Fundamental techniques available to treat cancer: Surgery Cancer Therapy The specific approach used to treat cancer depends upon the specific type, location, and stage of the cancer Fundamental techniques available to treat cancer: Surgery Radiation therapy Immunologic treatment Chemical based approaches Generally, each has its own merits, and a combination of these methods is used

Surgery: The cancer must still be in the primary tumor stage A high degree of confidence that the entire tumor can be excised Removing the tumor without causing significant damage to vital organs Radiation therapy: is used to shrink or destroy tumors This approach requires that the tumor be localized X-ray radiation is used by focusing an X-ray beam on the tumor Immunologic Therapy: Utilize the immune system to eradicate the cancer This methodology attempts to boost the level of T-cell and B-cell The major role of T-cell is to destroy foreign cells, including malignant cells B-cell is produced in the bone marrow and lymph nodes, make antibodies in response to a foreign protein

Section 2 Cancer Chemotherapy 一 Alkylating Agents （烷基化试剂） 1 Nitrogen mustards （氮芥） mechlorethamine Mechanism of Action 氮丙啶鎓

Alkylation of guanine in DNA by an alkylating agent 鸟嘌呤 Once alkylation occurs, the alkylated sites become prone to cleavage

3. Cyclophosphamide （环磷酰胺） 2. Melphalan （美法伦） L- L-Phenylalanine mustard or L-PAM L-PAM can be preferentially transported into cells, with the assistance of L-amino acid active transporter 3. Cyclophosphamide （环磷酰胺） Reduced nucleophilicity because of the amide-like phosphoramide linkage Less likely to form an aziridinium ion Chemically more stable Requires metabolic activation (pro-drug)

Cyclophosphamide （环磷酰胺） ？ Non enzymatic 丙烯醛 Metabolic activation of cyclophosphamide

Synthesis of Cyclophosphamide （环磷酰胺的合成） 3-氨基丙醇 氮芥磷酰二氯 Acidic hydrolysis of cyclophosphamide pH 4.0-6.0 （环磷酰胺的酸性水解）

Other Alkylating Agents --- Aziridine Derivatives 氮丙啶衍生物， 乙撑亚胺类 Less reactive agents 三乙蜜胺 塞替哌 替哌 前药 P450作用下转化为替哌 乳腺癌 提高抗肿瘤作用 减少毒副作用 白血病 最早用于临床 Aziridine is a three-membered nitrogen heterocycle that reacts with nucleophiles in order to relieve ring stain 氮丙啶为三元杂环，和亲核试剂或基团反应开环，可释放环的张力

安徽阜阳大头娃

Thiotepa（塞替哌）and its metabolic product TEPA（替哌） pKa=6.0 塞替哌

Other Alkylating Agents--- Quinone as transporter 癌抑散 三亚胺醌 卡波醌 Quinone part can reduce the electron density, decreased toxicity 醌部分可降低电子云密度，降低药物的毒性 Quinone part can interfere enzymatic Re-Ox, inhibit tumor cell division 醌类化合物干扰酶系统氧化-还原过程，抑制肿瘤细胞的有丝分裂

Metabolic activation of quinone aziridine 还原 氢醌 单氢醌 Activation of the aziridine part

Other Alkylating Agents-Mitomycin C（丝裂霉素 C） Quinone moiety, the aziridine ring, the carbamate Poor oral absorption, administered IV Treat pancreatic cancer, 胰腺癌 antibiotic Bio-reductive activation of mytomycin C and DNA alkylation

Stability of Mitomycin C

（三） Methyl sulfonate （甲磺酸酯类） Busulfan， 白消安，马利兰 CH3SO3 is a very good leaving group （甲磺酸基是很好的离去基团） 对白血病疗效显著

（四）Nitrosoureas （亚硝基脲类） 广谱抗肿瘤活性，可通过BBB Carmustine，卡莫司汀 Mechanism of Action Reactive species Reactive species Reactive species Reactive species Textbook, page 544, 图21-1 Formation of a vinyl cation from carmustine

Synthesis of Nirosoureas （亚硝基脲类） Carmustine

Other Nitrosourea analogs 洛莫司汀 司莫司汀 尼莫司汀

（五）三氮烯咪唑类衍生物 Dacarbazine （DTIC）达卡巴嗪 5-（3，3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide 5-Amino-4-carboxamide Proposed metabolism and mechanism of action of dacarbazine DTIC 主要用于治疗黑色素病、霍杰金氏病

