dNTP's

DNA template

POLPOL

Chain elongation

dNTPprecursors

Hydroxyurea

Methotrexate

Cytosine arabinosideGemcitabine

MMSCisplatin

BleomycinCisplatin

CamptothecinEtoposide

Doxorubicin

Aphidicolin

Ori

Cdk's

AcyclovirGanciclovir

Foscarnet

5-Fluorouracil

Pommier & Diasio, Fig. 1

Caffeine

Checkpoints

UCN-01

FlavopiridolRoscovitine

Mismatch repair

6-Thioguanine

6-MercaptoP.

Inhibition of Thymidylate Synthesis:

dUMP dTMP

CH2-FH4-Glun FH2-Glun

DHFR

MTX

TS

MTX-PG

Inhibition of de Novo Purine Synthesis:

GAR AICAR + FH4-Glun

AICAR IMP + FH4-Glun

CHO-FH4-Glun

GAR Transformylase

AICAR Transformylase

MTX-PG

NH

HN

O

O

F

1

5

5-Fluorouracil (5-FU)5-FU

N

N

N

NH2N

NH2

CH2

N C

CH3 OHN C

H

COOH

(CH2)2 C

O

R

R = OH

CH

HN (CH2)2

COOH

C

O

OH

n

R =

AMP

GMP

FUMP FUDP FUTP

FdUMP FdUDP FdUTP

dUMP dTMPTS

dTTP

RNAMismatch

Methotrexate (MTX):Methotrexate Polyglutamate (MTX-PG):

N

N

NH

N

SH

1

6

N

N

NH

N

SH

1

6

H2N

6-Mercaptopurine (6-MP)

6-Thioguanine (6-TG)

6-MP + PRPP TIMPHGPRT

Glutamine + PRPP Phosphoribosylamine

IMP GMP

GMP AMP

6-TG

6-TGMP 6-TGDP

6-TdGDP 6-TG DNAMismatch

RNR

6-TdGTP

Hydroxyurea (HU) GDP

ADP

UDP

CDP

dGDP

dADP

dUDP

dCDP

RNR

HU

NH

CNH2

O

HO

A

B C

D E

F G

H I

J K

Pommier and Diasio, Fig. 2

dUTP

DNAMismatch

O

R2OH

R1H

HH

HO N

N

NH2

O

Cytosine Arabinoside (AraC) :Deoxycytosine (dC) :

R1 = R2 = F

R1 = OH

R1 = R2 = H

R2 = H

Gemcitabine (dFdC) :

NH

N

N

O

NH2N

CH2

OHC

CH2

HO

R

R = H

R = CH2OH

Acyclovir (Acy) :Ganciclovir (Gan) :

P

O

O

C O

O

O

Na

Na

Na

Foscarnet (FOS)

HHO

H3C

CH3H

HO

H

HO

OH

POLPOL

AraCTP

dFdCTP

AraC

dFdC

dCTP

APH

dFdCDP

dCDP

CDP

dUTP

dUDP

dCMP

dFdCMP

dUMP

Aphidicolin (APH)

FOS

Acy

Gan

AcyMP AcyTPviral TK

GanMP GanTP

Incorporation into viral DNAand chain termination

A B

C

E F

G

Pommier and Diasio, Fig. 3

RR

dC

dC kinase

dU

viralphosphotransferase

NH

N

N

O

NH2N

O

H

HH

HHO

PO

O-

O

O-

7

SH3C

O

O

OCH3

DNA

DNA

NH

N

N

O

NH2N

O

H

HH

HHO

PO

O-

O

O-

7

SH3C

O

O

OH

DNA

DNA

H3C

Methylmethanesulfonate (MMS)

..6

Guanine

Pommier and Diasio, Fig. 4

N7-Methylated Guanine

Pt

H3N

H3N

Cl

Cl

Pt

H3N

H3N

O

O

O

O

Pt

H3N

H3N

Pt

NH2

NH2

O

O

Pt

NH2

N 2

O

O

Oxaliplatin

Carboplatin

Cisplatin

G

C

(CH2)2

N (CH2)2

G

C

R

N

(CH2)2

(CH2)2

R

R = CH2CHNH2

COOH

Melphalan (L-phenylalanine mustard)

Cyclophosphamide

Carboxyphosphamide

P

HN

O

O

PNH2

O

O COOH

Enzymaticoxidation

A

BCl

Cl

(CH2)3

Chlorambucil

COOH

R =

R =

R =

N

(CH2)2

R

Cl

N

(CH2)2

(CH2)2

R

N7-

Cl

Aziridinium reactiveintermediate

1 2

3

CN(CH2)2 C

O

NH R

NO

Cl

BCNU (Bischloroethylnitrosourea)

CCNU (Cyclohexylchloroethylnitrosourea)

(CH2)2 Cl

CH

R =

R =

H

G C

Pommier and Diasio, Fig. 5

H2C CH2

CG

G C

CG

G C

G C

Cis-diamine-PtIntrastrand Crosslink

Diamino cyclohexane-PtIntrastrand Crosslink

G-G interstrand-Crosslink

G-C interstrand-Crosslink

Guanine O6Adduct

Guanine N7Adduct

C

5'

5'

Aphidicolin(APH)

Top1

Top1Replication DSB

(Rep-DSB)

5'

Top1

5'

Top1

N

N

O

O

OHO

Camptothecin (CPT)

Pommier and Diaisio, Fig. 6

BD

E

F

Top2 (Top3)

O

H

P

O

OO

O

O

5'

3'

O

Top1

-1 base

+1 base

Top

A Top2

5'

Top2

Top2

5'

Top2

Top2Y

5'

Top2

I

J

O

OOCH3

OH

OH

R

O CH3

OHNH2

O

OH

CH2OH

CH3R =

R =

O

O

OO

HH3C

HOHO

O

OO

O

OCH3

OH

H3CO

O

Etoposide(VP-16)

Doxorubicin(Adriamycin)

Daunorubicin

20

G H

Decatenation

K

CleavageComplexes

N

N

N

N

O

H3C

O CH3

CH3

1

3 7

NN

N OHO

O

CH3

OCH3

NHCH3

H

H

H

NH

HN

N

S S O

NCH3

CH3

CH3

O

O

OH

HO

N

CH3

OH

Cl

O

N

N

N

N

HN

NH

H3C

HO

H3CCH3

NH

NH S

O

O

S NH2

O

0

Pommier and Diaisio, Fig. 7

7-hydroxystaurosporine (UCN-01)(Kyowa Hakko Kogyo)

N

N NH

N

H2N12

2-AminopurineCaffeine

Flavopiridol(Aventis)

(R)-Roscovitin (Selecid = CY202)(Cyclacel)

Indisulam (E7070)(EISAI)

BMS-387032(Bristol-Myers Squibb)