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)
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