Chemistry of Antineoplastic(anticancer) agents

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ANTI NEOPLASTICS Chemotherapeutic Agents By- Gaurav Kayal ( M.Pharm ) Assistant Professor (Pharmaceutical Chemistry)

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Contents Introduction Classification Individual categories with mechanism of action, uses, side effects and drugs with their synthesis. Alkylating agents Antimetabolites Tubulin binding agents Natural products

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By Gaurav Kayal Introduction: A neoplasm , or tumour is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue and continues in the same manner after cessation of the stimuli which have initiated it. A malignant tumour grows rapidly and continuously, and even when it has impoverished its host and source of nutrition, it still retains the potentiality for further proliferation. Besides, malignant tumours invade and destroy neighbouring tissues

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By Gaurav Kayal Causes of tumor: genetic factors chemical carcinogens e.g., arsenic, soot, coal tar, petroleum polycyclic hydrocarbon carcinogens ‘Why cancer is rather difficult to cure in comparison to other microbial infections?’ ( i ) Qualitative differences existing between the human and bacterial cells. It is well known that the bacterial cells possess distinctive cell walls; besides, the ribosomes also differ entirely from those of ‘human cells’ ( ii) Quantitative differences do prevail between normal and neoplastic human cells ( iii) Body’s immune mechanisms and other host defenses play a vital role in killing bacteria plus other susceptible foreign cells ; whereas they are not so prevalent in destroying cancerous cells.

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By Gaurav Kayal CLASSIFICATION Antineoplastic agents are classified under the following seven categories, namely : ( i ) Alkylating Agents (ii) Antimetabolites ( iii) Antibiotics (iv) Plant products ( v) Miscellaneous compounds (vi) Hormones ( vii) Immunotherapy.

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Alkylating agents Topoisomerase inhibitors Antimetabolites Molecularly targeted busulfan dactinomycin cytarabine erlotinib carboplatin daunomycin clofarabine imatinib carmustine doxorubicin fludarabine sorafenib cisplatin etoposide gemcitabine sunitinib cyclophosphamide etoposide phosphate mercaptopurine tretinoin dacarbazine idarubicin methotrexate Herceptin ifosfamide irinotecan nelarabine Miscellaneous lomustine liposomal daunomycin thioguanine arsenic trioxide mechlorethamine liposomal doxorubicin Tubulin binders asparaginase melphalan mitoxantrone docetaxel bleomycin oxaliplatin teniposide ixabepilone dexamethasone procarbazine topotecan vinblastine hydroxyurea temozolomide vincristine mitotane thiotepa vinorelbine PEG-asparaginase paclitaxel prednisone Antineoplastic Agents By Gaurav Kayal

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DNA RNA Protein tubulin Purines and Pyrimidines Asparaginase Tubulin binders Alkylating agents Topoisomerase Inh. Antimetabolites Chemotherapy: Mechanisms of Action By Gaurav Kayal

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By Gaurav Kayal Alkylating Agents Alkylating agents are chemically reactive compounds that combine most readily with nucleophilic centres . The term ‘ alkylating agents’ is applied to compounds which, in a sense, alkylate the substance with which they react, by joining it through a covalent bond . These are further sub-divided into four categories, namely : ( i ) Nitrogen Mustards ( ii) Methane sulphonates ( iii) Ethylenimines ( vi) Nitrosoureas

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The first class of chemotherapy agents. They stop tumour growth by cross-linking guanine nucleobases in DNA double-helix strands - directly attacking DNA This makes the strands unable to uncoil and separate As this is necessary in DNA replication, the cells can no longer divide Cell-cycle nonspecific effect A lkylating agents are also mutagenic and carcinogenic A T C G C G G A T G C General Characteristics:

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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects a. Nitrogen Mustards A. Mechlorethamine DNA cross-links, resulting in inhibition of DNA synthesis and function Hodgkin’s and non-Hodgkin’s lymphoma Must be given Orally Nausea and vomiting, decrease in PBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosis B. Cyclophosphamide Same as above Breast, ovarian, CLL, soft tissue sarcoma, WT, neuroblastoma Orally and I.V. Same as above C. Chlorambucil Same as above Chronic lymphocytic leukemia Orally effective Same as above D. Melphalan Same as above Multiple myeloma, breast, ovarian Orally effective Same as above E. Ifosfamide Same as above Germ cell cancer, cervical carcinoma, lung, Hodgkins and non- Hodgkins lymphoma, sarcomas Orally effective Same as above By Gaurav Kayal

