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DRUGS TARGETINGNUCLEIC ACIDSDNA & RNA
Patrick: An Introduction
to Medicinal Chemistry 5eChapter 9
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1. DRUGS ACTING ON DNA
•. There are many important drugs which target nucleic acids,
especially in the areas of antibacterial and anticancer therapy.
•. Drugs that interact with DNA are usually very toxic because
human DNA and pathogen DNA are very similar.
•. For cancer treatment, the only difference between cancer
cells and normal cells is the rapid cell division.
•. Therefore, drugs that halt mitosis (DNA synthesis) should
preferentially halt the mitosis of cancer cells.•. Ideally, a drug would be able to bind to specific sequences.
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Mechanism of action• Intercalating drugs are compounds that contain planar or heteroaromatic
features that slip between the base pair layers of the DNA double helix.• Some of these drugs prefer to approach the helix via the major groove; others
prefer access via the minor groove.• Once they are inserted between the nucleic acid base pairs, the aromatic/heteroaromatic rings are held there by van der Waals interactions
with the base pairs above and below.• Several intercalating drugs also contain ionized groups which can interact with
the charged phosphate groups of the DNA backbone, thus strengthening theinteraction.
• Once the structures have become intercalated, a variety of other processes maytake place which prevent replication and transcription, leading finally to celldeath.
1. DRUGS ACTING ON DNA1.1 Intercalating agents
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1. DRUGS ACTING ON DNA1.1 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
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1. DRUGS ACTING ON DNA1.1 Intercalating agents
Example - Proflavine
Proflavine (planar tricyclic system)
NH2N N H2
• Used as a topical antibacterial agent in the second world war• Targets bacterial DNA• Too toxic for systemic use• The amino substituents are protonated (completely ionized at pH 7)
and charged• The flat tricyclic ring intercalates between the DNA base pairs, and
interacts with them by van der Waals forces, while the ammoniumcations form ionic bonds with the negatively charged phosphate groupson the sugar phosphate backbone.
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T A
G C
H3N NH 3
O O
proavine
sugar phosphatebackbone
NH3N NH 3
Proflavine
Ionic interactions
T
DNA DOUBLE HELIX
TAG
C
ATC
GC
TAATCG
A
T AT A
TA
TAT A
G C
C
T ATA
AG CT
CGCG
ATAT
G
G
1. DRUGS ACTING ON DNA1.1 Intercalating agents
Example - Proflavine
van der Waals interactions
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Extra binding to sugar phosphate
backbone by NH 3
Doxorubicin (Adriamycin)
OMe
O
O
OH
OH H O
OH
OCH 2OH
O
NH3
H
H
H
H
MeH
HO
H
O
N
O
NH2
CH 3CH 3
C C
NH
O
NH
CC
D -Val
C
D -Val
L -Pro
N -Me-Gly
L -Pro
N -Me-Gly
C
O
N -Me- L -ValN -Me- L -Val
C
O
Me MeH H
CO O
H H
O
Dactinomycin
Extra binding to sugar phosphate
backbone by cyclic peptides
1. DRUGS ACTING ON DNA1.1 Intercalating agents
Examples - anticancer agents
Planar rings
Doxorubicin (Adriamycin)
OMe
O
O
OH
OH H O
OH
OCH 2OH
O
NH3
H
H
H
H
MeH
HO
H
O
N
O
NH2
CH 3CH 3
C C
NH
O
NH
CC
D -Val
C
D -Val
L -Pro
N -Me-Gly
L -Pro
N -Me-Gly
C
O
N -Me- L -ValN -Me- L -Val
C
O
Me MeH H
CO O
H H
O
Dactinomycin
Planar rings
