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© Oxford University Press, 2013

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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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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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


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


Examples - anticancer agents

Planar rings


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


C

O

Me MeH H

CO O

H H

O

Dactinomycin

Planar rings

Planar rings


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


C

O

Me MeH H

CO O

H H

O

Dactinomycin

Planar rings

Planar rings


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


C

O

Me MeH H

CO O

H H

O

Dactinomycin

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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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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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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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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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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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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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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


• 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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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


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Interstrand crosslinkingIntrastrand crosslinking

Crosslinking

Nu Nu Nu

Nu



X X

NuNu

X X

Nu

Nu

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Nucleophilic groups on nucleic acid bases


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


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


Guanine prefers

keto tautomer

Abnormal base p airing.

Alkylated guanine p refers enol tautomer

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ExampleChlormethine (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

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


Example - Nitrosoureas


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


Example - Nitrosoureas


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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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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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



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


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


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


• 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


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• Generates DNA diradical• DNA diradical reacts with oxygen• Results in chain cutting

1.5 Chain cutters


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


Mechanism

H

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1.6 Chain terminators


• 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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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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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



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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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



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


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'


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

46

A large number of clinically important antibacterial agentsprevent protein synthesis in bacterial cells by binding toribosomes and inhibiting the translation process.

3 DRUGS ACTING ON mRNA

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47

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


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


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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)


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)


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

Documents

Kuliah 6_2