Anticancer agents-Medicinal chemistry

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Anticancer Agents :

Anticancer Agents Prepared by Mr. Dharmendrasinh A Baria Assistant professor Department of Pharmaceutical Chemistry Smt. S. M. Shah Pharmacy college, Amsaran 1


Cancer* is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues . Cancer cells can spread to other parts of the body through the blood and lymph systems, this process is called metastasis . Characteristics of Cancer Cells: Cancer involves the development and reproduction of abnormal cells Cancer cells are usually nonfunctional Cancer cell growth is not subject to normal body control mechanisms Cancer cells eventually metastasize to other organs via the circulatory and lymphatic systems. (*National Cancer Institute, NCI) 2 By: Dharmendrasinh Baria


Types of Tumors : Benign : non cancerous and not an immediate threat to life, even though treatment eventually may be required for health. Malignant : tending to worsen and cause death, invasive and metastasis 3 By: Dharmendrasinh Baria


Categorized based on the functions/locations of the cells from which they originate: Carcinoma - skin or in tissues that line or cover internal organs . E.g., Epithelial cells. 80-90% reported cancer cases are carcinomas. Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia - White blood cells and their precursor cells such as the bone marrow cells, causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma - cells of the immune system that affects lymphatic system. Myeloma - B-cells that produce antibodies- spreads through lymphatic system. Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord. 4 By: Dharmendrasinh Baria


Antineoplastic agents are drugs used for the treatment of cancer. The fraction of tumor cells that are in the replicative cycle (“Growth factor”), influence their susceptibility to most cancer chemotherapeutic agent. Rapidly dividing cells are generally more sensitive to anticancer drugs , whereas non proliferating cells [those in G0 phase] usually survive the toxic effect of these drugs. Normal cells and tumor cells go through growth cycle. However , normal and neoplastic tissue may differ only in the number of cells that are in the various stages in the cycle. Chemotherapeutic agents that are effective only in replicating cells. 5 By: Dharmendrasinh Baria


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Based on site of action Chemical classification 1. Based on site of action Phase specific agents: These drugs acts at particular phase of cell cycle and more effective in proliferating cells. G1 – Vincristine S–Methotrexate, Cytarabine , 6-TG, 6-MP, 5-FU, Daunorubicin , Doxorubicin G2 – Daunorubicin , Bleomycin M – Vincristine, Vinblastne , Paclitaxel etc. 8 By: Dharmendrasinh Baria


Phase non specific agents: Nitrogen Mustards, Cyclphosphamide, Chlorambucil, Carmustine, Dacarbazine, Busulfan, L-Asparginase, Cisplatin, Procarbazine and Actinomycin D etc. These drugs are specifically effective against proliferating cells but they are not phase specific: e.g. Fluorouracil, cyclophosphamide, Dactinomycin. 9 By: Dharmendrasinh Baria

2. Chemical classification:

2. Chemical classification Alkylating Agents 1. Nitrogen mustards – Mechlorethamine ( Mustine HCL), Cyclophosphamide, Ifosfamide , Melphalan , Chlorambucil Chroambucil Melphalan Cyclophosphamide Ifosfamide Mechlorethamine 10 By: Dharmendrasinh Baria


Ethylenimine - Thio -TEPA, hexamethylmelamine ( Altretamine ) 3. Alkyl sulfonate – Busulfan 4. Nitrosoureas – Carmustine , Lomustine , Streptozocin Triethylene melamine Thiotepa Busulphan Carmustine Streptozocin Lomustine 11 By: Dharmendrasinh Baria


5. Triazines - Procarbazine , Dacarbazine , Temozolomide b. Platinum coordination complexes – Cisplatin , Carboplatin,Oxaliplatin Procarbazine Dacarbazine Temozolomide 12 By: Dharmendrasinh Baria


c. Antimetabolites – Pyrimidine analogs – 5-Fluorouracil , Cytarabine (cytosine arabinoside), Capecitabine, Gemcitabine 13 By: Dharmendrasinh Baria


Purine analogs – 6-Mercaptopurine, 6-Thioguanine, Azathioprine, Fludarabine, Cladribine, Pentostatin 14 By: Dharmendrasinh Baria


Folic acid analogues – Methotrexate, Pemetrexed 15 By: Dharmendrasinh Baria


d. Anticancer Antibiotics – Actinomycin -D ( Dactinomycin ) , Bleomycin, mitomycin -C, anthracyclines (e.g. Doxorubicin , Daunorubicin , Idarubicin , epirubicin , Valrubicin ), Streptozocin 16 By: Dharmendrasinh Baria


e. Plant products- vincristine, vinblastine, podophyllotoxin , etoposide, camptothecin , paclitaxal 17 By: Dharmendrasinh Baria


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f. Protein kinase inhibitors- g. Miscellaneous –L- Asparaginase , Arsenic trioxide Hydroxyurea Tretinoin 19 By: Dharmendrasinh Baria


h. Hormonal drugs – 1. Glucocorticoids – Prednisolone and others Prednisolone 2. Estrogens – Fosfestrol , Ethinylestradiol Fosfestrol Ethinylestradiol 20 By: Dharmendrasinh Baria


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9. Progestins – Hydroxyprogesterone acetate, etc 10. GnRH antagonists – Cetorelix, Ganirelix, Abarelix 24 By: Dharmendrasinh Baria


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The alkylating agents are a class of drugs that are capable of forming covalent bonds with important biomolecules. The major targets of drug action are nucleophilic groups present on DNA (especially the 7-position of guanine) ; however, proteins and RNA among others may also be alkylated. There are several potential nucleophilic sites on DNA, which are susceptible to electrophilic attack by an alkylating agent (N-2, N-3, and N-7 of guanine, N-1, N-3, and N-7 of adenine, 0–6 of thymine, N-3 of cytosine). Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the template function of DNA. The most important of these for many alkylating agents is the N-7 position of guanine whose nucleophilicity may be enhanced by adjacent guanine residues. 26 By: Dharmendrasinh Baria


Additionally, alkylation has been proposed to result in altered base pairing away from the normal G-C: A-T hydrogen bonds because of alterations in tautomerization. The alkylation also leads to increased acidity of the N-1 nitrogen reducing the pK from 9 to 7 to 8 giving rise to a zwitter ionic form that may also mispair. For those agents that possess two reactive functionalities, both inter strand and intra strand cross-linking becomes possible. When inter strand links occur, separation of the two strands during replication is prevented and therefore replication is blocked. A T C G C G G A T G C 27 By: Dharmendrasinh Baria


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1. Nitrogen mustard:

1. Nitrogen mustard Developed from mustard war gases of Word War I which were highly reactive vesicants. First chemicals used for cancer Rx. Not cell cycle specific, but still more active in dividing tissues. "Radiomimetic" -- action on DNA resembles radiation. The nucleophile may be- SH of protein -N of protein, DNA base =O of DNA base 29 By: Dharmendrasinh Baria


At physiological PH, aliphatic mustard hydrochlorie converted into aziridium ion that reacts with nucleophile. These agents acts by alkylating the N7 of guanine in DNA which leads to 30 By: Dharmendrasinh Baria


Mechlorethamine : 2,2 dichloro -N-methyl diethylamine hydrochloride Given by i.v administration of freshly prepared solution because gradual degradation of the aziridium ion by interaction with water. Uses: H odkin’s disease Lymphomas Thrombocytopenia Leucopenia Important candidate of well known MOPP regimen. M- Mechlorethamine , O- Oncovin , P- Procarbazine , P- Prednisone 31 By: Dharmendrasinh Baria


b) Chlorambucil : p- (di (2-chloroethyl) amino) phenyl butyric acid Quite stable compound to aziridium ion so it can be given orally. Uses: Especially in Chronic lumphocytic leukemia Primary macroglobulinemia Lymphosarcoma Hodkin’s disease c) Melphalan : 4- [Bis(2-chloroethyl)amino]-L- phenylalanine Uses: Multiple myeloma Breast cáncer Ovarian cancer 32 By: Dharmendrasinh Baria


d) Cyclophosphamide- ( RS )- N , N - bis (2-chloroethyl )- 1,3,2-oxazaphosphinan- 2-amine-2-oxide In these case, aziridinium cation formation is not possible until the electron-withdrawing function has been altered. In the case of cyclophosphamide, it was initially believed that the drug could be selectively activated in cancer cells because they were believed to contain high levels of phosphoramidase enzymes. Drug was activated by cytochrome P450 (CYP) isozymes CYP2B6 and CYP3A4/5 to give a carbinolamine that could undergo ring opening to give the aldehyde. The ionized phosphoramide is now electron-releasing via induction and allows aziridinium cation formation to proceed. Acrolein is also formed as a result of this process, which may itself act as an electrophile that has been associated with bladder toxicity. 33 By: Dharmendrasinh Baria


