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Chapter 8 Antineoplastic Agents Shanghai Jiao Tong University 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. Shanghai Jiao Tong University Cancer invasion and migration Shanghai Jiao Tong University 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. Shanghai Jiao Tong University 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) Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 【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. Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 【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. Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University (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) Shanghai Jiao Tong University 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. Shanghai Jiao Tong University (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 Shanghai Jiao Tong University 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. Shanghai Jiao Tong University (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 Shanghai Jiao Tong University 【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) Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University (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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 【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). Shanghai Jiao Tong University 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 Shanghai Jiao Tong University (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 Shanghai Jiao Tong University 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) Shanghai Jiao Tong University 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 Shanghai Jiao Tong University (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 O O OH A 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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 Shanghai Jiao Tong University OH O HN OH O HN H N N H 米托蒽醌 (Mitoxantrone) OH OH Shanghai Jiao Tong University 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 Shanghai Jiao Tong University 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) Shanghai Jiao Tong University (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 Shanghai Jiao Tong University 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 AcO O 10 NH Free 2'-hydroxyl group, or a hydroxylzable ester there of required OH 9 7 O 1 13 2' Phenyl group or a close analog required O OH 4 2 O H O 3' 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 Shanghai Jiao Tong University 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。