Nitrogen Mustards
H
N
O P
Cl
N
Cl
O
C y c lo p h o s p h a m id e - C y to x a n ® , N e o s a r ®
Indications: MANY: Malignant lymphomas,
mycosis fungoides and leukemias; several
non-malignant diseases: severe
rheumatoid arthritis and systemic lupus
erythematosus
Prodrug: requires CYP450 for activation
Cardiotoxicity possible,
immunosuppressive, preferably take on an
empty stomach, USE contraception
Indications: Germ cell testicular cancer
Cl
N
H
O P N
Cl
O
Ifo s fa m id e - Ife x ®
side effects – hemorrhagic cystitis, CNS
problems such as confusion and coma
Prodrug: requires CYP450 for activation
Powder for injection – obtain a urinalysis
prior to each dose, USE contraception
Cyclophosphamide
Synthesis
Cl
Cl
O
P
Cl
- HC l
Cl
HN
+
Cl
O
Cl
Cl
N
P
Cl
phosphorous oxy chloride
H2N
HO
H
N
O P
C yclo p h o sp h am id e
Cl
N
Cl
O
(C 2 H 5 ) 2 NH
dioxane (20-30 C )
C y c lo p h o s p h a m id e - C y to x a n ® , N e o s a r ®
Cl
Mode of action
It is believed that, it is inactive in the body until its ring structure was broken
down by an enzyme more common in cancer cells than in normal cells. But it was
found that cyclophosphamide is converted to the active metabolite in the liver
rather than in the tumor.
Acrolein is responsible for hemorragic cystitis, which results as adverse effect
of cyclophosphamide, which can be avoided by coadministration with Nacetylcysteine, or mercaptoethanesulfonate.
Mode of action
HO
Cl
H
N
O
P
Cl
H
N
liv er
O
H 2N
O
P
N
Cl
Cl
4-h y d ro xy cy clo p h o sp h am id e
o p en ch ain fo rm
Cl
O
n o n en z y m atically
P
N
+
H2C
OH
acro lein
Cl
p h o sp h o ram id e m u stard
O
H2N
P
N
+
cy clic az irid in iu m
(m ain alky lato r)
O
N
O
Cl
H2N
O
P
N
O
p ro d ru g
Cl
O
-
Cl
O
O
O
N
R
N
Nitrosoureas
Cl
O
Prototype
N
Cl
N
H
H
N
N
Indications: Palliative treatment for brain tumors, multiple
myeloma, Hodgkin’s and non-Hodgkin’s lymphomas
Cl
O
Non-vesicant, I.V. or topical
®
C a rm u s tin e - B iC N U , G lia d e l
®
Highly lipid soluble (may cross BBB)
1,3-Bis(2-chloroethyl)-1-nitrosourea
Long delay in bone marrow suppression (6 weeks) - do not
give more often than every 6 weeks
O
Indications: Brain tumors and Hodgkin’s disease
N
Cl
H
N
N
O
Bone marrow toxicity is cumulative - delayed for 6 weeks
Capsule: take on empty stomach to avoid N/V, avoid alcohol
Highly lipid soluble allows 50% higher CNS levels
L o m u s tin e - C e e N u ®
3-Cyclohexyl-1-(2-chloroethyl)-1nitrosourea
Mechanism of action of nitrosourea
P ro te in
O
O
C
N
R
P ro te in
L ys N H
ca rb a m oy la tio n
isocyanate
Cl
O
L ys N H 2
HN
R
N
N
N
H
N2
Cl
+
Cl
HO-
N
DNA
Cl
O
H
O
N
X
Y
a lk y la tio n
OH
A lk y la tin g
ag en t
(carbocation)
DNA
X
Isocyanic acid reacts with amines to give ureas
(carbamides):
This reaction is called carbamylation.
