chapter 8 antineoplastic agents. shanghai jiao tong university 8.1 introduction the characteristics...

Chapter 8 Antineoplastic

Agents

Shanghai Jiao Tong University

8.1 IntroductionThe 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.


Cancer invasion and migration


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.


Classification of antitumor drugs

Alkylating Agents

nitrogen mustards ( 氮芥 ) (melphalun, cyclophosphamide)

Nitrosoureas （亚硝基脲 ) (carmustine 卡莫司汀 )

platinum complexes （金属络合物） (cisplatin, carboplatin)

Antimetabolites

Pyrimidine antagonists (5-FU)

Purine antagonists (6-MP)

Antifolates(MTX 甲氨喋呤 )

Topoisomerase Inhibitors Topoisomerase inhibitors (topotecan Ⅰ 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 )


8.2 Alkylating Agents

(1) Nitrogen Mustards

R NCl

Cl

carrier alkylating part

bis (β-chloroethyl) amines

S

ClCl

N

ClCl .HCl

Mustard


Mechanism of Action

HN

N N

N

HN

N N

N

O

O

DNA A chain

DNA B chainH2N

H2N

N

HN

N N

N

O

DNA A chainH2N

NH

N

N

N

O

NH2DNA B chain

NCl- Cl-

R

ClCl N

Cl

R

ClNH

N

N

N

O

NH2DNA A chain

NCl

R Cl

NH

N

N

N

O

NH2DNA Achain

N

R ClCl

two damaged DNA chain

HN

N NH

N

O

H2N

NH

N

N

NH

O

NH2

NCl- Cl-

R

R

¢Ù ¢Ú

¢Û

¢Û

¢Ü


Structure-activity Relationships

R NCl

Cl


bis (β-chloroethyl) aminesR 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)

N

Cl

ClR NR Cl

X

N

XClR

NR X N

XYR

Y

-Cl

-Cl


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 .

R NCl

Cl


bis (β-chloroethyl) amines

N

Cl

ClAr NAr Cl

X

N

XClAr

NAr CH2 N

XYAr

Y

slow

CH2

fast

slow fast

X

-Cl

-Cl


【 Melphalan 美法伦】

* OH

O

NH2NCl

Cl

Chemical name:4-[bis(2-chloroethyl)amino]-L-phenylalanine4-[ 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.


NH2

O

50% CH3COOHN

OH

OH

POCl3/DMFN

Cl

Cl

OHC(CH3CO)2O, KHCO3

CONHCH2COOH

N

Cl

Cl

HC

O N

O

CH3COOH:Zn NCl

Cl

COOH

NHCOC6H525%HCl N

Cl

Cl

COOH

NH2

Synthetic route

CONHCH2COOH O NH

HO

O

NO

OHO

NO

O


【 Cyclophosphamide 环磷酰胺】

N PO

NOH

Cl

Cl

H2O

Chemical name:N,N-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-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.


N PO

N LiverN P

O

NOH

Normal tissueEnzyme

N PO

HNO

N PO

NH2O

4-Ketocyclophosphamide

N PO

NH2O

OOH

N PO

NH2O

CH2=CHCHO

O OH

O O

NH

Tumor Nonenzymaticprocess

Normal tissue Enzyme

Decomposition

H

Cl Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

CYP2B6

Activation of cyclophosphamide:


Synthetic route ：

NHHO

HON

Cl

Cl

N PO

NOH

Cl

ClPOCl3, C5H5N P

Cl

ClO

HO

H2N

H2O N PO

NOH

Cl

Cl

H2O

N

Cl

ClP

OON

H

.H2O


（ 2 ） Platinum Complexes

All the currently marketed platinum antitumor agents are Pt ( ) complexes Ⅱwith square-plannar geometry.

Platinum complex is a potent inhibitor of DNA polymerase.

PtH3N

H3N

Cl

Cl

O

O

O

O

Pt

NH3

NH3

O

O

O

O

Pt

H2N

NH2

Cisplatin （顺铂） Carboplatin （卡铂） Oxaliplatin （奥沙利铂）


PtNH3

Cl

2++

H2O H2O

-Cl

Cl

H3NPt

NH3

H2O Cl

H3NPt

NH3

H2O OH2

H3N

DNA-Guanine Guanine-DNA

N7 N7

-2H2O

2+

PtNH3H3N

DNA-Guanine Guanine-DNA

N7 N7

Crosslinked DNA strand

-Cl

monoaquo form (active)

diaquo form (fully active)

Cisplatin activation and DNA cross-linking

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.


