Antineoplastic.pptx

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1. ANTI-NEOPLASTIC OR ANTICANCER DRUGS

2. Classification of Anti-neoplastic Agents / Anticancer Drugs Alkylating Agents Nitrogen mustards: Melphalan , Cyclophosphamide, Ifosfamide Nitrosoureas Alkylsulfonates Ethyleneimines Triazene Methyl Hydrazines Platinum Coordination complexes: Cisplatin , Carboplatin, Oxaliplatin 2. Antimetabolites Folate Antagonists: Methotrexate Purine antagonists : Mercapturine Pyrimidine antagonists: 5-Fluorouracil , Cytarabibe

3. 3. Natural Products Plant Products Vinca Alkaloids: Vincristine , Vinblastine Taxanes : Paclitaxel, Docetaxel Epipodophyllotoxins : Etoposide Camptothecins : Irinotecan Microorganism Products Antibiotics: Doxorubicin, Bleomycin Enzymes: L- Asparaginase

4. . Miscellaneous Hydroxyurea Imatinib Mesylate Rituximab Epirubicin Bortezomib Zoledronic Acid Geftinib Leucovorin Pamidronate Gemcitabine

5. 4. Hormones and Antagonists Corticosteroids: Prednisone, Dexamethasone Estrogens: Ethinyloestradiol Antiestrogens : Tamoxifen Progesteron derivative: Megestrol Acetate Androgen: Testosterone propionate Antiandrogen : Flutamide , Bicalutamide Aromatase inhibitor: Letrozole , Anastrazole 5-alpha reductase inhibitor: Finasteride GnRH Analogue: Leuprolide , Buserelin Growth Hormone, glucagon and insulin inhibitor: Octreotide

6. In syllabus Tamoxifen = Antiestrogens Fluorouracil = Pyrimidine antagonists Mercapturine = Purine antagonists Methotraxate = Folate Antagonists And vincristine = Vinca Alkaloids

7. METHOTRAXATE (FOLATE ANTAGONISTS) Pharmacokinetic data Bioavailability : 17–90% Metabolism : hepatic Half-life : 3–15 hours (dose dependent) Excretion : renal 48–100%

8. MECHANISM OF ACTION Methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in thetetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion ofdihydrofolate to the active tetrahydrofolate . Folic acid is needed for the de novo synthesis of the nucleosidethymidine , required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates , The similar structure of dihydrofolic acid(top) and methotrexate bottom) suggests that methotrexate is a competitive inhibitor

9. 4-nitrobenzoyl chloride L-glutamic acid N-(4nitrobenzoyl)glutamic acid N-(4-aminobenzoyl)glutamic acid N-(4-methylaminobenzoyl)glutamic acid 2-amino-4-hydroxy-6-bromomethylpteridine 2,4,6-triaminopyrimidine malonic acid dinitrile guanidine 2,4,5,6-tetraaminopyrimidine 1,2-dibromopropionic aldehyde 2,4,6-triamino-5-nitrosopyrimidine

10. Structure Activity relationship   The binding ability of methotrexate to dihydrofolate reductase is because of diaminopyrimidine ring which is protonated at physiological pH 6. As the pH increase the binding become weaker. 2. Alkylation of the amino groups lead to decreased activity. 3. Partial reduction ,removal or relocation of heterocyclic compounds lead to decreased activity. 4. Replacement of nitrogen by carbons in pyridine rings increased lipophilicity . For example Piritrexim and Trimetrexate analogues of methotrexate with high lipophilicity as compare to methotrexate .

11. MERCAPTURINE (PURINE ANTAGONISTS) 6-mercaptopurine Pharmacokinetic data Bioavailability : 5 to 37% Metabolism: xanthine oxidase Half-life: 60-120 min longer for the active metabolite Excretion: Renal

12. uric acid barbituric acid urea malonic ester uramil isocyanic acid pseudouric acid 2,6,8-trichloropurine 9H-Purin-6-ol hypoxanthine

13. Structure Activity relationship When hydrogen at position 6 of 6-MP is replaced by an alkyl, aralkyl , or aryl group such substitution leads to decreased activity . 2. Substitution at position 2 with CH3, Cl , OH, or SH cause inactivation of 6-MP. The exception to this is the 2-amino-derivative ( thioguanine ) which, like 6-MP, is a close analog of a natural purine. Thioguanine is active.