To decrease the incidence of kidney and bladder toxicity, the sulfhydryl (-SH) containing agent mesna may be administered and functions to react with the electrophilic species that may be present in the kidney. The sulfonic acid functionality serves to help concentrate the material in the urine, and the nucleophilic sulfhydryl group may react with the carbinolamine, aziridinium cation, the chloro substituents of cyclophosphamide, or via conjugate addition with acrolein. This inactivation and detoxification may also be accomplished by other thiol- containing proteins such as glutathione. Increased levels of these proteins may occur as cancer cells become resistant to these alkylating agents. Uses - Multiple myeloma Chronic lymhatic leukemia Acute leukemia Acute lymphoblastic leukemia 34 By: Dharmendrasinh Baria


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e ) Mitomycin -C Antibiotic obtained from the cultures of s. cespitosus . 36 By: Dharmendrasinh Baria


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Alkylation step results from opening of the aziridium ring and also vinylogous carbinolamine Causes cross linking in double helical DNA. The 2-amino group of guanine residues are alkylated. Uses: Breast cancer Gastric cancer Pancreatic cancer 38 By: Dharmendrasinh Baria


2. Ethylenimine - Thio-TEPA, hexamethylmelamine (Altretamine) Thiotepa - 1,1',1''-phosphorothioyltriaziridine 39 By: Dharmendrasinh Baria


Uses: Breast cancer Ovarian cancer Bronchogenic cancer 40 By: Dharmendrasinh Baria

3. Alkyl sulfonates:

3. Alkyl sulfonates Busulfan- butane-1,4-diyl dimethanesulfonate Busulfan utilizes two sulfonate functionalities as leaving groups separated by a four-carbon chain that reacts with DNA to primarily form in- trastrand cross-link at 5’-GA-3’sequences. Uses: Chronic granulocytic leukemia Bone marrow transplant 41 By: Dharmendrasinh Baria


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4. Nitrosoureas (N-alkyl-N-Nitrosourea):

4. Nitrosoureas (N-alkyl-N- Nitrosourea ) Unstable in aqueous solution. They produce isocyanate and a diazohydroxide upon decomposition. 43 By: Dharmendrasinh Baria


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Carmustine - 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) Uses: Higher lipophilicity , so higher penetration in BBB. It can be used in cerebral tumors . Hodkin’s disease Lymphoma Lomustine - N -(2-chloroethyl)- N' - cyclohexyl - N - nitrosourea (CCNU) Uses: Primary and metastatic brain tumors . Secondary therapy in Hodkin’s disease. 45 By: Dharmendrasinh Baria


5. Triazines : Procarbazine - N -Isopropyl-4-[(2-methylhydrazino ) methyl] benzamide Procarbazine is an antineoplastic agent that was originally developed as a result of efforts to find new inhibitors of monoamine oxidase. Subsequent screening revealed antineoplastic activity. Uses: Hodkin’s disease b) Dacarbazine - 5-( 3,3-Dimethyl-1-triazenyl)imidazole-4-carboxamide It was initially thought to act as an inhibitor of purine biosynthesis, but latter was shown to be an alkylating agent. Activation of the agent occurs through the action of CYP (isozymes 1A1, 1A2, and 2E1) to give the demethylated product monomethyl triazenoimidazole carboxamide . 46 By: Dharmendrasinh Baria


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Cisplatin, Carboplatin, Oxaliplatin Platinum (II) is considered to be a “soft” electrophile and as a result, its complexes are subject to attack by “soft” nucleophiles such as thiol groups found on proteins. This can result in significant protein binding (88%–95%) and inactivation caused by the presence of thiols in albumin, glutathione, and other proteins. Cisplatin administration is also associated with significant nephrotoxicity and neurotoxicity that is dose limiting. 49 By: Dharmendrasinh Baria


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Antimetabolites are compounds closely related in structure to a cellular precursor molecule, yet these imposter substances are capable of preventing the proper use or formation of the normal cellular product. These antimetabolites are similar enough in structure in many cases to interact with the normal cellular process but differ in a manner sufficient to alter the outcome of that pathway. Most antimetabolites are effective cancer chemotherapeutic agents via interaction with the biosynthesis of nucleic acids. Therefore, several of the useful drugs used in antimetabolite therapy are purines, pyrimidines, folates, and related compounds. The antimetabolite drugs may exert their effects by several individual mechanisms involving enzyme inhibition at active, allosteric, or related sites. 51 By: Dharmendrasinh Baria


Most of these targeted enzymes and processes are involved in the regulatory steps of cell division and cell/tissue growth. Often the administered drug is actually a prodrug form of an antimetabolite and requires activation in vivo to yield the active inhibitor. The administration of many purine and pyrimidine antimetabolites requires the formation of the nucleoside and finally the corresponding nucleotide for antimetabolite activity. An antimetabolite and its transformation products may inhibit several different enzymes involved in tissue growth. These substances are generally cell cycle specific with activity in the S phase. The purine and pyrimidine antimetabolites are often compounds incorporated into nucleic acids and the nucleic acid polymers (DNA, RNA, etc.). 52 By: Dharmendrasinh Baria


The antifolates are compounds designed to interact at cofactor sites for enzymes involved in the biosynthesis of nucleic acid bases. The biosynthesis of these nucleic acid bases depend heavily on the availability of folate cofactors, hence antimetabolites of the folates find utility as antineoplastic agents. 53 By: Dharmendrasinh Baria


Purine analogues: The design of antimetabolites based on purine structure began with isosteric thiol/sulfhydryl group to replace the 6-hydroxyl group of hypoxanthine and guanine. One of the early drug was 6-mercaptopurine (6-MP), the thiol analog of hypoxanthine. This purine requires bio activation to its ribonucleotide, 6-thioinosinate (6-MPMP), by the enzyme HGPRT. The resulting nucleotide is a potent inhibitor of an early step in basic purine biosynthesis, the conversion of 5-phosphoribosylpyrophosphate into 5-phosphoribosylamine. The ribose diphosphate and triphosphates of 6-mercaptopurine are active enzyme inhibitors, and the triphosphate can be incorporated into DNA and RNA to inhibit chain elongation. However, the major antineoplastic action of 6-MP appears to be related to the inhibition of purine biosynthesis. 54 By: Dharmendrasinh Baria


It also inhibits the conversion of Inosinic acid to adenylic acid 55 By: Dharmendrasinh Baria


Uses: Acute leukemia Metabolic degradation of 6-MP by guanase gives 6-thioxanthine. 56 By: Dharmendrasinh Baria


Allopurinol Thiouric acid Allopurinol: It is an adjuvant to chemotherapy because it prevents uric acid formation. Kidney toxicity caused be the release of purines from destroyed cancer cells. Azathioprine Azathioprine: Heterocyclic derivative of 6-MP, azathioprine designed to protect it from catabolic degradation. Not significant better antitumor activity than 6-MP. Used as an immunosuppressanant . 57 By: Dharmendrasinh Baria


6-Thioguanine (6-TG): Thioguanine is also incorporated into RNA & its α -deoxy metabolite is incorporated in to DNA. Uses: Acute leukemia ADR: Delayed bone marrow depression, Thrombocytopenia 58 By: Dharmendrasinh Baria


Vidarabine : Adenine arabinoside . Obtained from the cultures of s. antibioticus . Epimeric with D-ribose at 2’ position. Competitive inhibitor of DNA polymerase enzyme Also having antiviral acticity . Limited use due to susceptibility to enzyme adenosine deaminase (responsible for resistance) R 1 =R 2 =H Vidarabine R 1 =F, R 2 = HOPO 2 Fludarabine Pentostatin Inhibition of the enzyme adenosine deaminase yielding increased cellular levels of deoxyadenosine and deoxyadenosine triphosphate (dATP) 59 By: Dharmendrasinh Baria


2-Chloro-2’-deoxyadenosine (cladarabine): Resistant to deaminase. Used to treat hairy cell leukemia. 60 By: Dharmendrasinh Baria


2. Pyrimidine analogues: 5-fluorouracil (5-FU) The pyrimidine derivative 5-fluorouracil ( 5-FU) was designed to block the conversion of uridine to thymidine. The normal biosynthesis of thymidine involves methylation of the 5-position of the pyrimidine ring of uridine . The replacement of the hydrogen at the 5-position of uracil with a fluorine results in an antimetabolite drug, leading to the formation of a stable covalent ternary complex composed of 5-FU, thymidylate synthase (TS), and cofactor ( a tetrahydrofolate species ). Anticancer drugs targeting this enzyme should selectively inhibit the formation of DNA because thymidine is not a normal component of RNA .. 61 By: Dharmendrasinh Baria


TS is responsible for the reductive methylation of de- oxyuridine monophosphate ( dUMP ) by 5,10-methylenetetrahydrofolate to yield dTMP and dihydrofolate 62 By: Dharmendrasinh Baria


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Uses: Management of carcinoma of - breast - Colon - Pancreas - Rectum - Keratoses Adverse effects: - GIT- Hemorrhage - Stomatitis - Esophagopharyngitis - Leukopenia - Diarrhoea 64 By: Dharmendrasinh Baria


Tetrahydrofluoro derivative of 5-FU ( Tegafur ): Slowly get metabolised to 5-FU. Active in clinical cancer. Less myelosupressive than 5-FU. Gemcitabine: Gemcitabine is the result of fluorination of the 2’-position of the sugar moiety. Gemcitabine is the 2’,2’-difluoro deoxycytidine species and after its anabolism to diphosphate and triphosphate metabolites, it inhibits ribonucleotide reductase and competes with 2’-deoxycytidine triphosphate for incorporation into DNA. Uses: Used with cisplatin for locally advanced metastatic adeno carcinoma of the pancreas. ADR: Myelosupression , Teratogenicity, renal toxicity. 65 By: Dharmendrasinh Baria


Cytarabine : Cytosine arabinoside ( ara -C or cytarabine ) is simply the arabinose sugar instead of ribose, and the only difference in structure is the epimeric hydroxyl group at the 2-position of the pentose sugar. This epimeric sugar is similar enough to the natural ribose to allow A ra-C to be incorporated into DNA, and its mechanism of action may include a slowing of the DNA chain elongation reaction via DNA polymerase or cellular inefficiencies in DNA processing or repair after incorporation . 66 By: Dharmendrasinh Baria


Deaminases causes resistance. New analogues of cytarabine is cyclocytidine ( ancitabine ) Resistant to deamination by deaminases laeds to better therapeutic index. Uses: Acute granulocytic leukemia 67 By: Dharmendrasinh Baria


Deaminase inhibitors: Pentostatin : Purine analogue - 7 membered ring structure 2’ deoxyformycin 2) EHNA: - Adenine moiety is modified in the ribose moiety. - Rationally designed inhibitors 68 By: Dharmendrasinh Baria

3. Folate antagonists:

3. Folate antagonists 69 By: Dharmendrasinh Baria


Methotrexate is the classic antimetabolite of folic acid structurally derived by N-methylation of the para-aminobenzoic acid residue (PABA) and replacement of a pteridine hydroxyl by the bioisosteric amino group. The conversion of -OH to –NH 2 increases the basicity of N-3 and yields greater enzyme affinity. This drug competitively inhibits the binding of the substrate folic acid to the enzyme DHFR, resulting in reductions in the synthesis of nucleic acid bases, perhaps most importantly, the conversion of uridylate to thymidylate as catalyzed by thymidylate synthetase. In addition, purine synthesis is inhibited because the N-10-formyl tetrahydrofolic acid is a formyl donor involved in purine synthesis. THFs are cofactors in at least two key steps in the normal biosynthesis of purines. 70 By: Dharmendrasinh Baria


It binds with enzyme so tightly, hence called pseudo-irreversible binding. The basis of this binding strength is in the diamino pyrimidine ring, which is protonated at physiological pH. Uses: Acute lymphocytic keukemia Prophylexis in meningeal leukemia Choriocarcinoma Combination therapy for palliative management of breast cancer and osteocarcinoma ADR: Ulcerative stomatitis, Leukopenia, Abdominal distress 71 By: Dharmendrasinh Baria


Leucoverin is used in “Rescue therapy” with methotrexate. It prevents the lethal effects of methotrexate on normal cells by overcoming the blockade of tetrahydrofolinic acid production. In addition it inhibits the active transport of methotrexate in to cell and stimulates its efflux. Vincristine Increases the cellular uptake of methotrexate. 72 By: Dharmendrasinh Baria


Dactinomycin ( Actinomycin -D) Obtained from the cultures of - Streptomyces parvulus - S. Chrysamallus - S. Antibioticus They are chromopeptide Chromophoric part is substituted 3-phenoxazone-1,9-dicarboxylic acid known as “ actinosin ”. 73 By: Dharmendrasinh Baria


Mechanism of action: Dactinomycin binds noncovalently to double-stranded DNA by partial intercalation between adjacent guanine-cytosine bases resulting in inhibition of DNA function. The structural feature of dactinomycin important for its mechanism of cytotoxicity is the planar phenoxazone ring, which facilitates intercalation between DNA base pairs. The peptide loops are located within the minor groove and provide for additional interactions. The preference for GpC base pairs is thought to be partly related to the formation of a hydrogen bond between the 2-amino groups of guanine and the carbonyls of the L-threonine residues. Additional hydrophobic interactions and hydrogen bonds are proposed to form between the peptide loops and the sugars and base pairs within the minor groove. 74 By: Dharmendrasinh Baria


The primary effect of this interaction is the inhibition of DNA-directed RNA synthesis and specifically RNA polymerase. DNA synthesis may also be inhibited, and the agent is considered cell cycle specific for the G and S phases . Uses: - Rhabdomyosarcoma - Wilm’s tumor - Life saving for women with chromosarcoma resistant to methotrexate - In combination with vincristine and cyclophosphamide in solid tumors in children ADR: Bone marrow depression, Alopecia, erythema 75 By: Dharmendrasinh Baria


2) Anthracyclines: Obtained from S. Coerulorubidus S. Peuceticus They have tetracycline ring structures with unusual sugar daunosamine attached by glycosidic linkage. 76 By: Dharmendrasinh Baria


Mechanism of action 77 By: Dharmendrasinh Baria


Note: Tissue with ample of superoxide Dismutase and glutathione peroxidase activity are protected. Cardiac tissue lacks superoxide dismutase and catalase enzynes . This may be the reason for the cardiotoxicity of anthra cyclines . 78 By: Dharmendrasinh Baria


Uses: Acute lymphocytic and granulocytic leukemia ADR: Bone marrow depression Stomatitis Alopecia Cardiac toxicity 79 By: Dharmendrasinh Baria


3) Bleomycin: Glycopeptide isolated from Streptomyces verticillus . Mixture of closely related compounds with bleomycin A 2 and B 2 which are available in nature as blue copper chelates. M/A: The cytotoxic property of bleomycin are due to fragmentation of DNA. It appears to cause scission of DNA by interacting with O 2 and Fe +2 It binds with DNA through its amino terminal peptide and the activated complex generates free radicals that causes DNA breaking. 80 By: Dharmendrasinh Baria


4) Streptozocin : Isolated from S. achromogens It is nitrosoureas derivative of α - Deoxyglucose . It is alkylation agent similar in reactivity to other nitrosoureas . Uses: Indicated only for malignant metastatic islet cell carcinoma of pancreas. ADR: Renal toxicity, mutagenicity. 81 By: Dharmendrasinh Baria


1) Vinca alkaloids Binds to the microtubular protein tubulin in a dimeric form The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation CCS agents- M phase Uses: Vinblastine- Systemic Hodgkin’s disease, Lymphomas Vincristine- With prednisone for remission of Acute Leukemia 82 By: Dharmendrasinh Baria


