Anti-Cancer-Agents.docx

Anti-Cancer-Agents.docx

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  Medicinal Chemistry-II(PHAR-3203) Anticancer drugsPage 1 Anti-cancer drugs Anticancer agents are chemical substances that inhibit or kill proliferating cancer cells, while leaving host cells unharmed, or at least recoverable. Cancer is one of the major causes of death and one of the most feared of diseases. Cancer chemotherapy may consist of using several drugs in combination for varying lengths of time because cancerous cells which are initially suppressed by a specific drug may develop a resistance to that drug.Unfortunately, most of the chemicals that have been found to be successful anti-cancer agents are extremely toxic and must be administered very carefully. There are three goals associated with the use of the most commonly-used anticancer agents- 1. Damage the DNA of the affected cancer cells. 2. Inhibit the synthesis of new DNA strands to stop the cell from replicating, because the replication of the cell is what allows the tumor to grow. 3. Stop mitosis or the actual splitting of the original cell into two new cells. Stopping mitosis stops cell division (replication) of the cancer and may ultimately halt the progression of the cancer. Classification of drugs used in cancer chemotherapy The main anticancer drugs can be divided into the following general categories. A).Cytotoxic drugs. they include: 1.alkylating agents and related compounds: which act by forming covalent bonds with DNA and thus impeding replication  cyclophosphamide  Cisplatin  Chlorambucil  Carmustine  Lomustine 2.Antimetabolites: which block or subvert one or more of the metabolic pathways involved in DNA synthesis a)Folate antagonists: Methotrexate b) Pyrimidine analogues: Fluorouracil, Cytarabine c) Purine analogues: Mercaptopurine, Pentostatin 3.Natural Products: a).Cytotoxic antibiotics: substances of microbial origin that prevent mammalian cell division(by causing intercalation)  Doxorubicin  Bleomycin
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  Medicinal Chemistry-II(PHAR-3203) Anticancer drugsPage 2  Dactinomycin  Mitomycin b)Vinca alkaloids: Vinblastin, Vincristine c) Epipodophylotoxin: Etoposide,Teniposide d) Enzymes: L-Asparaginase B).Hormones 1.Adrenocorticoids: Prednisone for leukaemias and lymphomas 2.Antiestrogen:Tamoxifen for breast tumours 3.Gonadotrophin-releasing hormone analogues: Leuprolide for prostate and breast tumours 4.Antiandrogens: Flutamide for prostate cancer 5.Estrogens:Diethylstilbestrol, Etinyl estradiol C).Miscellaneous agents that do not fit into the above categories. This group includes a number of recently developed drugs designed to affect specific tumour-related targets.  Procarbazine: inhibits DNA and RNA synthesis and interferes with mitosis.  Hydroxycarbamide (hydroxyurea ): inhibits ribonucleotide reductase.  Mitoxantrone (mitozantrone): causes DNA chain breakage.  Trilostane: inhibits adrenocortical steroid synthesis.  Monoclonal antibodies: rituximab, alemtuzumab, Trastuzumab  Imatinib: inhibits tyrosine kinase signalling pathways Synthesis of Cyclophosphamide
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  Medicinal Chemistry-II(PHAR-3203) Anticancer drugsPage 3 Structure-Activity Relationship of alkylating agent(Nitrogen mustards): 1.The biological activity of nitrogen mustards is based upon the presence of the bis-(2- chloroethyl) grouping. 2. Bifunctional alkylating agents have greater activity than monofuctional alkylating agents, e.g.Cyclophosphamide . 3. R=P-Butyric acid produces chlorambucil which is slowest acting & least toxic. 4. R=CH3 Produces a compound with cytotoxic activities but higher toxicities,e.g. Mechlorehtamine 5. linkage of the bis-(2- chloroethyl) group to election-rich substitutions such as unsaturated ring systems has yielded more stable drugs with greater selective killing of tumor cells. 6. Substitution of one of the two chloroethyl groups on the cyclic phosphoamide nitrogen of the oxazaphosphorine ring produces a compound with slower metabolism rate,requiring high dose with higher toxicities, e.g. Ifosfamide. Pharmacokinetics of Cyclophosphamide
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  Medicinal Chemistry-II(PHAR-3203) Anticancer drugsPage 4 ф Routes: Oral, intravenous ф Bioavailability: >75% (oral) ф Protein binding: >60% ф Metabolism: Hepatic ф Half life: 3-12 hours ф Excretion: Renal Indication of Cyclophosphamide  Acute & chronic lymphocytic leukemias  Hodgkin's diseases  Multiple myeloma  Neuroblastoma  Breast, ovary, lung, & cervix cancer  Side-effects of Cyclophosphamide  Nausea and vomiting  Severe bone marrow depression  Immunosuppression  Alopecia  Diarrhea  Hemorrhagic cystitis  Leukocytosis  Amenorrhea  Testicular atrophy  Aspermia  Sterility  Neurotoxicity  Blocks reproductive function and  May produce menstrual irregularities or premature ovarian failure in women and oligospermia in men. Contraindication of Cyclophosphamide -Bladder hemorrhage -Leucopenia -Thrombocytopenia -Pregnancy
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  Medicinal Chemistry-II(PHAR-3203) Anticancer drugsPage 5 Dose of Cyclophosphamide Initial, adult dose of 40-50 mg per kg, given intravenously in divided doses over 2 to 5 days ; Children : 2-8 mg per kg daily iv injection. Available Market Preparation Cyclophosphamide  ENDOXAN Inj. -Cycloph0sphamide anhydrous BP 200mg & 500mg as white powder in vial for reconstitution: injection.  ENDOXAN Tab. -Cyclophosphamide BP 50 mg/tablet.