(3) Other Alkylating Agents

S

PNN

N

ThiotepaBusulfan

Carmustine Dacarbazine

SO

OS

O O

OO

ClN N

O

ClN

ON

N

CONH2

N N N

噻替哌白消安

卡莫司汀达卡巴嗪


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.


(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 )

5-fluorouracil tegafure floxuridine cytarabine

HN

N

F

O

O

O

N

HN

O

O

F

HN

NH

F

O

O

OHO

HO

N

N

NH

N

N

O

NH2

OHO

HO OO

HO

HO

HO

cyclocytidine


【 Fluorouracil 氟尿嘧啶】

HN

NH

F

O

O

Chemical name:5-Fluoro-2,4(1H,3H)-pyrimidinedione5- 氟 -2,4 （ 1H,3H ） - 嘧啶二酮

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）

O

OH

HN

N

OF

O

CH2HO2PO

5-F-dUMP£¨ active£©

( false substrate )


Synthetic route ：

ClO CH3

O

KF FO CH3

O

HCOOC2H5

CH3ONa

O CH3

O

F

H

O

CH3ONa

NaO

H F

OCH3O H3C

ONH2

NH

CH3OH N

N

H3CO

OH

F HCl

H2O NH

HN

O

O

F

CH3CONH2

NH2

NHH3CO

OC2H5

ONa

FO HN

N

O

ONa

F

H3CO

H

HN

N

O

F

H3CO


Activation and mechanism of action of Fluorouracil

HN

NH

F

O

O

O

OHOH

HN

N

OF

O

CH2HO3PO O

OHOH

HN

N

OF

O

CH2H2O6P2O

5-FUMP 5-FUDP

O

OH

HN

N

OF

O

CH2H2O6P2O

5-F-dUDP

O

OH

HN

N

OF

O

CH2HO2PO

5-F-dUMP£¨ active£©

5,10-CH2-THF (cofactor)

O

OH

HN

N

O CH2

O

CH2HO2PO

F

S Cys

N

HNN

HN

H2N

O HNHN

O

(CH2)2

COO

COOH

HS-Cys-TS(enzyme)

TS

Stable fluorinated ternary complex( false substrate )

HN

N

O

O

dR P

+ Nu-Enz

TDRP

TS N

N

N

N

H

H2N

OH HN

O

Glu

5

10


(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 NH

N

SH

N

N NH

N

SH

H2N N

N NH

N

S

NNH3C

NO2

N

NN

NO

R2

R1

NH2

HO

OH

R1 R2

Cl F Clofarabine

F OH fludarabine

6-MP thioguanineazathioprine


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）

AICAR

Inosinic acid

AICARFT

AMP

GMP

10-CHO-THF

THF

GR

GARFT

formylglycinamide ribonucleotide

N

NN

NO

OH

HO3PO

HO OH

inosinic acid


【 Mercaptopurine 巯嘌呤】

N

N NH

N

SH

Chemical name:Purine-6-thiol ( 6-mercapto-purine)6- 嘌呤硫醇（ 6- 巯基嘌呤）

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） .

N

NN

NO

SH

HO3PO

HO OH

6-thioinosinate(active form)

N

NN

NO

OH

HO3PO

HO OH

N

NN

NO

NH2

HO3PO

HO OH

inosinic acid adenylic acid


Synthetic route:

N

N

OH

NH2HS

NH2 N

N

OH

NH2

NH2

N

N N

HN

OH

N

N N

HN

SH

HCOOH

Na2CO3, Ni

PS5

NH2

NH2S+ NC

O CH3

O

N

N

OH

NH2HS

N

N

OH

NH2HS

NO

C2H5ONa NaNO2, HCl

Na2S2O4, NaOH

C2H5OH


(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

NH

HNN

HN

H2N

O HN

HN

O

(CH2)2

COOH

COOH

N

HN

O

O

R

N

HN

O

O

R

CH3

dTMP

dUMP

7, 8-DHF

5,10-CH2-THF

TSTHF

SHMT

NADPH + H+

NADP+

serine

glycine

dTMP: dUMP:

DHFR

THF


N

N N

NN

NH2

H2N

NH

CO2H

O CO2H

R

HN

N

N

O

H3CCH3

S

O

HNCOOH

COOH

HN

N NH

O

H2N

NH

O

COOH

COOH

R: H aminopterin ( 氨基蝶呤 )

R: CH3 methotrexate ( 甲氨蝶呤 )

Antifolates

raltitrexed ( 雷替曲塞 )

Permetrexed ( 培美曲塞 )


8.4 Topoisomerase Inhibitors

N

N O

R2 R3

R1

O

OC2H5 OH

R1 R2 R3

H H H

H C2H5

OH H(H3C)2NCH2

N NO

O

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 )

camptothecin

topotecan

irinotecan

(1)Topoisomerase InhibitorsⅠ


(2) Topoisomerase II Inhibitors

Anthracyclines ( 蒽环类）

O

O

OH

OH

O

OH

O O

OHABCD

H3C

O

NH2

OH

CH3

aglycone

sugar portion

O

O

OH

OH

O

O O

OH

H3C

O

NH2

OH

CH3

O

O

OH

OH

O

O

OH

O

NH2

OH

CH3

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

adriamycin daunorubicin Idarubicin 伊达比星


Structure modification:

OH

OH O

O HN

HNNH

HN

OH

OH

Mitoxantrone( 米托蒽醌 )

OH

OH O

O HN

HNN

O

NO

Planarchromophore

N-oxides

OH

OH O

O HN

HNN

N

Planarchromophore

Tertiary amines

Prodrug targeting the CYP450

AQ4N


Pharmacophore ：Cheng propose a N-O-O triangle hypothesis

阿霉素

O

OO OH

OH

O

HOH

O

R1

ONH2

OH

O O

0.3nm

N


米托蒽醌（ Mitoxantrone ）

O

OOH HN

HNOH

HN

OH

NH

OH


O

O N

8Å

N

N

O

O

OHO

喜树碱娃儿藤素

阿霉素链黑霉素

OMe

NMeO

MeO

MeO

O

O

OH

OHOMe

OH

H O

O OH

NH2

OHMe

N

MeO

H2N

O

O

N COOH

MeH2N

OMe

OMe

OH


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 )

N

N

H

R1

C2H5

OR3

HOH

H3COCOR2

R1 R2 R3

CH3 OCH3 COCH3

CHO OCH3 COCH3

CH3 NH2 H431

NH

N

HO

H3COOC

CH3

1' 2'

4'6'

9'

vinblastine ( 长春碱 ) vincristine ( 长春新碱 ) vindesine ( 长春地辛 )


(2) Microtubule Stabilizers

Paclitaxel and Related Taxanes

O

NH

R1 O

O

H OH

H H

HO

OR2O

H

H

OH

O

O

OH

O

O

paclitaxel (taxol) R1=C6H5 R2=COCH3docetaxel (taxotere) R1=OC(CH3)3 R2=H


The SAR of taxanes

O

NH

OH

O

O

O

OHAcO O

HO O

O

H

OAc

May be esterfied,epimerized orremoved withoutsignificant loss ofactivity

Oxetane ring orsmall ring analogrequired for activity

Removal of acetate reducesactivity; some acyl analogshave improved activity

Acyloxyl group essential; certainsubstituted benzoyl groups and otheracylgoups have improved activity

Removal of1-hydroxylgruop reducesactivity slightly

Free 2'-hydroxyl group,or a hydroxylzable esterthere of required

Phenyl groupor a closeanalog required

N-Acyl grouprequired

Acetyl or acetoxyl groupmay be removed withoutsignificant loss of activity,some acyl analogs havemultidrug resistance-reversing activity

Reductionimprovesactivityslightly

1 24

7910

132'3'


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。

chapter 8 antineoplastic agents. shanghai jiao tong university 8.1 introduction the characteristics...

Documents

migration slide

sn2 reaction slide

aromatic r

alkylating agents

aromatic substituent

characteristics of cancer

cases of cancer

type of cell