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Chapter 8
Antineoplastic Agents
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8.1 Introduction
The characteristics of cancer are uncontrolled cellular growth and
proliferation, sometimes, tumor cell migration, invasion, and
spreading to other organs and tissues. Different factors and
conditions can transform normal cells into cancerous ones by
altering the normal function of a wide spectrum of regulatory,
apoptotic, and signal transduction pathways.
Cancer, which may arise from any type of cell and in any body
tissue, is not a single disease but a large number of diseases
classified according to the issue and type of cell of origin.
Cancer is the second leading cause of death after cardiovascular
disease, accounting for 10% of all deaths in the world.
Approximately 10 million cases of cancer are diagnosed
worldwide, resulting in an estimated 5 million annual death.
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Cancer invasion and migration
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Anticancer treatment：
Surgery (手术治疗）
Radiation（放射治疗）
Chemotherapy（化疗）
biological response modifiers
（生物效应调节）
The treatment modality adopted by the oncologist often includes more
than one approach, and is largely dependent on the type of tumor and
how far it has progressed in the patient.
Among various approaches, chemotherapy has become increasingly
important in recent year.
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Classification of antitumor drugs
nitrogen mustards (氮芥) (melphalun, cyclophosphamide)
Alkylating Agents
Nitrosoureas（亚硝基脲) (carmustine 卡莫司汀)
platinum complexes（金属络合物）(cisplatin, carboplatin)
Pyrimidine antagonists (5-FU)
Antimetabolites
Purine antagonists (6-MP)
Antifolates(MTX 甲氨喋呤)
Topoisomerase Inhibitors
TopoisomeraseⅠinhibitors (topotecan 拓扑替康)
Topoisomerase II inhibitors (doxorubicin
(adriamycin 阿霉素)
Microtubule Targeting Agents
Inhibitors of microtubule assembly (vincristine
长春新碱）
Microtubule stabilizers(paclitaxel 紫杉醇)
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8.2 Alkylating Agents
(1) Nitrogen Mustards
alkylating part
carrier
Cl
R N
Cl
bis (β-chloroethyl) amines
S
Cl
Cl
N
Mustard
Cl
.
Cl HCl
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Mechanism of Action
Cl
R
N
Cl
¢Ù
Cl
Cl
¢Ú
R
N
Cl
N R
Cl
N
H2N
N
O
HN
H2N
N
R
N
N
DNA A chain
N
N
DNA A chain
N
N
NH2
DNA B chain
¢Û
NH
O
O
HN
H2N
N
two damaged DNA chain
R
N
N
Cl- O
N
N
H
N
H
Cl-
N
NH
NH2
N
HN
H2N
¢Ü
¢Û
Cl
Cl- O
N
Cl-
N
NH
N
N
NH2
DNA A chain
O
HN
O
N
N
DNA B chain
R
N
Cl
O
N
NH
N
N
NH2
DNA Achain
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alkylating part
carrier
Structure-activity Relationships
Cl
R N
Cl
bis (β-chloroethyl) amines
R can be either aliphatic or aromatic
①R: an aliphatic substituent will push electrons to the amine. This
electronic enrichment enhances the nucleophilc character of the lone
pair of electrons and increases the speed at which the β-carbon of
mustard will be attacked (SN2 reaction)
Cl
R N
-Cl
Cl
R
-Cl
N
Cl
X
R N
Y
R
N
X
R N
X
Y
X
Cl
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②R: an aromatic substituent will stabilize the lone pair
of electrons through resonance. Resonance
delocalization slows the rate of intramolecular
nucleophilic attack, aziridinium ion formation, and DNA
alkylation. The higher stability of aromatic mustard not
only permits oral administration and attenuate the
severity of side effects .