Planar rings
Doxorubicin (Adriamycin)
OMe
O
O
OH
OH H O
OH
OCH 2OH
O
NH3
H
H
H
H
MeH
HO
H
O
N
O
NH2
CH 3CH 3
C C
NH
O
NH
CC
D -Val
C
D -Val
L -Pro
N -Me-Gly
L -Pro
N -Me-Gly
C
O
N -Me- L -ValN -Me- L -Val
C
O
Me MeH H
CO O
H H
O
Dactinomycin
Planar rings
Planar rings
Doxorubicin (Adriamycin)
OMe
O
O
OH
OH H O
OH
OCH 2OH
O
NH3
H
H
H
H
MeH
HO
H
O
N
O
NH2
CH 3CH 3
C C
NH
O
NH
CC
D -Val
C
D -Val
L -Pro
N -Me-Gly
L -Pro
N -Me-Gly
C
O
N -Me- L -ValN -Me- L -Val
C
O
Me MeH H
CO O
H H
O
Dactinomycin
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1. DRUGS ACTING ON DNA1.1 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
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1. DRUGS ACTING ON DNA1.1 Intercalating agents
Examples – Bleomycins (anticancer)
N N
CONH2HN
NH2
NH 2
O
H2NMe
O
HNNH
O
Me
HO
MeHN
OHO Me
NH
O
S
N
SN
R
O
O
NH
N
O
HO
OH
OH
O
OH
OHO
NH2
O
H
H
H
H
H
H H
H H
OH
BleomycinA 2 R =NHCH 2 CH 2 CH 2 SMe 2BleomycinB 2 R =NHCH 2 CH 2 CH 2 CH 2 NHC(NH 2 )=NH
imidazolering
pyrimidinering
primary amine
primary amine
primary amide
Bithiazoleinterca latingregion
N N
CONH2HN
NH2
NH 2
O
H2NMe
O
HNNH
O
Me
HO
MeHN
OHO Me
NH
O
S
N
SN
R
O
O
NH
N
O
HO
OH
OH
O
OH
OHO
NH2
O
H
H
H
H
H
H H
H H
OH
BleomycinA 2 R =NHCH 2CH 2CH 2SMe 2BleomycinB 2 R =NHCH 2CH 2CH 2CH 2NHC(NH 2)=NH
imidazolering
pyrimidinering
primary amine
primary amine
primary amide
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1. DRUGS ACTING ON DNA1.1 Intercalating agents
Notes on bleomycins• Intercalated 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
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• Enzymes within cells that remove excessive supercoiling—andthereby torsional stress—while maintaining sufficient supercoiling toensure a stable compact genome.
• These enzymes are apparent in every cellular function involved withDNA—transcription, replication, recombination, and chromosome
separation.• The enzymes complete their job in any of the above function bycleavage; that is, cutting.
• Type I topoisomerase cut only 1 strand of DNA, Type IItopoisomerase cut both (2) strands of DNA.
• JADI tugas enzim ini adalahah memotong DNA pada tempat tertentusehingga mudah untuk memutar (karena sudah dipotong), pada prosesreplikasi enzim ini juga berfungsi untuk memotong salinan DNAyang salah serta memasangkan kembali DNA yang terpotong.
Topoisomerase- Overview
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Action of topoisomerases during DNA replication (A) As the two strands of template DNA unwind, theDNA ahead of the replication fork is forced to rotate in the opposite direction, causing circular moleculesto become twisted around themselves. (B) his problem is solved b! topoisomerases, which catal!"e thereversible breakage and #oining of DNA strands. he transient breaks introduced b! these en"!mes serveas swivels that allow the two strands of DNA to rotate freel! around each other.
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• Are classed as poisons rather than inhibitors, because theystabilize the normally transient cleavable complex that isformed between DNA and topoisomerase enzymes, thusinhibiting the rejoining of the DNA strand or strands.
• In this section, we look at topoisomerase poisons which do notintercalate into the DNA structure.
• However, since DNA is part of the target complex, we can viewthese poisons as targeting DNA as well as the topoisomeraseenzyme.
