第七章抗肿瘤药

Cl HCl
Cl
N-甲基-N-（2-氯乙基）-2-氯乙胺盐酸盐
N-methyl-N-(2-chloroethyl)-2-chloroethylamine hydrochloride
Clinical application: mainly treatment for lymphosarcoma and Hodgkin's disease
Development: during the First World War, nitrogen mustard was used as a toxic gas, shortly after it was found the property of inhibiting bone marrow and lymphoid tissue of the victims. In 1942, Gilman from Yale University firstly used nitrogen mustard in the treatment of lymphoid neoplasms.
CH3
Cl
N
Cl
O
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2. Aromatic nitrogen mustards:
The introduction of aromatic ring led to reduction of alkalescence by reason of conjugation, so mechanism was changed, no formation of cyclic ethylene imine ion but the formation of carbon cation intermediate.
化物一水合物。 With a broad spectrum of anti-tumor。
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Physicochemical properties of cyclophosphamide
• White crystal or crystalline powder (失去结晶水 即液化)
• Soluable in water, unstable in aqueous solution and easily hydrolyze, easily decompose under heating condition.
Ar N
Cl -Cl Cl
Ar N
X Ar
X
N
Cl
Leabharlann Baidu
Cl
-Cl
Ar N
Y Ar
X
N
X
Y
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HO O N 苯 丁 酸 氮 芥
HOOC
Cl H NHR
Cl
N
Cl
Cl
R=H 溶 肉 瘤 素
R=CHO 氮 甲
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Cyclophosphamide
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2
1
5 6
P-[N，N-双-（β-氯乙基）]-1-氧-3-氮-2-磷杂环己烷-P-氧
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Cl S
Cl
芥子气
Cl R
N Cl
载体部分 烷基化部分
Different R：脂肪氮芥、芳香氮芥
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Alkylation process:
R N
Cl -Cl
N R
XR
X
N
Cl
Cl
Cl
乙撑亚胺离子
-Cl N
R
Y
R
X
N
X
Y
脂肪氮芥的氮原子碱性比较强，烷基化历程是双分子亲核取 代反应，活泼的乙撑亚胺离子极易与细胞成分的亲核中心起 烷化作用，属强烷化剂。
O
酶
O HN
NH2 CHO
(ClCH 2C H2)2 N P O O
(C lCH 2C H2)2 N P O O
酶
正常组织
肿瘤细胞
NH2 COOH (ClC H2C H2)2 N P O
O
NH2 (ClCH2CH2)2 N P O + CH2 CHCHO
O 磷酰氮芥
Cl HN
Cl
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Clinical application of cyclophosphamide
• 1. Alkylating agents • 2. Antimetabolites • 3. Drugs intefering with synthesis of
protein of tumor cells
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13.1 Biological alkylating agents
• 1.Nitrogen mustards • 2.Ethylene imines • 3.Sulfonates and halogenated polyols • 4.Nitrosourea
• However, bioalkylating drugs also inhibit the normal cells with the property of rapid proliferation such as bone marrow cells, intestinal epithelial cells at same time. So the bioalkylating agents have more serious side effects, such as nausea, vomiting, bone marrow suppression and hair loss. Clinical usually are carrying on combined use with other drugs.
Therapy：
Surgical operation Radiation therapy Chemical treatment
Antineoplastic agents aim at anti-malignant tumor, also known as anti-
cancer drugs.
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Classification by mechanism
NPO
CH3COCH3ClCH2CH2
O
．H2O
以二乙醇胺作为原料，用过量的三氯氧磷同时进行氯代和磷酰化， 制得氮芥磷酰二氯，再与3-氨基丙醇缩合。
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美法仑 Melphalan
CH2CH2Cl N
CH2CH2Cl
CH2 CH COOH * NH2
氮芥类的烷化剂，结构包括氮芥和L-苯丙氨酸部分， 氮芥部分在碱性水溶液中易水解，含有α－氨基酸 结构，会发生茚三酮显色反应，且有氨基酸两性性 质。
Chapter 13
Antineoplastic Agents
Malignant tumor is a serious threat to human health and the frequently-occurring diseases, the human death caused by malignant tumors is the second place among the death of all disease.