鸟嘌呤被DTIC（diazomethane）烷基化 鸟嘌呤烷基化

六：肼类， Procarbazine （丙卡巴肼） 偶氮 Prodrug 甲基肼 Metabolic activation of procarbazine

二、Cisplatin （顺铂） Mechanism of Action of Cisplatin 与鸟嘌呤碱基N7配位形成五元环，扰乱DNA的正常双螺旋，使局部变性失活 DNA的复制停止 Note: only the cis-isomer is active

三、Bleomycin, Dactinomycin D, Homoharringtonine 博来霉素、放线菌素D和高三尖杉酯碱 Bleomycins: antitumor antibiotic，糖肽类 discovered in 1966 Isolated from Streptomyces verticillus 放线菌 嘧啶 二噻唑 咪唑 主要用于治疗皮肤癌 糖 The two sugar ring: possible cell recognition and uptake site The imidazole, amide and the amine: Iron 2+ (Fe2+) chelating site The thiazole rings（二噻唑环）: DNA binding sites

2、 Dactinomycin D,放线菌素D Isolated from Streptomyces parvullus This ring system is aromatic, planar, can intercalate or insert into DNA between base pair steps

Homoharringtonine, 高三尖杉酯碱 Alkaloid, 生物碱 Isolated from homoharringtonine plant， 三尖杉植物 Inhibit protein synthesis; DNA synthesis 中国协和医科院，黄量院士，国家科技进步一等奖

四、Antitumor reagents– Topoisomerase as targets 作用于DNA拓扑异构酶的药物 Topoisomerases catalyze and guide the unknotting of DNA by creating transient breaks in the DNA using a conserved Tyrosine as the catalytic residue Top I and Top II : different function

（一）Camptothecin（喜树碱）, Hydroxy camptothecin （羟基喜树碱） Topisomerase I inhibitors Camptothecin is a natural product Addition of the hydroxyl and dimethylaminomethyl groups improved water solubility and reduced the occurrence of unpredictable side effects Mechanism of Action: cause single strand breaks in DNA

（二）Anthracyclines （阿霉素类属蒽醌类） Topoisomerase II inhibitors A tetracyclic quinone containing ring nucleus to which is attached a unique daunosamine sugar Reddish in color First isolated from the fermentation broths of Streptomyces peucetius Mechanism of Action: 1) The flat topography of the anthroquinone nucleus results in the ability of the anthracyclines to intercalate with DNA perpendicular to its long axis. 2) The anthroquinone ring system are capable of generating reactive oxygen species, the free radicals may produce destructive effects upon the cell which may include damage to the DNA The amino sugar confers added stability to this binding through its interaction with the sugar phosphate backbone of DNA

Other Anthracyclines Analogs 阿霉素 柔毛霉素 表柔比星，表阿霉素

Section III Antimetabolite antitumor agents 第三节 干扰ＤＮＡ合成的药物 第三节 干扰ＤＮＡ合成的药物 Antimetabolites are compounds that prevent the biosynthesis of normal cellular metabolites. Usually, this suggests a close chemical similarity between the natural metabolite and the antimetabolite. Narrow Antitumor Spectrum, normally effective for leukemia（白血病） 一、　Pyrimidine Antimetabolites （嘧啶拮抗物） 5-Fluorouracil, 5-FU. A pyrimidine with ring modifications Some tumors preferentially use uracil for pyrimidine biosynthesis

胸腺嘧啶脱氧核甙酸 Key intermediates in the synthesis of deoxythymidylic acid from deoxyuridylic acid

胸腺嘧啶脱氧核甙酸合成酶 5-FdUMP binds to thymidylate synthetase to give an intermediate that resembles the intermediate formed with uridylic acid, however, this intermediate cannot break down and the enzyme is inhibited

Metabolism of 5-fluorouracil

Synthesis of 5-FU

Stability in NaHSO3 base Ring open product

（二） Cytarabine （ARA-C,阿糖胞苷） 胞嘧啶衍生物 Pyrimidine antimetabolite in which sugar is modified 胞嘧啶 阿拉伯糖 主要用于治疗急性粒细胞白血病 The normal 2’ configuration is α

