DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1696
Fluoropyrimidine Analogs
H 3 C
OH
O
O
N
N
OH
NH
CO
F
O
H
N
O
O
N
H
F
HOH 2 C
OH
O
O
O
H
N
N
F
HO
O
P O
OH
CH
OH
H
O
O
N
O
N
F
SECTION VIII
CAPECITABINE
Cytidine Analogs
5-FLUOROURACIL
(5-FU)
5-FLUORODEOXYURIDINE
(FLOXURIDINE)
5-FLUORODEOXYURIDINE
MONOPHOSPHATE
(ACTIVE METABOLITE)
NH 2 NH 2 NH 2
NH 2
CHEMOTHERAPY OF NEOPLASTIC DISEASES
N N N
N
O N O N O N
HOCH 2
HOCH 2 HOCH 2
O OH
O O
OH OH OH
OH F
CYTOSINE ARABINOSIDE
(CYTARABINE; AraC)
5-AZACYTIDINE
Figure 61–8. Structures of available pyrimidine analogs.
thymidylate. The physiological complex of TS-folate-dUMP progresses
to the synthesis of thymidylate by transfer of the methylene
group and two hydrogen atoms from folate to dUMP, but this reaction
is blocked in the inhibited complex of TS-FdUMP-folate by the
stability of the fluorine carbon bond on FdUMP; sustained inhibition
of the enzyme results.
2 , 2 -Difluorodeoxycytidine
(gemcitabine)
F
N N
O N
HOCH 2
OH
O
Decitabine
5-FU is incorporated into both RNA and DNA. In 5-FU-treated
cells, both fluorodeoxyuridine triphosphate (FdUTP) and deoxyuridine
triphosphate (dUTP) (the substrate that accumulates behind the
blocked TS reaction) incorporate into DNA in place of the depleted
physiological TTP. The significance of the incorporation of FdUTP
and dUTP into DNA is unclear. Presumably, the incorporation of
Dihydro 5-FU
7
5-FU
1
2
FUR
FUdR
5
3
(PRPP)
4
FUMP FUDP FUTP RNA
inhibitor of
thymidylate
synthase
6
1 Uridine phosphorylase
2 Thymidine phosphorylase
3 Phosphoribosyl transferase
4 Thymidine kinase
5 Uridine kinase
6 Ribonucleotide reductase
7 Dihydropyrimidine dehydrogenase
FdUMP FdUDP FdUTP DNA
Figure 61–9. Activation pathways for 5-fluorouracil (5-FU) and 5-floxuridine (FUR). FUDP, floxuridine diphosphate; FUMP, floxuridine
monophosphate; FUTP, floxuridine triphosphate; FUdR, fluorodeoxyuridine; FdUDP, fluorodeoxyuridine diphosphate; FdUMP,
fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate.