Lecture 6- Antineoplastic Agents PDF

Antineoplastic agents  Abnormal growth Rapid, uncontrolled Cell death arrested growth (apoptosis). No growth stimulators N...

Antineoplastic agents  Abnormal growth Rapid, uncontrolled Cell death arrested growth (apoptosis). No growth stimulators Normal divide and proliferate Terminology Neoplasm: mean new growth Tumor: local swelling Cancer: fire cell Benign cancer: tumor that is not life threatening Malignant cancer: tumor that is life threatening Metastasis: separation of individual cancer cell from an established tumor, they enter blood supply & start up new tumor elsewhere in the body According to the type of tissue from which they arise Classification Carcinoma Sarcoma Mesodermal tissue e.g. Epithelial tissue Blastoma  Connective tissue  Muscle Blood & hemopoietic tissue  bone  Lymphoid  erythroid Causes of cancer 1. Carcinogenic chemicals in smoke 2. Viruses have been implicated in human cancer 3. Food & environment 4. Chemotherapy or radiotherapy can induce cancers Cancer treatment 1. Surgery and radiation are favored for ►►►localized cancers 2. Chemotherapy is reserved for ►►► systemic cancers. Classification of chemotherapeutics 1. Antimetabolites 2. Alkylation agents 3. Hormones  3) Antimetabolites Are false substrates that stop the de novo synthesis of DNA by inhibiting the formation of the nucleotides. 1. All are prodrug (they must be converted to nucleotide form) 2. As nucleosides, they are actively taken up into cells via a selective nucleoside transporter protein a) Dihydrofolate reductase inhibitors (DHFRI) Methotrexate  Dihydrofolic acid FH2 → tetrahydrofolic acid (FH4) by DHFR enzyme  FH4 transfer one carbon unite that help in conversion of uridine to thymidine by thymidylate synthase  Methotrexate inhibit binding of FH2 to DHFR → depletion of FH4 & thymidine NH2 N N NH2 N N CH3 H HN N N N N N O O NH2 O NH O NH O O O Folic acid Methotrexate H OH H OH OH OH b) Thymidylate synthase inhibitors: 5-Fluorouracil O F HN O N H  Inhibit thymidylate synthase (suicidal inhibition)  Thymidylate synthase convert dUMP → dTMP  This reaction require loss of proton as H+  in case of 5-fluorouracil , fluorine atom can not leave as positive ion  So the enzyme is irreversibly inhibited → no dTMP → no DNA synthesis c) DNA polymerases inhibitor They are enzymes that catalyze the synthesis of DNA Cytarabine NH2 NH2 N N NH2 O O N O N HN OH OH N metabolism O OH O N O N OH OH OH Cytarabine Deoxycytidine Uracil  It is prodrug  It is an analogue of deoxycytidine  It is competitive inhibitor of DNA polymerase  when incorporated in DNA chain termination  S.E.: metabolized by hepatic deamination to give inactive uracil derivatives d) Purine Antagonists: 6-Mercaptopurine Metabolism SH SH S-CH3 N N N N N N N N H2N N N H2N N N H H 6-Mercaptopurine thioguanine thio-dGTP It is prodrug that is converted in the body to thio-dGTP which 1. Inhibit purine synthesis 2. Incorporated into DNA & RNA ► chain termination & promotes apoptosis. Uses: orally in the treatment of leukemias II) Drugs acting directly on DNA They damage DNA either by alkylation or intercalation a) Alkylating agents They are highly electrophilic agents that react with nucleophilic groups in DNA to form 1. Interstrand cross-linking 2. Intrastrand cross linking Unfortunately  They react also with nucleophilic groups in proteins as well as in DNA which mean that they have poor selectivity  They can be mutagenic and carcinogenic, as a result of the damage they cause in DNA A) Nitrogen mustard They are related to sulfur containing mustard gases used during world first war 1. Aliphatic Nitrogen mustard Cl Mechlorethamine or Mustine H3C N The only aliphatic mustard that is used clinically Cl Bis-(2-chloro-ethyl)-methyl-amine Synthesis OH Cl OH SOCl2 H3C NH2 + 2 Cl H3C N H3C N Methyl amine 2-Chloroethanol OH Cl Mechanism Cl N N -Cl N N H3C N N N H3 C N H H3C N H N N H H N Cl Cl N Cl N N DNA H H N N N N N N H3C N H H3C N H N N H CH3 H N N N N N H H N N Intramolecular N N Intermolecular H H In step 1, intramolecular nucleophilic attack ►aziridinium ion intermediate. Step 2, the reactive aziridinium ion reacts with nucleophilic groups in DNA  N atom displace chloride ion by to form highly electrophilic aziridinium ion which can alkylate DNA  It can form intra- or intermolecular cross-linking Assay Hydrolysis with KOH yields KCl which can be determined using Volhard’s method  2. Aromatic Nitrogen mustard 1) Melphalan Phenyl alanine Cl N H2N COOH H Cl 2-Amino-3-{4-[bis-(2-chloro-ethyl)-amino]-phenyl}-propionic acid  Orally active (has good stability)  COOH gp ►↑water solubility  The L-isomer was used, because it is transported into cells by specific amino acid carrier proteins (homing device).  ↓ Side effects.  ↓ Incidence of nausea and vomiting (c.f. mechlorethamine) 2) Chlorambucil Cl Cl Metabolism HOOCH2CH2CH2C N HOOCH2C N Cl Cl 4-{4-[Bis-(2-chloro-ethyl)-amino] Phenylacetic acid mustard -phenyl}-butyric acid (active metabolite)  Phenyl ring ► ↓ reactivity ►↓Side effects ► good oral bioavailability.  COOH gp improve water solubility  Undergoes β-oxidation to give another active phenylacetic acid mustard. Synthesis 1)Nitration 2) CH3OH / H+ O 3) Reduction H3COOCC3H6 NH2 HOOC OH Cl SOCl2 Hydrolysis H3COOCC3H6 N H3COOCC3H6 N Chlorambucil OH Cl Oxazaphosphorines Their use depends on that some tumor cell may over produce phosphoramidase Cyclophosphamide Cl H O N P N O Cl  The most commonly used  Has broad application  It is a prodrug and is not toxic itself (because t is inactive)  Activation take place by cytochrome P 450 Activation of cyclophosphamide Cl Cl Cl H O H O O N P450 HO N O H2N P N P N P N O O O H Cl Cl Cl Cl O H O H2N P N OH Cl Acrolein Active form The active form react only with strong nucleophile such as guanidine? because the phosphamide group act as electron withdrawing and decrease nucleophilicity of N atom Unfortunately  The acrolein released cause kidney toxicity?  Because it react with cysteine residues in cell protein How to overcome this toxicity Toxicity can be reduced by co-administration of 2-nercaptoethane sufonate sodium that interact with acrolein and convert it to water soluble product eliminated in urine HSCH2CH2SO3 Na Mesna Synthesis Cl Cl HO Cl Cl O H O H2N N HN + Cl P O Cl P N P N Base Cl Cl O Cl Cl Cl Phosphoric trichloride SAR Cl H O 1. Bis(2-chlorothyl) is essential for activity N P N 2. Replacement of Cl with F, Br or I →↓ activity O Cl Conjugated nitrogen mustard Estramustine OH CH3 Urethane link O Cl N O Estradiol Cl Mustard moeity  The Alkylating group is linked to estradiol by urethane link  Urethane link lower nucleophilicity of N atom  Used orally for prostate cancer  2-Nitrosourea Carmustine & activation O Cl Cl Carmustine N N H N Cl O O N C Cl Cl N N Alkylating agent HO N2 + OH Carbamoylating agent  It is a chloroethylnitrosourea derivative  It is lipid soluble (can cross BBB) so used for treatment of brain tumor Decompose spontaneously in the body (with in 15 m) to 1. Alkylating agent react with proteins & inactivate DNA repair enzymes 2. Carbomylating agent Pure carmustine is solid & oily vial should be discarded (decomposed product) 3-Merthane sulfonate Busulfan H3C O S O O O O S CH3 O 1,4-Di(methanesulfonyoxy)butane  Sulfonate gp is a good leaving gp act as chlorine in nitrogen mustard  Mechanism:  It alkylate the N7 position in guanidine H3C O H3C O S O O S HO O O O S CH3 O O S O O O CH3 O HN N N HN H2N N N N H H2N N H Guanine Synthesis H3C O S OH 2 O OH + HO Busalfan Methane sulfonic acid Butane-1,4-diol Assay Busalfan is hydrolyzed in water and liberate methane sulfonic acid that can be titrated with NaOH using phenolphthalein as indicator H3C O NaOH Busalfan + H2O 2 S O OH PhPh 4- Platinum complexes Cl NH2 Pt Cl NH2  In the body Cl group is replaced with water → reactive positively charged species  Which bind strongly with region in DNA which contain several guanidine unites  It form an Intrastrand cross linking  Inhibit H-bonding between guanine & cytosine in DNA → inhibition of transcription + H2O NH2 Pt Cl NH2 NH2 Cl DNA NH2 Pt H2O DNA Pt Cl NH2 H2O ++ NH2 DAN NH2 Cl Pt H2O NH2 5- Mitomycin C O CH2OCONH2 H2N OCH3 H2C N NH O Mechanism OH CH2-NH-DNA O CH2OCONH2 1) Reduction H2N H2N OCH3 2) -CH3OH NH - DNA 3) DNA-NH2 H2C N H2C N NH OH NH2 O  Alkylating agent (Interstrand cross linking)  In the body it is activated by reduction and loss of methoxy group  Work better in anaerobic condition (as in solid tumor)  Has several side effects (one of the most toxic) B- Antisense therapy Oblimersen  Antisense drug  Consist of 18 deoxynucleotides Mechanism of action  Bind to the initiation codon of the mRNA which encode for Bal-2 (protein suppress cell death or apoptosis)  Suppressing this protein will increase probability for apoptosis especially with chemo- and radiotherapy C- Intercalating agents Amsacrine H3CO NHSO2CH3 HN N  It contain a planar heteroaromatic ring system which can slip into the double helix of the DNA and distort its structure.  As a result it can inhibit replication and transcription Natural products  Vinca alkaloids: (vincrestine & vinblastine ) & its semisynthetic derivative vindesine  Acridone alkaloids e.g. acronycine O OCH3 N O CH3 CH3 CH3