pyrimidine ring
Reaction with oxygen results in a ferric ion and reactive oxygen species
Results in radical formation and chain cutting
Bleomycin prevents DNA ligase from repairing damage
modified

10. 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples
Etoposide
Teniposide
Notes on etoposide and teniposide
Stabilise the complex between DNA and topoisomerase enzymes
Used as anticancer agents
Also cause chain cutting

11. 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples - Camptothecin
Lactone ring
Notes
Stabilises complex between DNA and topoisomerase I
Single-strand breaks accumulate in the chain
Irreversible double-strand breaks occur during transcription
Semi-synthetic analogues used as anticancer agents
Structure refreshed

12. 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples - Quinolones and fluoroquinilones
Nalidixic acid
Ciprofloxacin
Notes
Synthetic agents used as antibacterial agents
Stabilise complex between bacterial DNA and topoisomerases
Binding site for agents revealed once DNA strands are ‘nicked’
Modified
Both structures refreshed

13. 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples - Quinolones and fluoroquinilones
Topoisomerase
enzyme
Region binding to DNA
Region
binding
to enzyme
Stacking domain
modified
Fluoroquinolones
Four drug molecules are stacked in the bound complex
Bound to DNA and enzyme by hydrogen and ionic bonds

14. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Notes
Contain highly electrophilic groups
Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine)
Prevent replication and transcription
Useful anticancer agents
Toxic side effects (e.g. alkylation of proteins)
Can cause interstrand and intrastrand crosslinking if two electrophilic groups present
Alkylation of nucleic acid bases can result in miscoding

15. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Crosslinking
Intrastrand crosslinking
Interstrand crosslinking

16. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents
Nucleophilic groups on nucleic acid bases
Nucleophilic groups
Cytosine
Guanine
Adenine
Nucleophilic groups

17. Miscoding resulting from alkylated nucleic acid bases
1. DRUGS ACTING ON DNA
1.3 Alkylating agents
Cytosine
Guanine
Normal base pairing
Miscoding resulting from alkylated nucleic acid bases
Structures refreshed
Guanine prefers keto tautomer
Abnormal base pairing.
Alkylated guanine prefers enol tautomer

18. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example Notes
Chlormethine (nitrogen mustard)
Notes
Used medicinally in 1942
Causes intrastrand and interstrand cross-linking
Prevents replication
Mono-alkylation of guanine also possible
Analogues with better properties have been prepared

19. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents
Chlormethine - mechanism of action
Chlormethine
Aziridine ion
Mofified
Second set of curly rrows redrawn
Crosslinked DNA

20. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example - Nitrosoureas
Lomustine
Carmustine
Mechanism of action
Decompose in body to form an alkylating agent and a carbamoylating agent
Bottom diagram redone +
Isocyanate
(carbamoyating agent
Alkylating agent

21. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example - Nitrosoureas
Akylation
Cross linking
Isocyanate
Protein-Lys-NH2
Carbamoylation
Protein-Lys-NH
Notes
Alkylating agent causes interstrand crosslinking
Crosslinking between G-G or G-C
Carbamoylating agent reacts with lysine residues on proteins
May inactivate DNA repair enzymes
Diagrams copied from chapter 21

22. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Mechanism Busulfan
Synthetic agent used as anticancer agent
Causes interstrand crosslinking
Mechanism
Guanine
-MeSO3-
All structures copied from chapter 21
First part of sequence recopied
-MeSO3-

23. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Mechanism Dacarbazine
Prodrug activated by demethylation in liver
Decomposes to form a methyldiazonium ion
Alkylates guanine groups
Mechanism
Cyt P-450
Liver
-CH2O
Dacarbazine and two intermediates refreshed
N CH3

24. 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example - Mitomycin C
Notes
Prodrug activated in the body to form an alkylating agent
One of the most toxic anticancer drugs in clinical use

25. .. .. Reduction -MeOH Mitomycin C H2N-DNA -H + H2N-DNA Ring opening
Alkylating agent
Modified
Copied from chapter 21
Last two sets of curly arrows redrawn
-CO2
-NH3
Crosslinked DNA

26. 1. DRUGS ACTING ON DNA 1.4 Metallating agents Cisplatin Notes
Neutral inactive molecule acting as a prodrug
Platinum covalently linked to chloro substituents
Ammonia molecules act as ligands
Activated in cells with low chloride ion concentration
Chloro substituents replaced with neutral water ligands
Produces positively charged species
DNA +
H2O
Cisplatin 2+

