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SUMMARY OF ANTIMETABOLITES

Prepared by: Charrysse Bernadette V. Bati, BSP3F

Definition: a substance that interferes


with the normal metabolic processes
within cells, typically by combining with
enzymes
MOA: interacts with the biosynthesis of
nucleic acid enzyme inhibition

Classes:
1. Pyrimidine Analogues - 6-membered
ring consisting of four carbon atoms and
two nitrogen centers at the 1- and 3ring positions
2. Purine Analogues - purine is a
heterocyclic aromatic organic
compound. It consists of a pyrimidine
ring fused to an imidazole ring

Characteristics:
closely related in structure to a
cellular precursor molecule
prevent the biosynthesis of
normal cellular metabolites
S-phase-specific
Myelosuppression is the dose
toxicity for all drugs in this class
CELL CYCLE/ CELL DIVISION
3. Folates - a general term for a group of
water soluble b-vitamins, and is also
known as B9; compounds designed to
interact at cofactor sites for enzymes
involved in the biosynthesis of nucleic
acid bases

G0 phase (resting stage): The cell has not yet


started to divide
G1 phase: The cell starts making more proteins
and growing larger, so the new cells
will be of normal size.
S phase: The chromosomes containing the
genetic code (DNA) are copied so that
both of the new cells formed will have matching
strands of DNA.
G2 phase: The cell checks the DNA and gets
ready to start splitting into 2 cells.
M phase (mitosis): The cell actually splits into 2
new cells.

PURINE ANTIMETABOLITES

6-Mercaptopurine:
- inhibition of purine biosynthesis
- thiol analog of hypoxanthine
- should be activated to as
ribonucleoside, 6-thioinosate
6-Mercaptopurine
(prodrug)

HGPRT
(enzyme)

Allopurinol:
potent inhibitor of XO (xanthine oxidase)

6-thioinosate

HGPRT stands for Hypoxanthine-guanine


phosphoribosyl transferase
6 thioinosate inhibits conversion of 5phosphoribosylpyrophosphate into 5phosphoribosylamine
Ribose diphosphate and triphosphate of 6-MP
active enzyme inhibitors
P3 of 6-MP incorporates into DNA and RNA to
inhibit chain elongation

Thioguanine (6-TG) 6-mercapto


analog of guanine
Drug resistance: may be caused by
lower activity of activating enzymes or
higher activity of catabolic enzymes
Inactivation:

a.) S-methylation
6-MP
thiopurine 5-methyl-transferase
(TPMT)
S-methyl MP
b.) oxidation
6-MP xanthine oxidase thiouric acid

eto yung structure ng XO

- used as an adjuvant
- increases both potency and toxicity of 6-MP
- prevents uric acid kidney toxicity
Heterocyclic derivatives of 6Mercaptopurine: (for protection from catabolic reactions)
a.) Azathioprine
- less effective than 6-MP
- important role as IMMUNOSUPPRESSIVE
AGENT in organ transplants
b.) Vidarabine
- adenosine arabinoside
D-arabinose (sugar moiety):
-competitive inhibitor of DNA polymerase
- for antineoplastic and antiviral activity
-limited to antitumor effect by susceptibility to
adenosine deaminase (adenosine deaminase- siya

yung nagcoconvert ng D-arabinose to inactive hypoxanthine


arabinoside)

D-arabinose + Fluorine = resistance to


adenosine deaminase (see figure 10.9 yung nasa taas :D)

Thymidylate Synthase (TS)


-responsible for reductive methylation of dUMP
by 5,10-methylenetetrahydrofolate to yield dTMP
and dihydrofolate
***Thymidine is unique to DNA

c.) Fludarabine- + Fluorine = stable to adenoside


deaminase
d.) Cladribine
-resistant to adenosine deaminase
-triphosphate: inhibits enzymes required for DNA
repair
-phosphorylated by cytidine kinase

PYRIMIDINE ANTIMETABOLITES

(eto explanation ng figure 10.17)

*5-Fluororacil + tetrahydrofolate source =


greater enzyme inhibition
5-Fluororacil
-block the conversion of uridylate to thymidylate
thus diminishing DNA biosynthesis
-induced increase in acidity

The 5-fluorine is stable to elimination, and a


terminal product results, involving the enzyme,
cofactor, and substrate, all covalently bonded
- In order to inactivate TS, both 5-FU and
tetrahydrofolate sp. are required to form the
ternary complex
- administration of a tetrahydrofolate source prior
to treatment with 5-FU results in greater
inhibition of total TS activity
LEUCOVORIN:
-Siya yung administered source of N-5formyltetrahydrofolate
- source din siya ng 5,10methylenetetrahydrofolate

*** 5-FU activated to 5-fluoro-2-deoxyuridylic


acid (5-D-dUMP siya yung inhibitor of
thymidylate synthetase)

*** Capecitabine carbamate derivative


of 5-deoxy-5-fluorocytidine
(prodrug muna siya, then pag tinake saka lang siya
magiging active which is yung 5-FU :D)

PYRIMIDINE DRUGS

*** Inactivation:
a.) Inactivation by dihydropyrimidine
dehydrogenase (DPD)
- -fluoro--alanine: major human metabolite
of 5-FU
Remedy:
- 5-FU is dosed with uracil and 5-FU prodrugs
- 5-chloro-2,4-dihydroxypyrimidine (CDHP)
inhibitor of DPD

*** Tegafur
-tetrahydrofuran derivative
-require high doses
-esters of N-hydroxymethyl derivative of tegafur
show greater anticancer activity
*** Cytosine Structures:

Cytarabine (ara-C) to arabinose sugar instead of


ribose
MOA: slowing of the DNA chain rxn via DNA
polymerase or cellular inefficiencies in DNA
processing or repair
Gemcitabine:
-fluorinated, 2,2-difluoro deoxycytidine
-inhibits ribonucleotide reductase and competes
with 2-deoxycytidine triphosphate
Azapyrimidine one more nitrogen at the
heterocyclic ring
Deazapyrimidine one less nitrogen at the
heterocyclic ring
*** 5-azacytidine
-product of natural fungal metabolism
MOA: reversible inhibition of DNA
methyltransferase, the lack of methylated DNA
activates tumor suppressor genes

FOLATES

*** Methotrexate
-classic antimetabolite of folic acid
-inhibits binding of the substrate folic acid to the
enzyme dihydrofolate reductase (DHFR)
-resulting to reduction in synthesis of nucleic
acid bases, perhaps most importantly, the
conversion of uridylate to thymidylate as
catalyzed by TS
Side effect: bone marrow suppression,
pulmonary fibrosis, GI ulceration (pakitandaan salamat!)
Leucovorin is given 6-24 hours to prevent the
long term effects on normal cells by preventing
the inhibition of DNA synthesis

*** Pemetrexed
-inhibits DHFR, TS, and GARFT (Glycinamide
ribonucleotide formyl transferase

HYDROXYUREA
(structure yan ng folic acid)

MOA: Inhibition of DNA biosynthesis by


inhibition of ribonucleotide reductase
- The drug is available in 500 mg capsule
- Hydroxyurea readily enters the CNS and
distributes to human breast milk. A major portion
of the total dose is excreted unchanged in the
urine

(note: hindi siya kabilang dun sa tatlong classes, pero isa siyang antimetabolite..
kumbaga, unclassified antimetabolite??? :D)
Thankyou!! -chaz

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