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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects b. Alkyl Sulfonates A. Busulfan Atypical alkylating agent. Chronic granulocytic leukemia Orally effective Bone marrow depression, pulmonary fibrosis, and hyperuricemia c. Nitrosoureas 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Carmustine DNA damage, it can cross blood-brain barrier Hodgkins and non- Hodgkins lymphoma, brain tumors, G.I. carcinoma Given I.V. must be given slowly. Bone marrow depression, CNS depression, renal toxicity B. Lomustine Lomustine alkylates and crosslinks DNA, thereby inhibiting DNA and RNA synthesis. Also carbamoylates DNA and proteins, resulting in inhibition of DNA and RNA synthesis and disruption of RNA processing. Lomustine is lipophilic and crosses the blood-brain barrier Hodgkins and non- Hodgkins lymphoma, malignant melanoma and epidermoid carcinoma of lung Orally effective Nausea and vomiting, Nephrotoxicity , nerve dysfunction C. Streptozotocin DNA damage pancreatic cancer Given I.V. Nausea and vomiting, nephrotoxicity , liver toxicity By Gaurav Kayal

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d. Ethylenimines 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Triethylene thiophosphoramide ( Thio -TEPA) DNA damage, Cytochrome P450 Bladder cancer Given I.V. Nausea and vomiting, fatigue B. Hexamethylmelamine (HMM) DNA damage Advanced ovarian tumor Given orally after food Nausea and vomiting, low blood counts, diarrhea d. Triazenes 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Dacarbazine (DTIC) Blocks, DNA, RNA and protein synthesis Malignant Melanoma, Hodgkins and non- Hodgkins lymphoma Given I.V. Bone marrow depression, hepatotoxicity , neurotoxicity, bleeding, bruising, blood clots, sore mouths. By Gaurav Kayal

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By Gaurav Kayal ( i ) Nitrogen Mustards- Mechlorethamine Hydrochloride 2, 2-Dichloro-N-methyldiethylamine hydrochloride

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By Gaurav Kayal B. Melphalan 4-[ Bis (2-chloroethyl) amino]-L-phenylalanine

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By Gaurav Kayal C. Cyclophosphamide N, N- Bis (2-chloroethyl) tetrahydro-2H-1, 1, 3, 2-oxazaphosphorin-2-amine-2-oxide

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By Gaurav Kayal D. Chlorambucil 4-[p- Bis (2-chloroethyl) amino] phenyl] butyric acid

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By Gaurav Kayal (ii) Methanesulphonates Busalfan 1, 4-Butanediol dimethanesulphonate

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By Gaurav Kayal (iii) Ethylenimines A. Triethylenemelamine ( Tretamine ) 2, 4, 6-Tris (ethyleneimino)-S-triazine

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By Gaurav Kayal B. Triethylenethio Phosphoramide ( Thiotepa ) N, N′, N′′-Triethylenethio-phosphoramide

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By Gaurav Kayal (iv) Nitrosoureas A. Carmustine 1, 3-Bis (2-chlorethyl)-1-nitrosourea

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By Gaurav Kayal B. Lomustine 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea

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By Gaurav Kayal Antimetabolites Methotrexate Mercaptopurine Azathiopurine Fluorouracil Cytarabine Azaserine

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By Gaurav Kayal

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Tubulin Binding Agents a  Polymerization tubulin Depolymerization e.g., Vincristine, Vinblastine, Vindesine Vinorelbine: Inhibition of mitotic spindle formation by binding to tubulin. M-phase of the cell cycle. e.g., Paclitexal : binds to tubulin , promotes microtubule formation and retards disassembly; results in mitotic arrest. Paclitexal (taxol) Vincristine

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B. Natural Products 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Vincristine Cytotoxic : Inhibition of mitotic spindle formation by binding to tubulin . M-phase of the cell cycle. Metastatic testicular cancer, Hodgkins and non- Hodgkins lymphoma, Kaposi’s sarcoma, breast carcinoma, chriocarcinoma , neuroblastoma I.V. Bone marrow depression, epithelial ulceration, GI disturbances, neurotoxicity B. Vinblastine Methylates DNA and inhibits DNA synthesis and function Hodgkins and non- Hodgkins lymphoma, brain tumors, breast carcinoma, chriocarcinoma , neuroblastoma I.V. Nausea and vomiting, neurotoxicity, thrombocytosis , hyperuricemia . 1. Tubulin binding drugs 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects Paclitaxel ( Taxol ) Cytotoxic : binds to tubulin , promotes microtubule formation and retards disassembly; mitotic arrest results Melanoma and carcinoma of ovary and breast I.V. Myelodepression and neuropathy 2. Antimitotic Drugs By Gaurav Kayal