Cyclophosphamide has a broad spectrum of anti-tumor, clinical for treatment of malignant lymphoma, acute lymphocytic leukemia, multiple myeloma, lung cancer etc.
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Nitromin: Reduced the possibility of formation of ethylene imine for the reduced electronic cloud on nitrogen. Nitromin is less toxicity, but also the reduced anti-tumor activity.
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Synthesis of cyclophosphamide
NH2CH2
HOCH2CH2 NH POCl3 C5H5NClCH2CH2 N
Cl P
O
CH2 HOCH2
HOCH2CH2
ClCH2CH2Cl ClCH2CH2 Cl
ClCH2CH2
HN
NPO
ClCH2CH2
O
H2O ClCH2CH2
HN
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13.1.2 Ethylene imines
• 氮芥类药物是通过在体内转变成乙撑亚胺中间 体发挥烷化剂作用，乙撑亚胺的磷酰胺衍生物， 可提高抗肿瘤作用及减小毒性。
• Tepa was clinical used for treatment of leukaemi。
• Thiotepa changed into tepa in vivo. Clinical for the treatment of breast cancer, ovarian cancer, bladder cancer, and so on.
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Stability：
C H 3N
C l
H 2O pH >7
C H 3N
C l
O H O H
It is usually used as injection drug of aqueous solution, which pH value maintained at 3.0 ~ 5.0.
Chlormethine hydrochloride presented strong destruction to tumor cells, but with poor selectivity and large toxicity. Only Effective for lymphoma, so structural modification is necessary.
• Cyclophosphamide is a prodrug.在肝脏被活化， 经非酶促的β-消除反应生成丙烯醛（膀胱毒性）、 磷酰氮芥及去甲氮芥，三者都是较强的烷化剂。
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HN
(C lCH2CH 2)2 N P O
O
肝脏
OH
HN
(ClCH2CH2)2 N P O
4-羟 基 环 磷 酰 胺
正常组织
3
Biological alkylating agents
• Bioalkylating agents are cytotoxic drugs. In vivo, it is able to form a positive charged carbon-ion or other active electrophilic groups, and then the electrophilic ions combine covalently with electron rich groups (such as amino, sulfhydryl, hydroxyl, carboxyl, phosphate, etc.) of the cells of biological macromolecules (DNA, RNA, enzymes), lead to the breaking of DNA molecule, at last result in the death of tumor.
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13.1.1 Nitrogen mustards General formula of nitrogen mustards
R N CH2CH2Cl CH2CH2Cl
载体部分
烷基化部分
（1）Fraction of alkylation is anti-tumor function group, existing as bis-
Tepa Thiotepa
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13.1.3 Sulfonates and halogenated polyols
Sulfonates and halogenated polyols are non-nitrogen mustard alkylating agents。甲磺酸酯是较好的离去基团，生成碳正离 子与生物大分子发生亲核取代反应进行烷基化。Busulfan,also known as Myleran, named as:4-Butanediol dimethyl sulfonate。 Clinical for the treatment of chronic myeloid leukemia. 多元醇类药物主要是卤代多元醇，进入体内后会形成双环氧化 物而产生烷化作用。二溴甘露醇(Dibromomannitol)、二溴卫矛 醇(Dibromodulcilol)等。
β-chloro-ethylamine. （2）Fraction of carrier：可以改善药物药代动力学性质，选用不同 载体，可提高选择性和抗肿瘤活性。依据载体化学结构，可分为脂 肪氮芥、芳香氮芥、氨基酸氮芥、杂环氮芥和甾体氮芥。
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Mechlorethamine hydrochloride
CH3 N