Cl
Ar N
Cl
CH2
-Cl
slow
-Cl
slow Ar N
N
Ar
X
CH2
Cl
X
fast
Y
fast
Ar N
Ar N
X
Y
alkylating part
carrier
Cl
R N
Cl
bis (β-chloroethyl) amines
X
Cl
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【Melphalan 美法伦】
O
*
Cl
N
OH
NH2
Cl
Chemical name:
4-[bis(2-chloroethyl)amino]-L-phenylalanine
4-[双(2-氯乙基)氨基]-L-苯丙氨酸
Action:
The L-amino acid Phe is purposefully incorporated into this aromatic
mustard because naturally occurring L-amino acid is preferentially
transported into cells by the action of specific amino acid carrier proteins,
and the L-isomer is more potent than the D-isomer. It is active against
multiple myeloma, breast, testicular, and ovarian carcinoma.
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Synthetic route
OH
O
NH2
50% CH3COOH
O
HC
N
POCl3/DMF
N
OHC
(CH3CO)2O, KHCO3
N
OH
Cl
O
Cl
CONHCH2COOH
Cl
N
COOH
Cl
CH3COOH:Zn
Cl
NHCOC6H5
N
COOH
Cl
25%HCl
Cl
Cl
O
O
O
O
HO
HO
CONHCH2COOH
NH2
N
NH
O
N
O
N
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【Cyclophosphamide 环磷酰胺】
Cl
Cl
H
O N
N P
O
H2O
Chemical name:
N,N-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine2-oxide monohydrate
N,N-双(2-氯乙基)四氢-1,3,2-氧氮磷杂六环-2-胺-2-氧单水合物
Action
Cyclophosphamide is a prodrug, requiring activation by metabolic processes
in liver and . The toxic effects are lower.
It has been used for the treatment of lymphoma, leukemia, multiple
myeloma（多发性骨髓瘤）, mycosis fungoides（蕈状肉芽肿）,
neuroblastoma（神经母细胞瘤）, adenocarcinoma of the ovary（乳腺
癌）, retinoblastoma（视网膜母细胞瘤）, and breast carcinoma.
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Activation of cyclophosphamide:
Cl
Cl
H
O N
N P
O
Liver
Cl
CYP2B6
Normal tissue
Cl
Cl
Enzyme
O
H
O N
N P
O
Cl
Normal tissue
Enzyme
O
Cl
O NH2
N P
O
O NH2
N P
O
Cl
Cl
4-Ketocyclophosphamide
Cl
OH
H
O N
N P
O
OH Cl
Cl
Tumor Nonenzymatic
process
O NH2
N P
O
Decomposition
Cl
NH
Cl
O
CH2=CHCHO
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Synthetic route ：
O
N
H
O
P
Cl
Cl
N
HO
HO
NH
POCl3, C5H5N
Cl
HO
Cl
H2O
Cl
Cl
H
O N
N P
O
H2O
Cl
O
P
N
Cl
H2N
Cl
Cl
.H O
2
H
O N
N P
O
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（2）Platinum Complexes
All the currently marketed platinum antitumor agents are Pt (Ⅱ) complexes
with square-plannar geometry.
Platinum complex is a potent inhibitor of DNA polymerase.
O
H3N
Cl
Pt
H3N
NH3
O
O
O
O
Cisplatin （顺铂）
O
Pt
Pt
Cl
H2
N
NH3
O
O
Carboplatin （卡铂）
N
H2
Oxaliplatin（奥沙利铂）
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Cisplatin activation and DNA cross-linking
NH3 -Cl
H3N
H3N
Pt
Cl
NH3 -Cl
+
Pt
H2O
Cl
H2O
Cl
monoaquo form
(active)
H2O
H3N
H2O
-2H2O
N7
DNA-Guanine
2+
Pt
NH3
NH3
OH2
diaquo form
(fully active)
N7
H3N
2+
Pt
DNA-Guanine
N7
Guanine-DNA
N7
Guanine-DNA
Crosslinked DNA strand
Clinical use:
Cisplatin has been a particularly effective drug in the treatment of testicular
and ovarian cancers. Other tumors that have shown sensitivity to cisplatin
include penile cancer(阴茎癌）, bladder cancer（膀胱癌）, cervical cancer
（子宫颈癌）, head and neck cancer, and small-cell lung cancer.