Y
DNA
Crosslinking
R
Mode of action
Lomustine
Lomustine medac®
iso cyan ate
O
N
H
Cl
N
N
O
W eak
base
N
Cl
N
N
O
H
O
+
N
N
N
O
N
O
N
C
O
N
OH
H 20
N2
CO2
OH
R eactive vin ilic catio n
NH2
D N A -N u
Other Alkylating Agents: Aziridines
N
N
P
N
S
T h io te p a - T h io p le x ®
Tris-1-aziridinylphosphine sulfide
Indications: Adenocarcinoma of the breast or ovary, control of intracavity
effusions, urinary bladder papillary carcinoma, lymphomas
IV use only
MOA: Alkylates by ethyleneimine radical disrupting DNA  Chain scission
Monitor renal and hepatic function - decrease dosage as appropriate
Monitor blood counts for at least three weeks following cessation of therapy very highly toxic to bone marrow - discontinue if sharp drop in WBC’s or
platelets
Other Alkylating Agents
Indications: selective for bone marrow
C H3SO3
Very well tolerated drug but severe
myelosuppression
O 3S C H3
Discontinue at first sign of bone marrow
abnormalities –can cause hyperuricemia—use
allopurinol to avoid (xanthine oxidase
inhibitor)
B u s u lfa n - M y le ra n ® , B u s u lfe x ®
Remission rate ~90% after one dose!
O
O
S
H 3C
O
O
S
O
CH3
O
Sulfonate
(good leaving group)
O
O S O 2C H 3
O
S
H 3C
O
O
CH3
S
O
N
O
N
- C H 3S O 3
NH
7
N
NH2
N
DNA
DNA
O
N
O
N
N
DNA
N
DNA
NH
N
- C H 3S O 3 -
NH
NH2
NH2
N
-
N
N
NH
O
O
N
O
NH
N
DNA
NH2
N
NH2
Other Alkylating Agents
Mono or dialkylation
Better leav. gr, not 3-membered ring intermed
cf dimethyl sulfate
Busulfan
O
O
S
O
O
S
O
O
Not reg. N
Thiotepa
E v en m o re re ac tiv e at lo w p H
S
Nu
N
P
N
N
H
S
N
P
N
N
Other Alkylating Agents
Methylhydrazines
H3C
H
N
N
H
H
N
C H3
C H3 O
P ro c a rb a z in e H C l - M a tu la n e ®
Indications: Hodgkin’s disease
MOA: Free radical methylation of DNA: results in cessation of
protein, DNA and RNA synthesis
Initial treatment should be considered via hospitalization due to
hepatic and renal impairment - metabolism in liver and kidneys produce
cytotoxic metabolites
Capsules, warn patients of ethanol-disulfiram like reactions, avoid
sympathomimetics such as cold-cough preps and tyramine containing
foods due to possibility of hypertensive crisis
Procarbazine
Prodrug •
methyl radical (CH3.) methyl group
guanine base •
•
Dacarbazine
HN
N
H 3C
N
CH3
N
NH2
N
O
Platinum compounds
Cisplatin (Platinol) ®
Cl
H 3N
Pt
H 3N
Cl
Diamminedichloroplatinum
It has divalent platinum bound to two potential leaving
groups; the chloride ions; in trans position to the chlorides
are two NH3 groups bound irreversibly and in firm
coordinate covalent bonds.
Other Alkylating Agents
Platinum Alkylating Agents
Cl
Indications: Carboplatin - Ovarian carcinoma;
Cis-Platin – testicular, ovarian and bladder
cancers of metastatic type
NH3
Pt
Cl
NH3
C is -p la tin -P la tin o l-AQ ®
O
O
NH3
Pt
O NH3
O
C a rb o p la tin - P a ra p la tin ®
N H2
O
O
O
O
Pt
N H2
O x a lip la tin - E lo x a tin ®
Prodrug – aquation or hydration necessary to
produce active species - this occurs more rapidly
with carboplatin than cis-platin  different
pharmacokinetics and potency
Bone marrow suppression is dose related
producing infection and anemia, may be
cumulative and require transfusions, dosage
adjustment a function of renal creatinine
clearance and platelet and neutrophil counts
Side-effects include hepatotoxicity, severe
vomiting (less severe with carboplatin), renal
damage, ototoxicity (more severe in children),
Analyphylaxis (immediate-treat with epinephrine,
antihistamines, corticosteroids)
Platinum Compound
Cisplatin:
Mechanism of Action:
Cisplatin binds to guanine in DNA and RNA, and •
the interaction is stabilized by hydrogen bonding.
The molecular mechanism of action is unwinding and
shortening of the DNA helix.
In vitro studies have revealed that only cis form can form •
interstrand cross-links between adjacent guanine residues in
DNA.
