Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 7

NUCLEIC ACIDS AS DRUG

TARGETS

Part 1: Sections 7.1 - 7.2 (DNA & RNA)

©1
Contents

Part 1: Sections 7.1 - 7.2 (DNA & RNA)

1. Deoxyribonucleic Acid (DNA)

1.1. Primary Structure (6 Slides)
1.2. Secondary Structure - Double Helix (4 slides)
1.3. Tertiary Structure

2. Ribonucleic Acid (RNA)

2.1. Primary structure
2.2. Secondary structure
2.3. Tertiary structure (2 slides)
2.4. Transcription
2.5. Translation - protein synthesis (7 slides)

[25 slides]

©1
1. DEOXYRIBONUCLEIC ACID (DNA)
.1 Primary Structure

NH2
5' end 5' end
N N
O O
5' N N Base
O P O CH2
OH
O O P O O
H H 1' NH2
OH
H
3' H H N
O O Base
N O
O P O CH2 O P O O
O
OH H H OH
H H O
H
N NH
O O Base
N N NH2
O P O CH2 O P O O
O
OH H H OH
H H O
H Me
NH O
O Base
N O O P O O
O P O CH2
O OH
OH H H
H H
3' H 3' End
3' End
Sugar phosphate backbone
©1
1. DEOXYRIBONUCLEIC ACID (DNA)
.1 Primary Structure

ilding blocks - Nucleotides

NH2 O O NH2

N N CH3
N N HN N

N N H2N N N O N O N
HO3PO HO3PO HO3PO HO3PO
O O O O

H H H H H H H H
H H H H H H H
H
HO H HO H HO H HO H

Deoxyadenosine Deoxyguanosine Deoxythymidine Deoxycytidine

phosphate phosphate phosphate phosphate

©1
1. DEOXYRIBONUCLEIC ACID (DNA)
.1 Primary Structure

cleotide = Phosphate + sugar + base

NH2
Base
N
N

Deoxyadenosine N N
phosphate HO3PO
O
Phosphate
H H
H H Sugar
HO H

©1
1. DEOXYRIBONUCLEIC ACID (DNA)
.1 Primary Structure

ucleosides = Sugar + Base

NH2 O O NH2
N N N CH3
N HN N
N N H2N N
N O N O N
HO HO HO HO
O O O O
H H H H H H H H
H H H H H H H H
HO H HO H HO H HO H

Deoxyadenosine Deoxyguanosine Deoxythymidine Deoxycytidine

©1
1. DEOXYRIBONUCLEIC ACID (DNA)
.1 Primary Structure

Sugar HOCH2 OH
O

Deoxyribose H H
H H

OH H
Nucleic acid bases

NH2 O NH2 O
N 6 N CH3
N1 6 5 7 HN1 5 7 N3 4 5 HN3 4
5
4 9 8 8
2 2 4 9 2 6 2 1 6
3 3 1
N N H2N N N O N O N
H H H H

Adenine Guanine Cytosine Thymine

Purines Pyrimidines

©1
1. DEOXYRIBONUCLEIC ACID (DNA)
.1 Primary Structure
NH2
N N Adenine (A)
O N N
O P O CH2
O
OH H H NH2
H H
H N
O Cytosine (C)
N O
O P O CH2
O
OH H H
H H O
H
N NH
O
N N NH2
Guanine (G)
O P O CH2
O
OH H H
H H O
H Me
NH
O
N O Thymine (T)
O P O CH2
O
OH H H
H H
H

e: Sugar phosphate backbone is constant

©1
Bases attached in apparently random order
1. DEOXYRIBONUCLEIC ACID (DNA)
Secondary Structure - Double Helix

o
10A • Sugar phosphate backbone
G C
AT
TA
T A
is ionised and faces
Major
groove
G C
G C
TA
outward (favourable
T A
T A
interactions with water)
Minor A T
groove
A T
T A
C G
o
34A • Nucleic acid bases point
G C

TA
T A
inward and pair up A-T or
G C
G C G-C
GC
T A
A T
C G
• Purine pairs with
TA
T A pyrimidine - constant
diameter to helix
DNA DOUBLE HELIX
• Base bairs are stacked (vdw
interactions between pairs)
• Chains are complementary
©1
1. DEOXYRIBONUCLEIC ACID (DNA)
Secondary Structure - Double Helix

