Transcript patrick_ch07_p3

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 7
NUCLEIC ACIDS AS
DRUG TARGETS
Part 3: Section 7.3 (Drugs acting on RNA)
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Contents
Part 3: Section 7.3 (Drugs acting on RNA)
4. Drugs Acting On rRNA
- Antibiotics
5. Drugs Acting On mRNA
- Antisense Therapy (2 slides)
6. Drugs related to nucleic acid building blocks
- Examples: Antiviral agents (2 slides)
- Examples
[7 slides]
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4. DRUGS ACTING ON rRNA
Antibiotics
NH
NH
H2N
C
NH
HN
H
C
NH2
H
OH
HO H
OH
OH H
HO
H
Me
H
H
N
Me
H
O2N
O
CH2OH
HN H
O
Me
Chloramphenicol
(vs typhoid)
H
Me
HO
H
H
H
H
H
OMe
O
C
Streptomycin
OH
H
OH
Me
H
Me
O
CHCl2
O
CH2OH
H MeHN
H
H
OH
Me H OH
H
NMe2
CH3
HO
O
Rifamycins
O
OH
O
H3C
CH3
HO
OH
NH2
OH
Cl
HO
Me
H3C
O
O
CH3
O
CH3
CH3
OH
O
Me
Chlortetracycline
(Aureomycin)
O
CH3
H
NMe2
O
HO
O
O
Me
O
OH
O
O
CHO
H
OH
Me
C
O
R
O
OH
H
Erythromycin
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OMe
5. DRUGS ACTING ON mRNA
Antisense Therapy
antisense
molecule
Protein synthesis
m-RNA
A G U C U A C G U U
antisense
molecule
G U A A U C A G A U G C A A A A G U
m-RNA
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5. 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
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6. Drugs related to nucleic acid building blocks
Examples: Antiviral agents
O
Azidothymidine (AZT)
(Zidovudine;Retrovir)
O
CH3
HN
O
N
O
O
O
HO P O P O P O
HO
O
CH3
HN
OH
OH
O
N
O
OH
N3
N3
Chain terminating
group
•Enzyme inhibitor
•AZT is phosphorylated to a triphosphate in the body
•Triphosphate has two mechanisms of action
- inhibits a viral enzyme (reverse transcriptase)
- added to growing DNA chain and acts as chain terminator
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6. Drugs related to nucleic acid building blocks
Examples: Antiviral agents
O
HN
H2 N
Acyclovir
(Zovirax)
AcO
N
N
O
HO
N
N
Chain
terminating
group
N
OAc
Famciclovir
(Famvir)
N
N
NH2
Chain
terminating
group
Notes:
Same mechanisms of action as AZT
Used vs herpes simplex and shingles
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6. Drugs related to nucleic acid building blocks
Examples:
Antisense nucleotides - see earlier
Uracil mustard - see earlier
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