Platinum Alkylating Agents
Cl
NH3
Pt
Cl
NH3
C is -p la tin -P la tin o l-AQ ®
2 D N A -N u
X
H 3N
X
Pt
NH3
D N A -N u
H 3N
N u -D N A
Pt
+ 2 Cl
NH3
cis
(C o m ple xes w ith trans isom e rs a re m o re re ad ily re go gnize d an d re pa ired )
Part II; Drugs acting on enzyme
(Antimetabolites)
Antimetabolits: sites of drug action
23
Antimetabolites
General Characteristics：
 Antimetabolites are S phase-specific
drugs that are structural analogues of
essential metabolites and that interfere
with DNA synthesis.
 Myelosuppression is the dose-limiting
toxicity for all drugs in this class.
Antimetabolite
• Pyrimidine Antagonists
– Methotrexate, Fluorouracil, Floxuridine,
Capecitabine
• Purine Antagonists
– Mercaptopurine, Thioguanine
• DNA Polymerase/ DNA Chain Elongation
Inhibitors
– Cytarabine, Gemcitabine, Fludarabine,
Cladribine, Clofarabine
• Miscellaneous Antimetabolite
– Hydroxyurea
Pyrimidine Antagonist
• dTMP Synthesis Inhibitors
– Direct inhibitor: Fluorouracil, Floxuridine,
Tegafur.
– Indirect inhibitors: Methotrexate
Antimetabolites—Folic Acid Antagonist
Methotrexate （MTX）
Mechanism of Action：
 The structures of MTX and folic acid are similar.
MTX is actively transported into mammalian cells and
inhibits dihydrofolate reductase, the enzyme that
normally converts dietary folate to the
tetrahydrofolate form required for thymidine and
purine synthesis.
Methotrexate
Folic acid
_
dTMP
DHFR
DHF
_
DHFR
THF
N5,N10-Methylene-THF
Thymidylate
Synthase
dUMP
Antimetabolites——
Folic Acid Antagonist
NH2
COOH
N
O
N
N
H2N
N
N
H3C
NH
COOH
Methotrxate
L-(+)-N-[p[[2,4-diamino-6pteridinyl)methyl]methylamino]-benzoyl]glutamic acid
Folic acid
Methotrexate
(DHF)
pteridine
ring
DHFR ---- MTX -----DHF
Antimetabolites——
Folic Acid Antagonist
Methotrexate （MTX）
Adverse Effects：
 MTX is myelosuppressive, producing severe
leukopenia, bone marrow aplasia, and
thrombocytopenia.


This agent may produce severe gastrointestinal
disturbances.
Renal toxicity may occur because of precipitation
(crystalluria) of the 7-OH metabolite of MTX.
Antimetabolites——
Pyrimidine Antagonists
O
F
HN
5-Fluorouracil (5-FU)
Mechanism of Action：
O
N
H
• Fluorouracil is an analogue of thymine in which the
methyl group is replaced by a fluorine atom. It has
two active metabolites: 5-FdUMP and 5-FdUTP. 5FdUMP inhibits thymidylate synthetases and prevents
the synthesis of thymidine, a major building block of
DNA. 5-FdUTP is incorporated into RNA by RNA
polymerase and interferes with RNA function.
5-FU
Mechanism of the cytotoxic action of 5FU
• 5-FU is converted to 5-FdUMP, which
competes with deoxyuridine
monophosphate (dUMP) for the enzyme
thymidylate synthetase.
• 5-FU = 5-fluorouracil
• 5-FUR = 5-fluorouridine
• 5-FUMP = 5-fluorouridine
monophosphate
• 5-FUDP = 5-fluorouridine diphosphate
• 5-FUTP = 5-fluorouridine triphosphate
• dUMP = deoxyuridine monophosphate
• dTMP = deoxythymidine monophosphate
• 5-FdUMP = 5-fluorodeoxyuridine
monophosphate.
34
Antimetabolites——
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Adverse Effects：
• Fluorouracil may cause nausea and vomiting,
myelosuppression, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.
• With fluorouracil, myelosuppression is more
problematic after bolus injections, whereas mucosal
damage is dose-limiting with continuous infusions.