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(3) Other Alkylating Agents
S
P
N
N
N
O
O
S
O
Busulfan
O
S
O
O
Thiotepa
白消安
噻替哌
Cl
O
O
N
N
N
Carmustine
卡莫司汀
CONH2
N
Cl
N
N N N
Dacarbazine
达卡巴嗪
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8.3 Antimetabolic Agents
Antimetabolites are compounds that prevent the formation or utilization
of a normal cellular metabolite.
Most antimetabolites are enzymes inhibitors. The rate-limiting enzymes
of nucleotide biosynthesis are often the primary target for the
antimetabolites.
Antimetabolites can also inhibit other enzymes required in the
biosynthesis of DNA and arrest chain elongation by promoting the
incorporation of false nucleotides into the new DNA strand.
Antimetabolites are usually closely related to the structure of metabolite.
They are derivatives of the building blocks of DNA itself, such as the
nucleoside based inhibitors, or analogs of critical cofactors such as the
antifolates.
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(1) Pyrimidine Antagonists
Starting with the observation that uracil was used more rapidly than other
bases in tumor tissue, fluorine was chosen as the substituent to replace C5-H
of uracil based on the principle of isosterism.
The choice was well founded, as 5-fluorouracil (5-FU) soon became one of the
most widely used antitumor agents.In recent years, more pyrimidine
antagonists have been developed to be effective in the treatment of tumors,
such as tegafure (替加氟), and floxuridine(氟尿苷).
Pyrimidine antagonists also consist of cytosine nucleosides. cytarabine (阿糖
胞苷), cyclocytidine (环胞苷)
O
HN
O
O
O
HN
F
HN
F
N
H
5-fluorouracil
O
N
O
N
N
N
O
N
HO
HO
floxuridine
O
O
HO
HO
O
tegafure
NH
NH2
F
HO
cytarabine
HO
N
O
O
HO
cyclocytidine
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【Fluorouracil 氟尿嘧啶】
O
F
HN
O
O
O
N
H
Chemical name:
5-Fluoro-2,4(1H,3H)-pyrimidinedione
5-氟-2,4（1H,3H）-嘧啶二酮
F
HN
N
HO2PO CH2 O
OH
5-F-dUMP£¨ active£©
( false substrate )
Action:
5-FU must be converted to its active 5-fluorodeoxyuridine
monophosphate (5-F-dUMP) form, a potent inhibitor of
TS(胸腺嘧啶合成酶）
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Synthetic route：
O
Cl
CH3
F
CH3CONH2
O
O
CH3
NaO
H
KF
O
O
H3C
CH3ONa
O
O
CH3OH
F
H3CO
H3CO
NH
HCl
H2O
N
O
HN
NH2
ONa
H
O
O
H3CO
CH3
O
H
F
HN
O
N
H
O
F
F
HN
N
CH3ONa
O
F
N
OC2H5
O
F
OH
NH2
NH
F
HCOOC2H5
CH3
ONa
H3CO
N
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Activation and mechanism of action of Fluorouracil
O
O
HN
O
O
F
F
HN
O
H
N
O
F
N
O
HO3PO CH2 O
F
HN
N
O
H2O6P2O CH2 O
N
H2O6P2O CH2 O
N
H
OH OH
OH OH
5-FUMP
OH
5-FUDP
H2N
N
5-F-dUDP
H
N
O
HN
F
HN
N5
O
O
N
HO2PO CH2 O
O
5,10-CH2-THF (cofactor)
H
N
COOH
(CH2)2
HN
HS-Cys-TS(enzyme)
O
O
OH
F
HN10
CH2
N
COO
S Cys
HO2PO CH2 O
TS
5-F-dUMP£¨ active£©
( false substrate )
Stable fluorinated ternary complex
OH
O
HN
O
N
dR P
TDRP
+
Nu-Enz
TS
H2N
N
N
H
N
O
Glu
N
OH
HN
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(2) Purine Antagonists
8-Azaguanine(氮杂鸟嘌呤）, the first purine analog, was introduced into
clinical trials but was abandoned in favor of newer and more effective
agents such as mercaptopurine (6-MP), thioguanine (巯鸟嘌呤), and
heterocyclic derivatives of mercaptopurine, azathioprine (硝基咪唑巯嘌呤).