27. 1. DRUGS ACTING ON DNA 1.4 Metallating agents Cisplatin
Binds to DNA in regions rich in guanine units
Intrastrand links rather than interstrand
Localised unwinding of DNA double helix
Inhibits transcription

28. 1. DRUGS ACTING ON DNA 1.5 Chain cutters Intercalating agent
Bleomycin
Used vs skin cancer
BLEOMYCIN A R = NHCH2CH2CH2SMe2
BLEOMYCIN B R = NHCH2CH2CH2CH2NHC(NH2)=NH
modifued
Intercalating agent
Abstracts H from DNA to generate radicals
Radicals react with oxygen resulting in chain cutting
Bleomycin also inhibits repair enzymes

29. 1. DRUGS ACTING ON DNA 1.5 Chain cutters Generates DNA diradical
Calicheamicin g1I
Antitumour agent
Enediyne
system
Structure refreshed
Generates DNA diradical
DNA diradical reacts with oxygen
Results in chain cutting

30. 1. DRUGS ACTING ON DNA 1.5 Chain cutters Mechanism . DNA . Michael
addition
Cycloaromatisation
DNA
. DNA .
(Diradical)
Modifed
Last structure refreshed O2
Oxidative
cleavage

31. 1. DRUGS ACTING ON DNA 1.6 Chain terminators Notes
Enzymes
in vivo
Azidothymidine (AZT)
(Zidovudine;Retrovir)
Chain terminating
group
modified
Notes
Azidothymidine is a prodrug used in the treatment of HIV
AZT is phosphorylated to a triphosphate in the body
Triphosphate has two mechanisms of action
- inhibits a viral enzyme (reverse transcriptase)
- is added to growing DNA chain and acts as a chain terminator

32. 1. DRUGS ACTING ON DNA 1.6 Chain terminators
Aciclovir
(Zovirax)
Famciclovir
(Famvir)
Chain
terminating
group
Chain
terminating
group
Prodrugs used as antiviral agents
Same mechanisms of action as AZT
Used vs herpes simplex and shingles

33. 1. DRUGS ACTING ON DNA 1.6 Chain terminators a) Normal replication A T3 ' D N t e m p l a r o w i n g c h
GPPP redone

34. 1. DRUGS ACTING ON DNA 1.6 Chain terminators b) Chain termination A T3 ' D N t e m p l a r o w i n g c h
Chain termination
DrugPPP redone

35. 1. DRUGS ACTING ON DNA 1.7 Control of gene transcription Notes
Design of synthetic molecules capable of controlling gene transcription
Molecules capable of recognising and binding to specific base pairs
Hairpin polyamides containing heterocyclic rings are capable of binding to the minor groove
Binding involves amide groups and heterocycles
Particular patterns of heterocyclic rings allow recognition of particular base pairs
Capable of inhibiting transcription
Designed to bind to regulatory element of a gene
modified

36. 1. DRUGS ACTING ON DNA Py Im Hp
DNA and molecule refreshed

37. 2. DRUGS ACTING ON rRNA Antibiotics Streptomycin Chloramphenicol
Rifamycins
Chloramphenicol
(vs typhoid)
Erythromycin
Chlortetracycline
(Aureomycin)

38. 3. DRUGS ACTING ON mRNA Antisense Therapy Protein synthesis Antisense
molecule
Protein synthesis
m-RNA
Antisense
molecule
m-RNA
Bottom interactions refreshed

39. 3. DRUGS ACTING ON mRNA Antisense Therapy Advantages
Same effect as an enzyme inhibitor or receptor antagonist
Highly specific where the oligonucleotide is 17 nucleotides or more
Smaller dose levels required compared to inhibitors or antagonists
Potentially less side effects
Disadvantages
‘Exposed’ sections of mRNA must be targeted
Instability and polarity of oligonucleotides (pharmacokinetics)
Short lifetime of oligonucleotides and poor absorption across cell membranes

40. 3. DRUGS ACTING ON mRNA Micro-RNA (miRNA)
Short segments of double stranded RNA
Recognised by enzyme complex RISC to produce single stranded RNA (siRNA) in the form of a guide strand
Guide strand remains bound to RISC and also binds to a complementary region of mRNA
mRNA is then cleaved by the enzyme complex
AllRisc structurerefreshed
Duplex
Passenger strand
Guide strand
m-RNA

41. 3. DRUGS ACTING ON mRNA Micro-RNA (miRNA) Advantages
siRNAs have potential to be used in gene therapy
Greater efficiency in silencing mRNA than conventional antisense therapy
One siRNA could lead to cleavage of several mRNA molecules
Problems
siRNAs need to be metabolically stable
Need to reach target cells
Need to enter target cells