Thymine Adenine
o
10A
O P
Me O H2N N O
G C O O
AT
O P 3'
TA NH N N
T A O
Major
G C
G C O N N 5'
groove O O
TA 5' O
T A O
T A
NH2 O O P
Minor A T 3'
N O
groove
A T o O
T A 34A
C G O P N O
G C
O N HN 3'
TA O N N
T A O 5'
G C
5' O H2N O
G C
GC O
T A
A T 3' Cytosine Guanine O P
C G O O
TA O P O
T A O

DNA DOUBLE HELIX

Base Pairing
G-C base pairing involves 3 H-bonds
A-T base pairing involves 2 H-bonds
©1
1. DEOXYRIBONUCLEIC ACID (DNA)
Secondary Structure - Double Helix
New
DNA
chains
New
DNA
chains
Template Template

DNA Replication DNA

Double Helix Daughter helices
©1
1. DEOXYRIBONUCLEIC ACID (DNA)
Secondary Structure - Double Helix

Trinucleotide
Template Template Template
5' chain X 5' chain 5' chain
A

A A A
X-
C C X C
T T A T A
3'
C G C G C G
3' 3'
G C G C G C

3' 5' 3' 5' 3' 5'

Growing Growing Growing
chain chain chain

Approach of trinucleotide Base pairing Enzyme catalysed 'splicing'

©1
1. DEOXYRIBONUCLEIC ACID (DNA)
3
.3 Tertiary Structure

• Double helix coils into a 3D shape -

supercoiling

• Double helix has to unravel during

replication

• Unravelling leads to strain

• Relieved by enzyme catalysed cutting and

repair of DNA chain

• Important to the activity of the quinolone

and fluoroquinolone antibacterial agents
which act as enzyme inhibitors ©1
2. RIBONUCLEIC ACID (RNA)
.1 Primary structure

milar to DNA with the following exceptions

bose is used instead of deoxyribose
acil is used rather than thymine
O
HOCH 2 O OH

H H HN
H H

OH OH O N
H

Ribose Uracil

©1
2. RIBONUCLEIC ACID (RNA)
.2 Secondary structure

• Single stranded

• Some regions of helical secondary structure

exist due to base pairing within the same
strand (see t-RNA)

• Adenine pairs to uracil; guanine pairs to

cytosine

©1
2. RIBONUCLEIC ACID (RNA)
3 Tertiary structure

• Three types of RNA are involved in protein

synthesis:

• Messenger RNA (mRNA)

Relays the code for a protein from DNA to the
protein production site

• Transfer RNA (tRNA)

The adapter unit linking the triplet code on

mRNA to specific amino acids

• Ribosomal RNA (rRNA)

Present in ribosomes (the production site for
protein synthesis). Important both ©1
2. RIBONUCLEIC ACID (RNA)
3'p
3 Tertiary structure end
A AMINO
ACID
C
C
5'p
A
end
G C
Base Pairing
G C Yeast alanine-tRNA
G U
mI Methylinosine C G
G C
I Inosine U U
UH2 Dihydrouridine G
A U
G C U UA
G
T Ribothymidine UH2 C G C G mGU A G G C C
G
Ps Pseudouridine C U C C G G
G A
G C G C m 2G C T PsC
mG Methylguanosine G UH2 C G A UH2
Amino
G acid
m2G Dimethylguanosine U A
C G
C G t-RNA
C G
U Ps
U mI AC G
I C
G Anticodon
binding region
ANTICODON for m-RNA

Anticodon - the 3 bases are specific for the attached amino

acid

m-
- base pair to the complementary triplet code on
RNA (the codon)
© 1
2. RIBONUCLEIC ACID (RNA)
.4 Transcription

ing of a segment of DNA which codes for a specific

G
U
A
U
C
U
G
mRNA U
C
C
G G C
T C T G C U
A A A U A U
T T T A T A
C A C U A
T G T C G
G A G U A
T
C
C
C
A
G
T
C
G
U
C
C
A
G
mRNA
C
C G C C G
T G T C G
T A T U A
A A A U A
T A T

