DNA_Agents_Handout.pdf

8/10/2019 DNA_Agents_Handout.pdf

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DRUG TARGETS:NUCLEIC ACIDSDNA & RNA


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T A

G C

H3N NH3

O O

proflavine

sugar phosphatebackbone

NH3N NH3

Proflavine

van der Waals interactions

Ionic interactions

T

DNA DOUBLE HELIX

TAG

C

ATC

GC

TAATCG

AT A

T ATA

TAT A

G CC

T ATA

AG CT

CGCG

ATAT

G

G

Example Proflavine (antibiotic)

Intercalating agents


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Proposed interaction of camptothecin with DNA and topo I, based on: (from wikipedia)Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNAScience 6 March 1998: Vol. 279. no. 5356, pp. 1504 1513. DOI: 10.1126/science.279.5356.1504

Matthew R. Redinbo, * Lance Stewart, * Peter Kuhn, James J. Champoux, Wim G. J. Hol


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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 enzyme


X8 N

R6

R7

R5 O

O

O

R1X8 N

R6

R7

R5 O

O

O

R1



X8 N

R6

R7

R5 O

O

O

R1


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Interstrand cross linkingIntrastrand cross linking

Cross linking

NuNu

X X

NuNu Nu

Nu

X X

Nu

Nu

Alkylating agents


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Cytosine Guanine

N

N

NH2

OR

HN

N

N

NO

H2N

R

Normal base pairing

Alkylating agents

Thymine Alkylated guanine

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 pairing.

Alkylated guanine prefersenol tautomer


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Crystal structure of double-stranded DNA containing the major adduct of theanticancer drug cisplatin, Patricia M. Takahara, Amy C. Rosenzweig,

Christin A. Frederick, Stephen J. Lippard. Nature . 1995 . Vol. 377 , Iss. 6550;p. 649.


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

enediynesystem

Calicheamicin 1I

Antitumour agentO OMe

I

CH3

O

OHMeOHO

H3C

OMe

S

O

OH3C

OH

O NH

OH3C

HO O

O

MeO

HN

H3C

H

SS

SH3C

HOO

NHCO2Me

Chain cutters


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BLEOMYCIN A2 R = NHCH 2CH 2CH 2S Me 2BLEOMYCIN B2 R = NHCH 2CH 2CH 2CH 2NHC( NH2)=NH

Chain cutters


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Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from theSugar Moiety, Chem. Rev., 1998 , 98 (3) , pp 1089 1108, DOI: 10.1021/cr960437i Wendy KnappPogozelski and Thomas D. Tullius *

Proposed H- 4-Abstraction Pathway for DNA Strand Scission Mediated by ActivatedBleomycinFe(II) under Anaerobic Conditions (adapted from Worth et al. 39 and Hecht 90 )
http://pubs.acs.org.proxy.brynmawr.edu/doi/full/10.1021/cr960437ihttp://pubs.acs.org.proxy.brynmawr.edu/doi/full/10.1021/cr960437ihttp://pubs.acs.org.proxy.brynmawr.edu/doi/full/10.1021/cr960437ihttp://pubs.acs.org.proxy.brynmawr.edu/doi/full/10.1021/cr960437i


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Normal replication

A

T

C

G

A

A

C

C

T

A OH3'

DNAtemplate Growingchain

PG

P P

A

T

C

G

A

A

C

C

T

A

G OH3'



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PDrug

P P

Chain termination

A

T

C

G

A

A

C

C

T

A OH3'


A

T

C

G

A

A

C

C

T

A

Drug

Chain te rminatio

DNAtemplate

Growingchain


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A

C

A

T

G

T

T

G

T

A

C

A

5'3'

O

O

NH

N N Me

NO

H

NMe

O

O NH

N

N

N

H

O

Me

O N

H

N

O

H

NMe

MeH

Me

NMe

N HO

N OMe

N H

O

N N

Me

H

N

NMe

O

N

H

H

H

Py

Im

Hp

Py

Py

Py

Hp

Im

Linker

ArmArm


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Antisense Therapy

m-RNA

antisensemolecule

Protein synthesis

U C A G A U G C A A

A G U C U A C G U U

AAUG A A G Um-RNA

antisensemolecule


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Structural Comparison


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T7-RNA polymerase


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Rifampin and Sorangicin bound to Taq RNA polymerase

Rifampin Sorangicin

Documents

DNA_Agents_Handout.pdf