A number of purine nucleoside analogs were also developed. Clofarabine
(氯伐拉滨), an analogue of fludarabine (氟达拉滨)
N
N
N
H3C N
SH
SH
N
H
H2N
S
N
N
N
thioguanine
NH2
N
HO
O
N
R2
OH
N
N
R1
NO2
N
N
N
H
N
6-MP
N
N
H
azathioprine
R1
R2
Cl
F Clofarabine
F
OH fludarabine
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Mechanism of action:
To interfere the biosynthesis of purine by inhibition of synthetic enzyms
of AMP and GMP
Biosynthesis of AMP and GMP The cell’s ability to provide the needed purine
nucleotides for DNA and RNA synthesis is also critical to its survival. The
biosynthesis of purine nucleotides involves 10 separate enzyme catalyzed
reactions starting with 5-phosphoribosyl-1-pyrophosphate and leading to
inosinic acid（次黄嘌呤核苷酸）
OH
AMP
N
HO3PO
O
N
N
N
Inosinic acid
GMP
AICARFT
AICAR
HO
OH
inosinic acid
THF
10-CHO-THF
formylglycinamide
ribonucleotide
GARFT
GR
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【Mercaptopurine 巯嘌呤】
OH
SH
HO3PO
O
N
N
HO
N
NH2
N
N
H
N
N
N
N
HO3PO
N
N
OH
HO
inosinic acid
SH
N
Chemical name:
Purine-6-thiol ( 6-mercaptopurine)
6-嘌呤硫醇（6-巯基嘌呤）
O
N
HO3PO
O
HO
N
OH
adenylic acid
N
N
OH
6-thioinosinate(active form)
Action：
Mercaptopurine must be converted into corresponding 6-thioinosinate, which
is a potent inhibitor of the conversion of 5-phosphoribosyl-1-pyrophosphate
into 5-phosphorribosylamine, a rate-controlling step in the synthesis of purine.
It also inhibits the conversion of inosinic acid to adenylic acid（腺苷）.
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Synthetic route:
OH
NH2
NH2
S
O
+ NC
CH3
C2H5ONa
C2H5OH
O
HS
NO
SH
H
N
N
N
NH2
N
HS
NH2
OH
HCOOH
N
NH2
OH
NH2
N
Na2S2O4, NaOH
N
HS
OH
OH
N
NaNO2, HCl
N
N
PS5
H
N
N
N
N
Na2CO3, Ni
NH2
N
N
NH2
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(3) Antifolates
The biosynthesis of nucleic acid precursors depends on folate metabolism.
THF, along with its cofactors, are the main carriers of one carbon units in the
synthesis of thymidine and purine nucleosides. THF accepts the carbon atom
of serine to give 5,10-CH2-THF
H
H2N
N
HN
O
N
N
H
HN
COOH
(CH2)2
H
N
THF
O
COOH
NADPH + H+
dTMP
7, 8-DHF
DHFR
NADP+
O
TS
THF
serine
dTMP:
SHMT
dUMP
5,10-CH2-THF
glycine
CH3
HN
O
O
dUMP:
N
R
HN
O
N
R
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Antifolates
O
N
H
NH2
N
N
H2N
N
CO2H
N
O
HN
N
S
CH3
N
COOH
HN
COOH
O
O
N
N
H
raltitrexed (雷替曲塞)
COOH
N
H
HN
H2N
R: H aminopterin (氨基蝶呤)
R: CH3 methotrexate (甲氨蝶呤)
N
R
O
H3C
CO2H
COOH
Permetrexed (培美曲塞)
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8.4 Topoisomerase Inhibitors
(1)TopoisomeraseⅠInhibitors
Camptothecin and Analogs
camptothecin (喜树碱 ) is a natural product,
first isolated and characterized from bark of
Camptotheca acuminate
Structure modification:
topotecan (拓扑替康)
irinotecan (伊立替康)
R2
R3
R1
R1
R2
R3
H
H
H
camptothecin
H
topotecan
C2H5
irinotecan
O
N
N
O
O
C2H5
OH
(H3C)2NCH2
OH
O
N
N
O
H
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(2) Topoisomerase II Inhibitors