DNA double helix DNA unravelled Transcription

to reveal gene
©1
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis

Growing
protein chain

His

Ribosome
60S

P-site
A-site
GCU GCA
CGA CAU GUC
mRNA
40S

©1
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis

Protein chain
transferred

OH His

Ribosome
60S

P-site
A-site
GCU GCA
CGA CAU GUC
mRNA
40S

©1
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis

OH Protein chain
transferred

His

GCU

Ribosome
60S

P-site
A-site
GCA
CGA CAU GUC
mRNA
40S

©1
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis

Protein chain
transferred

His

Ribosome
60S

P-site
A-site
GCA
CGA CAU GUC
mRNA
40S

©1
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis

Protein chain
transferred

His Val

tRNA
Ribosome
60S

P-site
A-site
GCA CAG
CGA CAU GUC
mRNA
40S

Translocation

©1
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis
PEPTIDE
NH NH2

R C H R' C H
O C O C
HO O HO O
H
H
H H H OH H H H OH

O O P O PEPTIDE
Adenine O O P O Adenine
O O NH
t RNA t RNA R C H
O C
Transfer of NH
growing peptide
chain to next R' C H
amino acid HO OH O C
H H
H H HO O
OH H H
O O P O H H
Adenine OH
O O O P O
Adenine
t RNA O
©1 t RNA
2. RIBONUCLEIC ACID (RNA)
Translation - protein synthesis
mRNA
view Ribosome

Amino acid
DNA
tRNA

mRNA

Translation

Transcription

Nucleus

Protein

©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)

©1
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]

©1
3. DRUGS ACTING ON DNA
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
©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

Topo 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

©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

Topo II

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

• Tyrosine residues in the enzyme are involved in the

chain breaking process
he • The residues
enzyme pulls theform covalent
chains apart bonds to DNA
to create a gap

©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

Topo II

Tyr

DNA
Tyr
Topo II

• Tyrosine residues in the enzyme are involved in the

chain breaking process
• The residues form covalent bonds to DNA
he enzyme pulls the chains apart to create a gap
he intact strand of DNA is passed through the gap
©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
3

Topo II

Tyr
5' 3'
3' 5'

Tyr
Topo II

•Tyrosine residues in the enzyme are involved in the

chain breaking process
• The residues form covalent bonds to DNA
he enzyme pulls the chains apart to create a gap
he 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
4

Topo 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
he enzyme pulls the chains apart to create a gap
he intact strand of DNA is passed through the gap
• The break is resealed ©1
3. DRUGS ACTING ON DNA
Topoisomerase II
chanism of chain cutting

5' Base
O
H H
5' Base
O H H
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'

©1
3. DRUGS ACTING ON DNA
1 Intercalating agents
xample - Proflavine

H2N N NH2

Proflavine

ar tricyclic system
amino substituents are protonated and charged
as a topical antibacterial agent in the second wor
ets bacterial DNA
toxic for systemic use

©1
3. DRUGS ACTING ON DNA
1 Intercalating agents
xample - Proflavine
Proflavine
G C
AT
TA
T A
G C
H 3N N NH3
G C
sugar phosphate
TA
T A backbone
T A
A T T A
A T
T A
C G
G C
proflavine
TA H 3N NH3
T A
G C
G C O O
GC
T A G C
A T
C G
TA
T A

DNA DOUBLE HELIX

van der Waals interactions

Ionic interactions
©1
3. DRUGS ACTING ON DNA
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
H O
N NH2
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 backbone by
phosphate backbone by
cyclic peptide
NH3 ©1
3. DRUGS ACTING ON DNA
1 Intercalating agents
amples- antimalarial agents

H
CH3 CH2CH 3
H NH CH (CH2)3 N
HO N CH2CH3
MeO

Cl N
N

Quinine Chloroquine

©1
 3. DRUGS ACTING ON DNA
.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)

xample
echlorethamine (nitrogen mustard)
Cl

CH3 N

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

X X
X X

Nu Nu
Nu
Nu Nu Nu
Nu
Nu

Intrastrand cross linkingInterstrand cross linking

©1
 3. DRUGS ACTING ON DNA
.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 N NH2
N N NH2

