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

Modification of Base
CYTOSINE
(Capecitabine)
HN C O (CH 2 ) 4 CH 3
H 2 N
N C
O
N (5-Azacytidine)
C F
O N
(Capecitabine)
THYMINE
O
N
O
N
Modification of Deoxyribose
HO
(5-Fluorouracil)
F
CH 2
CH 3
CH 3
(Capecitabine)
OH
O
H
H
GUANINE
H 2 N
(Cladribine)
(Clofarabine)
Cl
Base
Strategies for inhibiting DNA synthesis are based on the ability
to create analogs of these precursors that readily enter tumor cells
and become activated by intracellular enzyme. As an example, the
first successful pyrimidine analog, 5-FU, is converted to a deoxynucleotide,
fluorodeoxyuridine monophosphate (FdUMP), which in
turn blocks the enzyme; TS, required for the physiological conversion
of dUMP to dTMP, a component of DNA. Other analogs incorporate
into DNA itself and thereby block its function.
Cells can make the purine and pyrimidine bases de novo and
convert them to their active triphosphates (dNTPs). The dNTPs then
act as substrates for DNA polymerase and become linked in 3′-5′ phosphate
ester bonds to form DNA strands; their base sequence provides
the code for subsequent RNA and protein sequences.
As an alternative to synthesis of new precursor molecules,
cells can salvage either free bases or their deoxynucleosides (Figure
61–7) from the bloodstream, presumably the products of degradation
of DNA. Certain bases, such as uracil, guanine, and their analogs,
can be taken up by cells and converted intracellularly to (deoxy)
nucleotides by the addition of deoxyribose and phosphate groups.
Antitumor analogs of these bases (5-FU, 6-thioguanine) can be formulated
as simple substituted bases. Other bases, including cytosine,
N
O
N
H
(6-Mercaptopurine)
ADENINE
H
H 2 N
N
N
(6-thioguanine,
6-mercaptopurine)
S
N
N
F
(Fludarabine)
2 β-OH (Cytosine arabinoside, Fludarabine)
2 β-F (Clofarabine)
2 -2 α,β-di F (Gemcitabine)
Figure 61–7. Structural modification of base and deoxyribonucleoside
analogs. The yellow ellipses indicate sites modified to
create antimetabolites. The specific substitutions are indicated
in red for each drug. Modifications occur in the base ring systems,
in their amino or hydroxyl side groups, and in the deoxyribose
sugar found in deoxyribonucleosides.
N
N
thymine, and adenine, and their analogs can only be utilized as
deoxynucleosides, which are readily transported into cells and activated
to deoxynucleotides by intracellular kinases. Thus, cytarabine
(cytosine arabinoside; Ara-C), gemcitabine, 5-azacytidine, and adenosine
analogs (cladribine), are nucleosides readily taken up by cells,
converted to nucleotides, and incorporated into DNA (Figure 61–8).
Fludarabine phosphate, a nucleotide, is dephosphorylated
rapidly in plasma, releasing the nucleoside that is readily taken up
by cells. Analogs may differ from the physiological bases in a variety
of ways: by altering in the purine or pyrimidine ring; by altering
the sugar attached to the base, as in the arabinoside, Ara-C; or
by altering both the base and sugar, as in fludarabine phosphate
(Figure 61–7). These alterations produce inhibitory effects on vital
enzymatic pathways and prevent DNA synthesis.
Fluorouracil, Capecitabine, and
Floxuridine (Fluorodeoxyuridine)
5-fluorouracil (5-FU)
HO
O
HO
HN
O
O
N
FLOXURIDINE
(FLUORODEOXYURIDINE;
FUdR)
F
H 3 C
O
HO
Mechanism of Action. 5-FU requires enzymatic conversion to the
nucleotide status (ribosylation and phosphorylation) in order to exert
its cytotoxic activity (Figure 61–9). Several routes are available for
the formation of floxuridine monophosphate (FUMP). 5-FU may be
converted to fluorouridine by uridine phosphorylase and then to FUMP
by uridine kinase, or it may react directly with 5-phosphoribosyl-1-
pyrophosphate (PRPP), as catalyzed by orotate phosphoribosyl
transferase, to form FUMP. Further metabolic pathways are available
to FUMP. As the triphosphate FUTP, it is incorporated into
RNA. In an alternative reaction sequence crucial for antineoplastic
activity, it is reduced to FUDP by ribonucleotide reductase (RNR) to
the deoxynucleotide level and forming of FdUMP. 5-FU also may be
converted by thymidine phosphorylase to the deoxyriboside fluorodeoxyuridine
(FUdR) and then by thymidine kinase to FdUMP, a
potent inhibitor of thymidylate synthesis. This complex metabolic
pathway for the generation of FdUMP may be bypassed through
administration of floxuridine (fluorodeoxyuridine; FUdR), which is
converted directly to FdUMP by thymidine kinase. FUdR rarely is
used in clinical practice.
FdUMP inhibits TS and blocks the synthesis of TTP, a necessary
constituent of DNA (Figure 61–10). The folate cofactor, 5,10-
methylenetetrahydrofolate, and FdUMP form a covalently bound
ternary complex with TS. This inhibited complex resembles the transition
state formed during the enzymatic conversion of dUMP to
N
O
HN
N
O
OH
O
F
CAPECITABINE
CH 3
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CHAPTER 61
CYTOTOXIC AGENTS