O
O
O
6
HN 1
2
O
F
HN 1
5
2
4
3
O
O
N
H
-O
P
6
3
HN 1
F
5
2
O
4
3
CH2
O
OH
5-Fluorouracil
(fluorinated pyrimidine
prodrug)
HO
deoxyribonucleotide form;
5-F-dUMP (active form)
2
2. Floxuridine
(fluoro deoxyuridine nucleoside
prodrug)
O
HN 1
H
2
5
O
O
3
6
3
H
5
4
N
4
N
H
Uracil
(nucleic pirimidine base)
4
CH2
O
HO
O
6
5
N
O
HN 1
F
N
HO
O
6
-O
P
O
CH2
O
OH
HO
dUMP
Antimetabolites——
Pyrimidine Antagonists
O
3. Tetrahydrofuranyl derivative
of uracil
It is a prodrug slowly
metabolized to 5-FU
F
HN
O
O
N
T e g a fu r
O
F
HN
O
Thymidine
URACIL
37
N
H
5-FU
Antimetabolites—— Purine Antagonists
(Mercaptopurine, Thioguanine)
N
Purine
N
H
N
N
N
N
H 2N
N
N
H
Guanine
SH
SH
N 1 6
2
3
N
N
5
4
N
7
6
N
8
9
N
H
6-Mercaptopurine
H 2N
N
N
H
6-Thioguanine
6-Mercaptopurine (6-MP) &
Thioguanine
• Both 6-MP and Thioguanine are
activated by HGPRT to toxic
nucleotides that inhibit several
enzymes involved in purine
metabolism
• ***Resistance is due to cancer
cells having d activity of HGPRT
• Cancer cells also es alkaline
phosphatase that inactivate toxic
nucleotides
39
(IMP) A family of IGF-II (insulin-like
growth factor) mRNA-binding protein
mRNA binding proteins
Purines antagonists
SH
6-Mercaptopurine
H
N
N
N
Mode of action:
N
It inhibits purine biosynthesis as it replaces hypoxanthene, which is a
natural intermediate in syntheses of nucleic acid purine bases.
Metabolism generating
bioactive compounds
“S-methylation”
HGPRT = hypoxanthine guanine •
phosphoribosyl transferase
TPMT = thiopurine methyl transferase•
SAM = S-adenosylmethionine •
(cofactor)
Purines antagonists
6-mercaptopurine is rapidly metabolized by xanthene
oxidase enzyme, which is responsible for oxidation of
hypoxanthene and xanthene into uric acid. So when 6mercaptopurine is co-administered with allopurinol
(xanthine oxidase inhibitor) its half-life will be
increased.
OH
OH
H
N
N
N
N
N
N
H y p o x a n th e n e
N
A llo p u rin o l
N
H
6-MP & Allopurinol
• 6-MP is metabolized in the liver by
xanthine oxidase and the inactive
metabolites are excreted in the urine
• ***Allopurinol is used frequently to
treat/prevent hyperuricemia caused
by many anticancer drugs.
• If Allopurinol is used with 6-MP then
the dose of 6-MP is reduced by more
than 75%
43
Antimetabolites——
Purine Antagonists
6-Mercapapurine（6-MP）
Indications:
• Mercaptopurine is used primarily for the maintenance
of remission in patients with acute lymphocytic
leukemia and is given in combination with MTX for
this purpose.
Adverse Effects:
• Well tolerate.
• Myelosuppression is generally mild with
thioguanine.Long-term mercaptopurine use may cause
hepatotoxicity.
DNA Polymerase/ DNA Chain Elongation Inhibitors
Cytarabine and Gemcitabine
NH2
NH2
H
N
O
HO
C lO
N
CH2
HO
O
N
N
CH2
O
F
HO
OH
Cytarabine
T1/2 = 3.6 hrs
OH
F
Gemcitabine
T1/2 = 19 hrs
Cytidine-base nucleosides
DNA Polymerase/ DNA Chain Elongation Inhibitors
Cytarabine
Indications：
• Cytarabine has a narrow clinical spectrum and is
primarily used in combination with daunorubicin or
thioguanine for the treatment of acute
nonlymphocytic leukemia.
Adverse Effects:
• High doses of cytarabine can damage the liver,
heart, and other organs.
DNA Polymerase/ DNA Chain Elongation Inhibitors
Fludarabine, Clabribine, and Clofarabine
NH2
NH2
N
N
O
HO
F
P
OH
N
N
O
CH2
O
NH2
N
N
Cl
HO
N
N
CH2
O
HO
OH
Fludarabine
phosphate
N
N
Cl
HO
N
N
CH2
O
F
OH
Cladribine
OH
Clofarabine
2-Halogenated adenosine base nucleosides
Miscellaneous Antimetabolites
• Pentostatin and Hydroxyurea (self study)
Hydroxyurea
Pentostatin
Miscellaneous Antimetabolites
Hydroxyurea
• Inhibits ribonucleotide reductase
– Important in de novo DNA
synthesis and DNA repair
• Orally bioavailable