1. DRUGS ACTING ON DNA1.2 Topoisomerase poisons - non-intercalating
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1. DRUGS ACTING ON DNA1.2 Topoisomerase poisons - non-intercalating
Examples
OO
O
O
Me O
OH
OMe
O
OO
OHO
Me
H
HO
4'
4
Etoposide
OO
O
O
Me O
OH
OMe
O
OO
OHO
H
HO
4'
4
S
Teniposide
Notes on etoposide and teniposide• Stabilise the complex between DNA and topoisomerase enzymes• Used as anticancer agents• Also cause chain cutting
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1. DRUGS ACTING ON DNA1.2 Topoisomerase poisons - non-intercalating
Examples - Camptothecin
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
N
N
O
O
OHO
A B C
D
E Lact one ri
Me
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1. DRUGS ACTING ON DNA1.2 Topoisomerase poisons - non-intercalating
Examples - Quinolones and fluoroquinilones
Notes•
Synthetic agents used as antibacterial agents• Stabilise complex between bacterial DNA and topoisomerases• Binding site for agents revealed once DNA strands are ‘nicked’
N N
O
CH 2CH 3
CO2H
Me
N a l id
N
CO2H
N
O
HN
F
C i p r o
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1. DRUGS ACTING ON DNA1.2 Topoisomerase poisons - non-intercalating
Examples - Quinolones and fluoroquinilones
Fluoroquinolones
Topoisomeraseenzyme
• Four drug molecules are stacked in the bound complex• Bound to DNA and enzyme by hydrogen and ionic bonds
X8 N
R6
R7
R5 O
O
O
R1
Region binding to DNA
Stacking domain
X8 N
R6
R7
R5 O
O
O
R1
Regionbindingto enzymeRegionbinding
to enzymeX8 N
R6
R7
R5 O
O
O
R1X8 N
R6
R7
R5 O
O
O
R1
Regionbindingto enzymeRegionbinding
to enzymeX8 N
R6
R7
R5 O
O
O
R1
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1.3 Alkylating agents
1. DRUGS ACTING ON DNA
• Alkylating agents are highly electrophilic compounds that react withnucleophiles to form strong covalent bonds.
• There are several nucleophilic groups present on the nucleic acid bases ofDNA which can react with electrophiles — in particular the N-7 of guanine.
• Drugs with two alkylating groups can react with a nucleic acid base on eachchain of DNA to cross-link the strands such that they disrupt replication ortranscription.
• Alternatively, the drug could link two nucleophilic groups on the same chainsuch that the drug is attached like a limpet to the side of the DNA helix. Thatportion of DNA then becomes masked from the enzymes required to catalyseDNA replication and transcription.
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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
1. DRUGS ACTING ON DNA
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Interstrand crosslinkingIntrastrand crosslinking
Crosslinking
Nu Nu Nu
Nu
1.3 Alkylating agents
1. DRUGS ACTING ON DNA
X X
NuNu
X X
Nu
Nu
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1.3 Alkylating agents
Nucleophilic groups on nucleic acid bases
1. DRUGS ACTING ON DNA
nucleophilicgroups
n u c l e o p h i licg r o u p s
NH2
N
N
N
N
1
3
R
H2N
HN
N N
N
O7
R
NH2
N
NR
O
3
CytosineGuanineAdenine
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Cytosine Guanine
N
N
NH2
OR
HN
N
N
NO
H2N
R
Normal base pairing
1.3 Alkylating agents
T h y m i nA l k
N
NH
O
O
Me
R
N
N
N
NHO
R
H2N
DRUG
Miscoding resulting fromalkylated nucleic acid bases
1. DRUGS ACTING ON DNA
Guanine prefers
keto tautomer
Abnormal base p airing.