Metabolic activation and inactivation of ARA-C 阿糖胞苷在体内的代谢激活与失活 Inactive species

Mechanism of Action for ARA-C ARA-CTP inhibits the conversion of cytidylic acid to 2’-deoxycytidylic acid ARA-CTP 抑制磷酸胞苷转换为脱氧磷酸胞苷 ARA-CTP also inhibits DNA-dependent DNA polymerase 抑制依赖DNA的DNA多聚酶 ARA-C causes miscoding after being incorporated into DNA 掺入DNA后编码错误，DNA合成终止

Synthesis of Cytarabine 氰胺 D-阿拉伯糖 氯代丙烯氰 cyclocytidine 2-氨基-D-阿糖噁唑啉

二、 Purine Antimetabolites （嘌呤拮抗剂） 巯嘌呤 Na2SO3/H2O Poor water solubility 主要用于各种急性白血病的治疗 Na+

Mechanism of Action of 6-mercaptopurine 6-MPMP inhibits several key enzymes involved in the biosynthesis of purine The overall action of 6-MP is inhibition of the de novo synthesis of purines

Synthesis of Mercaptopurine 硫脲

三、 Folic acid antimetabolites （叶酸拮抗剂） Pterine， Pteridoxamine，碟呤 Folic acid is an essential component for the biosynthesis of DNA and RNA 叶酸是核酸生物合成的关键组分 An important factor for red cell development 是红细胞发育生长的重要因子

Folic acid antimetabolites （叶酸拮抗剂） 氨基碟呤，白血宁 甲氨碟呤， MTX MTX competes with the normal substrate folic acid, inhibits DNA synthesis

Other Anticancer Drugs 1. Taxol, or Paclitaxel （紫杉烷） Antimicrotuble Agent Taxol promotes the assembly of microtubules from tubulin dimers Formula：C47H51NO14。MW：853.92， 1971年 Pacific Yew，1967 红豆杉 Ovarian, breast, lung and colon cancer

Mansukh C. Wani Monroe E. Wall Taxol ® CamptothecinTM RTI， NC 2008， Kettering Prize--the highest honor in the field of cancer research 1992年美国政府将专利转让给施贵宝（BMS），紫杉醇面世。 1994年紫杉醇创世界抗癌药物全球销量冠军。 2000年紫杉醇销量创百亿（后受原料供应未有进一步上升） 2004年施贵宝专利到期，全球更多药厂介入紫杉醇生产。 2005年中央再次发文，全国普查红豆杉资源，鼓励种植。 2005年此项目接受个人投资者投资。

2. Anti apoptotic protein inhibitors—ABT737 Abott Lab Target: anti-apoptotic Bcl-2 protein family member Binding to the protein BH3 domain

Anti apoptotic protein inhibitors—Gossypol

Summary 小结 Target DNA directly （直接作用于DNA） Alkylating Agents （烷基化试剂） Cisplatin （顺铂） 三 Bleomycin, Dactinomycin D, Homoharringtonine 博来霉素、放线菌素D和高三尖杉酯碱 四 Antitumor reagents– Topoisomerase as targets 作用于DNA拓扑异构酶的药物

Antimetabolite Antitumor Agents 干扰ＤＮＡ合成的药物 一、 Pyrimidine Antimetabolites （嘧啶拮抗物） 二、 Purine Antimetabolites （嘌呤拮抗剂） 三、 Folic acid antimetabolites （叶酸拮抗剂） Antiapoptotic Agents （抗细胞凋亡抑制剂） Target the Bcl2 family protein, P53 et al

Typical Structures （典型的结构） 丝裂霉素 亚硝基脲类，卡莫司汀 肼类， 丙卡巴肼 三氮稀咪唑，达卡巴嗪

Typical Structures （典型的结构）II Cisplatin 博来霉素 顺铂 Homoharringtonine, 高三尖杉酯碱 Dactinomycin D,放线菌素D

Typical Structures （典型的结构）III 阿霉素 Anthracyclines 喜树碱 Topisomerase II inhibitor Topisomerase I inhibitor

Typical Structures IV 巯嘌呤 阿糖胞苷 氟尿嘧啶 MTX， 甲氨蝶呤