M/A 83 By: Dharmendrasinh Baria


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2) Taxanes First isolated from bark of Western / Pacific yew ( Taxus brevifolia ) It is used for treatment of lung, ovarian and breast cancer. Taxanes hyper-stabilizes microtubule structure ( freez them). Taxanes binds to the β subunit of tubulin ,the resulting microtubule/ Taxanes complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules is necessary for their function. 85 By: Dharmendrasinh Baria


M/A 86 By: Dharmendrasinh Baria


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3) Epipodophyllotoxin : From Podophyllum peltatum ( May apple) Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme Uses: Testicular cancer, small-cell lung carcinoma, Hodgkin lymphoma, carcinoma of breast, Kaposi’s sarcoma associated with AIDS 88 By: Dharmendrasinh Baria


Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II 89 By: Dharmendrasinh Baria


4) Camptothecin analogues First isolated from Camptotheca acuminata (Chinese tree ). Used in Ovarian cancer, Small cell lung cancer. 90 By: Dharmendrasinh Baria

f. Protein kinase inhibitors-:

f. Protein kinase inhibitors- Tyrosine Kinase Inhibitors – Imatinib, geftinib, erlotinib, sorafenib, sunitinib, lapatinib etc. IMATINIB- First selectively targeted drug to be introduced Inhibits a specific tyrosine protein kinase – “ Bcr-abl” tyrosine kinase expressed by CML cells and related receptor tyrosine kinases including PDGF receptor that is constitutively active in dermatofibrosarcoma protuberans , stem cell receptor and c-kit receptor active in GIST. 91 By: Dharmendrasinh Baria


Very sucessful in chronic phase of CML (remission> 90%) and in metastatic c-kit (+) GIST . Also indicated in Dermatofibrosarcoma protuberans. Resistance develops mainly due to point mutation in Bcr-Abl tyrosine kinase. metabolised mainly by CYP3A4 , metabolites excreted in faeces through bile. ADR- Abdominal pain, vomitting , fluid retention,periorbital oedema,pleuarl effusion,myalgia and CHF. Dasatinib and Nilotinib are similar drugs used in case of Imatinib resistance 92 By: Dharmendrasinh Baria

g. Miscellaneous – L-Asparaginase, Asparaginase, Hydroxurea, Mitoxantrone:

g. Miscellaneous – L- Asparaginase , Asparaginase , Hydroxurea , Mitoxantrone L- Asparaginase : An enzyme isolated from E.Coli . Causes catabolic depletion of serum asparagine to aspartic acid and ammonia resulting in reduced blood glutamine levels and inhibition of protein synthesis. Neoplastic cells require external source of asparagine. Treats childhood acute leukemia Can cause anaphylactic shock 93 By: Dharmendrasinh Baria


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Hydroxyurea- An analog of urea Inhibits the enzyme ribonucleotide reductase. Resulting in the depletion of deoxynucleoside triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous leukemia Adverse effects: Myelosuppression (Minimal), Hypersensitivity, Hyperglycemia, Hypoalbuminemia 95 By: Dharmendrasinh Baria


Mitoxantrone Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute myelogenous leukemia, non-Hodgkin’s lymphomas, and breast cancer Causes cardiac toxicity 96 By: Dharmendrasinh Baria


It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. 97 By: Dharmendrasinh Baria


Glucocorticoids – Prednisolone and others Glucocorticoids such as prednisolone and dexamethasone have marked inhibitory effects on lymphocyte proliferation. Used in the treatment of leukaemias and lymphomas. Their ability to lower raised intracranial pressure, and to mitigate some of the side effects of anticancer drugs, makes them useful as supportive therapy . Examples 98 By: Dharmendrasinh Baria

2. Estrogens:

2. Estrogens Physiological antagonists of androgens. Thus used to antagonize the effects of androgens in androgen dependent prostatic cancer. The agonist is occasionally used to treat prostate cancer through suppression of testosterone production. Diethylstilbestrol and ethinyloestradiol are two oestrogens used clinically in the palliative treatment of androgen-dependent prostatic tumours. The latter compound has fewer side effects. These tumours are also treated with gonadotrophin-releasing hormone analogues Oestrogens can be used to recruit resting mammary cancer cells into the proliferating pool of cells, thus facilitating killing by other cytotoxic drugs 99 By: Dharmendrasinh Baria