Alkylated guanine p refers enol tautomer
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1.3 Alkylating agents
ExampleChlormethine (nitrogen mustard)
1. DRUGS ACTING ON DNA
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
Me N
Cl
Cl
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Mechlorethamine
H3C N
Cl
Cl Cl
NH3C
Aziridine ion
G = Guanine
DNA
G
N
HN
NN
N
N NH
N
O
O
NH 2
NH 2
G
DNA
N
N
N
NN
HN
NH
N
O
NH 2
O NH 2
H3C N
Cl
DNA
NN
N
N NH
N
O
NH 2
N
HNO NH 2
NH3C
DNA
CH 3
N
N
N
N
N
N
HN
NH
N
O NH 2
O
NH 2
Crosslinked DNA
Mechanism of action
Alkylating agents
Chlormethine
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Cl
N2 + H O
Alkylatingagent
1.3 Alkylating agents
Example - Nitrosoureas
1. DRUGS ACTING ON DNA
MechanismDecompose in body to form an alkylating agent and a carbamoylating agent
O
N NH
NO
Cl Cl
C a r m u s t in e
O
N NH
NO
Cl
L o m u s t in e
ClN N
N
O
O
R
H
H O
O C N R
ClN
NOH
+
Isocy anate(carbam o ylatagent)
Cl
N2 + H O
Alkylatingagent
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Cl DNA X Y
Cl
X YC ro s s -lin k i n g
DNA DNA
A lk y l a t io nA lk y l a t in ga g e n t
1.3 Alkylating agents
Example - Nitrosoureas
1. DRUGS ACTING ON DNA
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
O C N RIs o c y a n a t e
P r o t e i n - Ly s -N H2P r o t e i nN H
O
HN RC a r b a m o y l a t i
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1.3 Alkylating agents
1. DRUGS ACTING ON DNA
Synthetic agent used as anticancer agentCauses interstrand crosslinking
BusulfanOO
SMe
OO
SMe
OO
Mechanism
OO
SMe
OO
SMe
OO
HN
N N
N
O
H2N
Guanine
DNA
-Me S O3-
N
N
DNA
N
N
DNA
N
N
DNA
N
N
DNA
-Me S O3-
OS O2Me
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1.3 Alkylating agents
1. DRUGS ACTING ON DNA
Mechanism
• Prodrug activated by demethylation in liver• Decomposes to form a methyldiazonium ion• Alkylates guanine groups
HN N
CONH2NN
NH3C
CH 3
Cyt P-450
liv er
HN N
CONH2NN
N
CH 3OHH
HN N
CONH2NHN
N
CH 3
-CH 2O
H
HN N
CONH2H2N
N N CH 3
AIC
Methyldiazonium ion
N2 + CH 3
HN N
CONH2NN
NH3C
CH 3
Dacarbazine
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O
O
N
H 2 N
Me
CH 2 O CO NH 2
NH
O Me
1.3 Alkylating agents
1. DRUGS ACTING ON DNA
Example - Mitomycin C
Notes• Prodrug activated in the body to form an alkylating agent• One of the most toxic anticancer drugs in clinical use
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OH
OH
N
H2N
Me
CH 2
NH2
NH
NH
HN
N N
N
O
HN
N N
N
O Guanine
Guanine
H 2N-DNA
O
O
N
H2N
Me
CH 2OCONH 2
NH
OMe
O
OH
N
H2 N
Me
CH 2 OCONH 2
NH
H
-MeOH
O
OH
N
H2N
Me
CH 2OCONH 2
NH2
Ringopening
-H +
Alkylating agent
OH
OH
N
H 2N
Me
CH 2
NH 2
NH-DNA
NH-DNA
-CO 2-NH
Crosslinked DNA
OH
OH
N
H2N
Me
CH 2OCONH 2
NH
OMe
Reduction
OH
OH
N
H 2N
Me
CH 2
NH 2
NH-DNA
O
C
O
NH 2
H2N-DNA
H
H
H
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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
1.4 Metallating agents
1. DRUGS ACTING ON DNA
PtNH3Cl
NH3Cl
Cisplatin
PtNH3Cl
NH3Cl
H2OPt
NH3H2O
NH3ClPt
NH3H2O
NH3H2O
+ 2 +
+DNA
PtNH3DNA
NH3DNA
C i s p l a t in
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Notes
1.4 Metallating agents
1. DRUGS ACTING ON DNA
PtNH3Cl
NH3Cl
Cisplatin
• Binds to DNA in regions rich in guanine units•
Intrastrand links rather than interstrand• Localised unwinding of DNA double helix• Inhibits transcription
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1.5 Chain cutters
1. DRUGS ACTING ON DNA
• Chain cutters cut the strands of DNA and prevent the enzymeDNA ligase from repairing the damage.• This compound binds to the minor groove of DNA• They appear to act by creating radicals on the DNA structure.• The reaction starts with a nucleophile attacking the trisulfide
group.• These radicals react with oxygen to form peroxy species, and the
DNA chain fragments.
