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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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]

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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

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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

T opo II

Tyr

5' 3'
3' 5'
DNA

• Tyrosine residues in the enzyme are involved in the chain breaking

process
• The residues form covalent bonds to DNA

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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

T opo II

Tyr
5' 3'
3' 5'
DNA
Tyr
Topo II

• Tyrosine residues in the enzyme are involved in the chain breaking

process
• residuespulls
The enzyme formthe
covalent
chainsbonds
apartto
to DNA
create a gap

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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

T opo II

Tyr

DNA
Tyr
T opo 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
• The intact strand of DNA is passed through the gap
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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

T opo II

Tyr
5' 3'
3' 5'

Tyr
T opo 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
• The intact strand of DNA is passed through the gap
• The break is resealed ©1
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

T opo II

Tyr
5' 3'
3' 5'

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

5' Base
O
H H
5' Base H H
O
H H TopoII HO H
H H TopoII
HO Tyr
O Tyr
O H
O P O P
O O Base O O Base
O O
H H H H
H H H H
O H O H

3' 3'

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3. DRUGS ACTING ON DNA
3.1 Intercalating agents
Example - Proflavine

H2N N NH2

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

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3. DRUGS ACTING ON DNA
3.1 Intercalating agents
Example - Proflavine
Proflavine
G C
AT
TA
TA H 3N N NH3
G C
G C
sugar phosphate
TA
T A backbone
T A
AT T A
AT
T A
C G
G C
proflavine
TA H 3N NH3
T A
G C
GC O O
GC
T A G C
A T
C G
TA
T A

DNA DOUBLE HELIX

van der Waals interactions

Ionic interactions
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3. DRUGS ACTING ON DNA
3.1 Intercalating agents
Examples
Planar rings
N-Me-Gly N-Me-Gly
O OH O
N-Me-L-Val L-Pro N-Me-L-Val L-Pro CH2OH
D-Val D-Val
O O
OH
C C
C O C O
H C H C
H H
Me Me OMe O OH H O
NH NH
C O O C H
O
N NH2 H
Me
H H
H
O O Planar rings HO
H
CH3 CH3 NH3

Dactinomycin Doxorubicin (Adriamycin)

Extra binding to sugar
Extra binding to sugar phosphate phosphate backbone by NH3
backbone by cyclic peptide
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3. DRUGS ACTING ON DNA
3.1 Intercalating agents
Examples- antimalarial agents

H
CH3 CH2CH3
H NH CH (CH2)3 N
HO N CH2CH3
MeO

Cl N
N

Quinine Chloroquine

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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)
Cl

CH3 N

Cl ©1
3. DRUGS ACTING ON DNA
3.2 Alkylating agents
Cross linking

X X
X X

Nu Nu
Nu Nu
Nu Nu
Nu
Nu

Intrastrand cross linking Interstrand cross linking

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 3. DRUGS ACTING ON DNA
3.2 Alkylating agents
Mechanism of action
DNA DNA

H G = Guanine
O N NH2
H
Cl O N NH2
N
N
+ N
CH3 N CH3 N N N
CH3 N N
G
Cl Cl
Cl
Mechlorethamine Aziridine ion
N NH2 N N NH2
N
NH
NH N
N G
O O

DNA DNA

H
H O N NH2
O N NH2
N

N
N N
N
Crosslinked DNA
CH3 N N
+

N N N NH2
N N NH2
NH
N
NH CH3 N

O
O
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3. DRUGS ACTING ON DNA
3.2 Alkylating agents
Mechlorethamine analogues

Cl
Cl O
N
N HN

Cl
Cl O N
H

Aromatic ring - e withdrawing effect Uracil mustard

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

Cisplatin Mitomycin C
O CH2OCONH2
Cl NH3
H 2N OMe
Pt
Cl NH3 N NH
Me
O

Binds to DNA in regions rich in guanine Converted to alkylating agent in the

units body
Intrastrand links rather than interstrand
Inhibits transcription

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 H
O OH O CH2OCONH 2
CH2OCONH2 CH2OCONH2
H 2N OMe H 2N OMe H2N

-MeOH
N NH Reduction N NH N NH
Me Me Me H
O OH OH

O H
C
NH2
H O
O CH2OCONH 2 OH CH2
H2N H2N H2N-DNA
-H +
Ring H2N-DNA NH-DNA
opening N
Me Me N
NH2 NH2
OH OH
Alkylating agent
O Guanine

HN N

N N
NH
NH-DNA OH
OH CH2 O Guanine
CH2
H2N N
H2N HN
NH
NH-DNA N
-CO2 N
Me N
-NH3 N
Me NH2
NH2 OH
OH
Crosslinked DNA ©1
3. DRUGS ACTING ON DNA
3.3 Chain cutters

CONH2 NH2

N
NH2 O Bleomycin
H
O
N R
Used vs skin cancer
N N CH3 O
H
O HO N
O NH N S
H2N
CH3 HN O
N CH3 HO CH3 S
H

HO O N
OH
O N
O H BLEOMYCIN A2 R = NHCH2CH2 CH2SMe2
OH BLEOMYCIN B2 R = NHCH2CH2CH2 CH2NHC(NH2)=NH
OH

OH
O
OH

O NH2

• Abstracts H from DNA to generate radicals

• Radicals react with oxygen resulting in chain cutting
• Bleomycin also inhibits repair enzymes ©1
3. DRUGS ACTING ON DNA
3.3 Chain cutters

O
HO
CH3 O NHCO2Me
S S
I H3C H3C S
S O H
H3C
O N O Calicheamicin g 1I
O OMe HHO
OH O Antitumour agent
OMe
H3C O
HO H O
MeO N enediyne
OH H3C MeO system

• Generates DNA diradical

• DNA diradical reacts with oxygen
• Results in chain cutting
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3. DRUGS ACTING ON DNA
3.3 Chain cutters

H
O
HO O O
HO HO
Michael
NHCO2Me NHCO2Me addition NHCO2Me

S S S
S R R R
MeS
Nu

O O
Cycloaromatisation HO HO
NHCO2Me
NHCO2Me H
DNA DNA
(Diradical) S
S
O2 R
R H
Oxidative
cleavage

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