N NH
NH
N G
O O

DNA DNA

H
O N NH2
H
O N NH2
N

N
N N
N
Crosslinked DNA
CH3 N N
+

N N N NH2
N N NH2
NH
NH CH3 N

©1
N
O
O
 3. DRUGS ACTING ON DNA
.2 Alkylating agents
echlorethamine analogues

Cl
Cl O
N
N HN

Cl
Cl O N
H

Aromatic ring - e withdrawing Uracil mustard

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

in guanine units agent in the body
Intrastrand links rather than
interstrand
Inhibits transcription
©1
 H
O OH O CH2OCONH 2
CH2OCONH2 CH2OCONH2
H 2N OMe H 2N OMe H2N

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

O H
C NH2
H O
O CH2OCONH 2 OH CH2
H2N H2N H2 N-DNA
-H +
Ring H2 N-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 Me N
NH2
NH2 OH
OH
Crosslinked DNA ©1
 3. DRUGS ACTING ON DNA
.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
H2N O NH N S

CH3 HN O
N CH3 HO CH3 S
H

HO O N
OH
O N
O H BLEOMYCIN A2 R = NHCH2CH2CH2SMe2
OH OH
BLEOMYCIN B2 R = NHCH2CH2CH2CH2NHC(NH2)=NH

OH
O
OH

O NH2

bstracts H from DNA to generate radicals

adicals react with oxygen resulting in chain cuttin
leomycin also inhibits repair enzymes ©1
3. DRUGS ACTING ON DNA
.3 Chain cutters

O
HO
CH3 O NHCO2Me
S S
I H3C H3C S
S O H
H3C
O N O Calicheamicin 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
©1
3. DRUGS ACTING ON DNA
.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

©1
 Patrick
An Introduction to Medicinal Chemistry 3/e

Chapter 7

NUCLEIC ACIDS AS
DRUG TARGETS

Part 3: Section 7.3 (Drugs acting on RNA)

©1
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]

©1
4. DRUGS ACTING ON rRNA
NH
Antibiotics NH
H HN C NH2
H2N C NH
H
OH H
H HO
OH OH Me
H H OH
HO H Me N
H
O
O2N H O
CH2OH O CHO
O R H
HN H Me H
Me OH Me OH Streptomycin
C O H
O CHCl2 OH O
HO O
O Me Me H
H H CH2OH
Chloramphenicol H MeHN
H
(vs typhoid) H H
H H Me
OMe O Me H OH OH H
C
CH3 NMe2
O
O HO
Rifamycins H3C CH3
HO O
OH O OH O O HO O CH3
OH

NH2 H3C CH3

O CH3
O
O
OH CH3
HO Me H
Cl NMe2 O OH
Me OMe
Chlortetracycline
(Aureomycin)
Erythromycin ©1
 5. DRUGS ACTING ON mRNA
Antisense Therapy
antisense
molecule

Protein synthesis
m-RNA

antisense
molecule
A G U C U A C G U U

G U A A U C A G A U G C A A A A G U
m-RNA

©1
 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
1
 6. Drugs related to nucleic acid building blocks
amples: Antiviral agents
O
O CH3
zidothymidine (AZT) CH3
HN
HN
Zidovudine;Retrovir)
O N
O N O O O
HO P O P O P O O
HO O OH OH OH

N3
N3
Chain terminating
group
me inhibitor
is phosphorylated to a triphosphate in the body
hosphate has two mechanisms of action
- inhibits a viral enzyme (reverse transcriptase)
- added to growing DNA chain and acts as chain term
©1
gs related to nucleic acid building blocks
amples: Antiviral agents
O
N N
HN N
AcO
N N N NH2
H2 N N

O Chain OAc
Chain
HO terminating terminating
group group
Acyclovir Famciclovir
(Zovirax) (Famvir)

otes:
ame mechanisms of action as AZT
sed vs herpes simplex and shingles

©1
gs related to nucleic acid building blocks
es: Antisense nucleotides - see earlier
Uracil mustard - see earlier

©1