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• Intercalating agent• Abstracts H from DNA to generate radicals• Radicals react with oxygen resulting in chain cutting• Bleomycin also inhibits repair enzymes
BLEOMYCIN A2 R = NHCH 2CH 2CH 2SMe 2BLEOMYCIN B2 R = NHCH 2CH 2CH 2CH 2NHC( NH 2)=NH
BleomycinUsed vs skin cancer
N N
NH
NH2CONH2
NH2
H2N
CH 3 H N
O
NH
O HO
CH 3
CH 3
OCH 3HO
HN
NH N
S
S
N
O
ONH
N
O
HO
OH
OH
OH
OH
OHO
O N H2
O
RO O
1.5 Chain cutters
1. DRUGS ACTING ON DNA
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• Generates DNA diradical• DNA diradical reacts with oxygen• Results in chain cutting
1.5 Chain cutters
1. DRUGS ACTING ON DNA
O
OMe
I
CH 3
O
OHMe OHO
H3C
OMe
S
O
OH3C
OH
O NH
OH3C
HO O
O
Me O
HN
H3C
H
SS
SH3C
HOO
NHC O2Me
Calicheamicin 1I
Antitumour agent !nediyne
system
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RS
HO O
NHCO 2Me
S
MeSNu
RS
HOO
NHCO 2Me
Cycloaromatisation
RS
HOO
NHCO 2Me
O2
Oxidativecleavage
DNA DNA(Diradical
RS
HOO
H
H
NHCO 2Me
Michaeladdition
RS
HO O
NHCO 2Me
1.5 Chain cutters
1. DRUGS ACTING ON DNA
Mechanism
H
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1.6 Chain terminators
1. DRUGS ACTING ON DNA
• Chain terminators are drugs which act as 'false substrates' and areincorporated into the growing DNA chain during replication.
• Once they have been added, the chain can no longer be extended and chaingrowth is terminated.
• The drugs which act in this way are 'mistaken' for the nucleotidetriphosphates that are the authentic building blocks for DNA synthesis.
• The mechanism by which these nucleotides are added to the end of thegrowing DNA chain involves the loss of a diphosphate group — a processcatalysed bythe enzyme DNA polymerase.
• Before each building block is linked to the chain, it has to be 'recognized'by the complementary nucleic acid base on the template chain.
• This involves base pairing between a nucleic acid base on the template andthe nucleic acid base on the nucleotide.
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1.6 Chain terminators
1. DRUGS ACTING ON DNA
Chain terminators therefore have to satisfy three conditions:1. First, they have to be recognized by the DNA template by interacting with
a nucleic acid base on the template strand.2. Secondly, they should have a triphosphate group such they can undergo
the same enzyme-catalysed reaction mechanism as the normal buildingblocks.