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By Gaurav Kayal 3. Epipodophyllotoxins 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Etoposide Binds to and inhibits Topoisomerase II and its function. Fragmentation of DNA leading to cell death, apoptosis. Testicular cancer, small-cell lung carcinoma, Hodgkin lymphoma, carcinoma of breast, Kaposi’s sarcoma associated with AIDS I.V. Myelosuppression , alopecia B. Teniposide Same as above Refractory acute lymphocytic leukemia I.V. Myelosuppression , 4. Enzymes: L- asparaginase 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects L- asparaginase Hydrolyzes L- asparagine (to L-aspartic acid) an essential amino acid to many leukemic cells Acute lymphocytic leukemia, induction of remission in acute lymphoblastic leukemia when combined with vincristine , prednisone, and anthracyclines I.V. or I.M. Nausea and vomiting, Poor appetite, Stomach cramping, Mouth sores, Pancreatitis. Less common: blood clotting

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By Gaurav Kayal 5. Antibiotics 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects a. Dactinomycin (ACTINOMYCIN D) It binds to DNA and inhibits RNA synthesis, impaired mRNA production, and protein synthesis Rhabdomyosarcoma and Wilm's tumor in children; choriocarcinoma (used with methotrexate I.V. Bone marrow depression, nausea and vomiting, alopecia, GI disturbances, and ulcerations of oral mucosa b. Daunorubicin (CERUBIDIN) Doxorubicin (ADRIAMYCIN) inhibit DNA and RNA synthesis Acute lymphocytic/granulocytic leukemias ; treatment of choice in nonlymphoblastic leukemia in adults when given with cytarabine I.V. Side effects: bone marrow depression, GI disturbances and cardiac toxicity (can be prevented by dexrazoxane ) inhibit DNA and RNA synthesis Acute leukemia, Hodgkin's disease, non Hodgkin's lymphomas (BACOP regimen), CA of breast & ovary, small cell CA of lung, sarcomas, best available agent for metastatic thyroid CA I.V. Cardiac toxicity, Doxorubicin mainly affects the heart muscles, leading to tiredness or breathing trouble when climbing stairs or walking, swelling of the feet . c. Bleomycin (BLENOXANE) fragment DNA chains and inhibit repair Germ cell tumors of testes and ovary, e.g., testicular carcinoma (can be curative when used with vinblastine & cisplatin ), squamous cell carcinoma Given I.V. or I.M. Mucosocutaneous reactions and pulmonary fibrosis; bone marrow depression much less than other antineoplastics

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By Gaurav Kayal C. Antimetabolites 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects 1. Methotrexate inhibits formation of FH4 ( tetrahydrofolate ) from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR); since FH4 transfers methyl groups essential to DNA synthesis and hence DNA synthesis blocked. Choriocarcinoma , acute lymphoblastic leukemia (children), osteogenic sarcoma, Burkitt's and other non-Hodgkin‘s lymphomas, cancer of breast, ovary, bladder, head & neck Orally effective as well as given I.V. bone marrow depression, intestinal lesions and interference with embryogenesis. Drug interaction : aspirin and sulfonamides displace methotrexate from plasma proteins. 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects 2. Pyrimidine Analogs: Cytosine Arabinoside inhibits DNA synthesis most effective agent for induction of remission in acute myelocytic leukemia; also used for induction of remission acute lymphoblastic leukemia, non-Hodgkin's lymphomas; usually used in combination chemotherapy Orally effective bone marrow depression

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By Gaurav Kayal 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects 3. Purine analogs: 6-Mercaptopurine (6-MP) and Thioguanine Blocks DNA synthesis by blocking conversion of AMP to ADP; also blocks first step in purine synthesis. Feedback inhibition blocks DNA synthesis by inhibiting conversion of GMP to GDP; also blocks first step in purine synthesis by feedback inhibition most effective agent for induction of remission in acute myelocytic leukemia; also used for induction of remission acute lymphoblastic leukemia, non-Hodgkin's lymphomas; usually used in combination chemotherapy Orally effective bone marrow depression,

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THANK YOU For Doubts/ Queries- Mr. Gaurav Kayal Assistant Professor (Pharmaceutical Chemistry) (Ph-9009991186, [email protected])

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