Anthracyclines (蒽环类）
Doxorubicin (Adriamycin,阿霉素) and daunorubicin daunorubicin（多柔比
星）were isolated from Streptomyces peucetius var caesius （波赛链霉菌）
and proved to be useful antitumor agents
O
OH
O
O
OH
O
O
OH
O
OH
H3C
D
C
B
A
O
O
OH
O
O
CH3
OH
NH2
adriamycin
OH
OH
aglycone
H3C
sugar portion
O
O
OH
O
OH
O
OH
O
CH3
OH
NH2
daunorubicin
O
O
CH3
OH
NH2
Idarubicin伊达比星
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Structure modification:
OH
O
H
N
HN
OH
Mitoxantrone(米托蒽醌 )
OH
O
HN
N
H
OH
Prodrug targeting the CYP450
Planar
chromophore
OH
O
HN
O
N
Planar
chromophore
OH
O
HN
Tertiary amines
N-oxides
OH
O
HN
OH
N
O
AQ4N
N
O
HN
N
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Pharmacophore：
Cheng propose a N-O-O triangle hypothesis
O
OH
O
R1
H
O
O
OH
OH
O
NH 2
O
OH
0.3nm
O
阿霉素
O
0.8
0 .6
nm
nm
N
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OH
O
HN
OH
O
HN
H
N
N
H
米托蒽醌 （Mitoxantrone）
OH
OH
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6Å
3Å
O
OMe
O
MeO
N
N
O
N
O
HO
N
MeO
娃儿藤素
O
喜树碱
8Å
MeO
O
O
OH
O
MeO
OH
H 2N
OH
OMe O
H
OH
阿霉素
O
N
O
NH 2
Me OH
N
H 2N
COOH
Me
OH
链黑霉素
OMe
OMe
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8.5 Microtubule Targeting Agents
(1) Inhibitors of Microtubule Assembly(微管聚合抑制剂 )
The vinca bis-indole alkaloids, isolated from Catharanthus roseus, are a family of
important antitumor agents. Four structure-closely related compounds have antitumor
activity: vinblastine (长春碱), vincristine (长春新碱), vindesine (长春地辛). Further
evaluation of the vinca SAR has led to the identification of several analogs, including
vinflunine (长春氟宁)
9'
1'
N
H
H3COOC
H3CO
HO 4'
6'
N
2'
CH3
N
C2H5
1
34 H
N
OR3
H
COR
2
R HO
1
R1
R2
R3
CH3
OCH3
COCH3
CHO OCH3
COCH3
CH3
NH2
H
vinblastine (长春碱)
vincristine (长春新碱)
vindesine (长春地辛)
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(2) Microtubule Stabilizers
Paclitaxel and Related Taxanes
R2O H
O
R1
H
N
H
O
H OH
O
H
H
O
HO
O
OH
O
O
H
O
O
paclitaxel (taxol)
R1=C6H5
R2=COCH3
docetaxel (taxotere) R1=OC(CH3)3 R2=H
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The SAR of taxanes
Acetyl or acetoxyl group
may be removed without
significant loss of activity,
some acyl analogs have
multidrug resistancereversing activity
N-Acyl group
required
Reduction
improves
activity
slightly
O
OH
10
9
7
1
2
AcO
O
NH
O
13
2'
Phenyl group
or a close
analog required
Free 2'-hydroxyl group,
or a hydroxylzable ester
there of required
3'
OH
4
O
H
O
HO
O
Removal of
1-hydroxyl
gruop reduces
activity slightly
May be esterfied,
epimerized or
removed without
significant loss of
activity
O
Oxetane ring or
small ring analog
required for activity
OAc
Removal of acetate reduces
activity; some acyl analogs
have improved activity
Acyloxyl group essential; certain
substituted benzoyl groups and other
acylgoups have improved activity
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本章重点:
1. 抗肿瘤药物按作用机制分类,各类的代表性药物。
2. 烷化剂的概念，分类、作用机制，氮芥类烷化剂的构效关系。
3.抗代谢物的概念、分类及作用机制。
4.代表性药物美法伦、环磷酰胺、顺铂、5-FU、6-MP的结构，合成和作用。