3. Thirdly, their structure must make it impossible for any further buildingblocks to be added.
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1.6 Chain terminators
1. DRUGS ACTING ON DNA
a) Normal replication
PG
P P
A
T
C
G
A
A
C
C
T
A
G OH3'
DNAtemplate
Growingchain
A
T
C
G
A
A
C
C
T
A OH3'
DNA
templateGrowing
chain
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PDrug
P P
1.6 Chain terminators
1. DRUGS ACTING ON DNA
b) Chain termination
A
T
C
G
A
A
C
C
T
A OH3'
DNA
templateGrowing
chain
A
T
C
G
A
A
C
C
T
A
Drug H3'
DNAtemplate
Growingchain
C"ain termination
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1 DRUGS ACTING ON DNA
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H N
N
O
H2 N N
N
O
H O
Aciclovir(Zovirax)
Notes:• Prodrugs used as antiviral agents• Same mechanisms of action as AZT• Used vs herpes simplex and shingles
Famciclovir(Famvir)
N
NN
N N H 2Ac O
O Ac
1.6 Chain terminators
1. DRUGS ACTING ON DNA
Chain
terminatinggroup
H N
N
O
H2 N N
N
O
H O
Chain
terminatinggroup
N
NN
N N H 2Ac O
O Ac
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1.7 Control of gene transcription
1. DRUGS ACTING ON DNA
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 perticularbase pairs
• Capable of inhibiting transcription• Designed to bind to regulatory element of a gene
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A
C
A
T
G
T
T
G
T
A
C
A
5'3'
1. DRUGS ACTING ON DNA
O
O
NH
NN Me
NO
H
NMe
O
ONH
N
N
N
H
O
Me
ON
H
N
O
H
NMe
MeH
Me
NMe
N HO
N OMe
N H
O
NN
Me
H
N
NMe
O
N
H
H
H
Py
Im
Hp
Py
Py
Py
Hp
Im
Linker
ArmArm
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2. DRUGS ACTING ON rRNA
O2NCH 2OH
HO
HN
H
H
CO CH Cl 2
Chloramphenicol(vs typhoid)
R
Me
O
HNMe
Me
OHO
OHOH
OH
O
Me
O
O
C
Me Me
OMe O MeMe
OH
H
H
H
H
H
H
H
H
Rifamycins
Streptomycin
H2N C
NH
NH
O
HN C
NH
NH2
O
OO
H
OHH H O
HH
OHHH
CH O
OH
H
Me
CH 2OH
HHO
H
OH
H
H
MeH NH
H
OOHOOH
Cl
OH
NMe 2
O
HO
NH2
Me H
OH
Chlortetracycline(Aureomycin)
HO
O
O
O
H3C
CH 3
CH 3
O
CH 3
CH 3
HO
H3C
O O
O
CH 3
CH 3
Me
NMe 2
HO
OHOMe
Erythromycin
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A large number of clinically important antibacterial agentsprevent protein synthesis in bacterial cells by binding toribosomes and inhibiting the translation process.
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A great deal of research has been carried out into the possibility ofusing oligonucleotides to block the coded messages carried by mRNA.The rationale is as follows:• Assuming that the primary sequence of a mRNA molecule is known, an
oligonucleotide can be svnthesised containing nucleic acid bases that are
complementary to a specific stretch of the mRNA molecule.• Since the oligonucleotide has a complementary base sequence, it is calledan antisense oligonucleotide.
• When mixed with mRNA, the antisense oligonucleotide recognizes itscomplementary section in mRNA, interacts with it and forms a duplexstructure such that the bases pair up by hydrogen bonding.
• This section now acts as a barrier to the translation process and blocksprotein synthesis.
Antisense Therapy
3. DRUGS ACTING ON mRNA
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Antisense Therapy
Protein synthesis
3. DRUGS ACTING ON mRNA
m$%NA
antisensemolecule
U C A G A U G C A A
A G U C U A C G U U
AAUG A A G U
m-RNA
antisensemolecule
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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
Antisense Therapy
3. DRUGS ACTING ON mRNA
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•
Short segments of double stranded RNA• Recognised by enzyme complex RISC to produce singlestranded RNA - small interfering or small inhibitory RNA(siRNA)
• Binds to complementary region of mRNA• mRNA is cleaved by enzyme complex
Micro-RNA (miRNA)
3. DRUGS ACTING ON mRNA
RI SC
miRNA
RISC
miRNA
R ISC
s i R N A
RISC
mRNA
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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
Micro-RNA (miRNA)
3. DRUGS ACTING ON mRNA
Problems
• siRNAs need to be metabolically stable• Need to reach target cells• Need to enter target cells
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Tugas Belajar
• Farmakokinetik•
Fase-fase farmakokinetik obat• Dikumpulkan minggu depan• Bisa ditanyakan pada UTS•
Bobot: 5 % dari nilai akhir