3. Selective estrogen receptor modulators- Tamoxifen, Toremifene:

3. Selective estrogen receptor modulators- Tamoxifen, Toremifene 100 By: Dharmendrasinh Baria


Selective estrogen receptor modulator (SERM), have both estrogenic and anti-estrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational changes in the receptor Has anti-estrogenic effects on breast tissue. The ability to produce both estrogenic and anti-estrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifen’s affects occur in the G1 phase of the cell cycle 101 By: Dharmendrasinh Baria

Therapeutic Uses:

Therapeutic Uses Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational When used prophylactically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease 102 By: Dharmendrasinh Baria

4. Selective estrogen receptor down regulators- Fulvestrant :

4. Selective estrogen receptor down regulators- Fulvestrant Pure estrogen antagonist Uses : Metastatic ER+ Breast Cancer in postmenopausal women MOA: Inhibits ER dimerization & prevents interaction of ER with DNA ER is down regulated resulting in more complete supression of ER responsive gene function. 103 By: Dharmendrasinh Baria

5. Aromatase Inhibitors:

5. Aromatase Inhibitors Aromatase is the enzyme responsible for conversion of androstenedione (androgen precursor) to estrone (estrogenic hormone). - 1 st gen.- A minoglutethimide - 2 nd gen.- F ormestane , Fadrozole , Rogletimide - 3 rd gen.- E xemestane , Letrozole,Anastrozole Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. As breast and ovarian cancers require estrogen to grow, Aromatase inhibitors are taken to either block the production of estrogen or block the action of estrogen on receptors. 104 By: Dharmendrasinh Baria


Aminogluthethimide - Mechanism of Action: Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone . Inhibits the extra-adrenal synthesis of estrone and estradiol. Inhibits the enzyme aromatase that converts androstenedione to estrone . ADR: Dizziness, Lethargy, Visual blurring, Rash Therapeutic Uses: ER- and PR-positive metastatic breast cancer 105 By: Dharmendrasinh Baria


106 By: Dharmendrasinh Baria

6. Antiandrogens – Flutamide, Bicalutamide :

6. Antiandrogens – Flutamide , Bicalutamide Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting androgen production. Antiandrogens are most frequently used to treat prostate cancer. 107 By: Dharmendrasinh Baria

7. 5-α reductase Inhibitors – Finasteride, Dutasteride :

7. 5- α reductase Inhibitors – Finasteride, Dutasteride 108 By: Dharmendrasinh Baria

8. GnRH analogues – Nafarelin, Leuprorelin, triptorelin:

8. GnRH analogues – Nafarelin , Leuprorelin , triptorelin NAFERELIN : nasal spray / SC inj ↓FSH & LH release from pituitary- ↓ the release of estrogen & testosterone. USE : Breast Ca, Prostatic Cancer 9. Progestins : Medroxyprogesterone acetate, hydroxyprogesterone caproate and megestrol 2 nd line hormonal therapy for metastatic hormone dependent breast ca and endometrial cancer. Hydroxyprogesterone – used in metastatic endometrial Cancer. A/E : bleeding 109 By: Dharmendrasinh Baria

10. GnRH antagonists – Cetorelix, Ganirelix, Abarelix :

10. GnRH antagonists – Cetorelix, Ganirelix, Abarelix Cetrorelix , ganirelix and abarelix are antagonist of GnRH decrease the release of gonadotropins without causing initial stimulation can be used in prostatic ca without the risk of flare up reaction. 110 By: Dharmendrasinh Baria


111 By: Dharmendrasinh Baria


112 By: Dharmendrasinh Baria


113 By: Dharmendrasinh Baria


Antineoplastic agents, J.H Block & J.M Beale., Wilson & Giswold’s Textbook of Organic Medicinal Chemistry & pharmaceutical chemistry 12 th Edition, 2011, pg. No. 355-412. Tripathi KD, Anticancer drugs , Chemotherapy of neoplastic diseases; 7th ed ; 857-877. Foye’s Principles of medicinal chemistry, Sixth Edition, Thomas L. Lemke, David A. Williams. 114 By: Dharmendrasinh Baria


115 By: Dharmendrasinh Baria

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