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Medicinal Chemistry 745
Medicinal Chemistry 745
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1Ashok Philip, Ph.D. Assistant Professor of Pharmaceutical Sciences 731-661-5704 (office) firstname.lastname@example.org Antineoplastic Agents-3 1. Wilsons and Gisvold?s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Edition, Copyright ©2011 Lippincott Williams & Wilkins 2. FOYE?s Principles of Medicinal Chemistry, 6th Edition, Copyright ©2008 Lippincott Williams & Wilkins 3. Drug Labels accessed from: http://dailymed.nlm.nih.gov/dailymed/about.cfm 4. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (2nd edition) Golan et. al; Lippincott Williams & Wilkins, 2008 5. Goodman and Gilman?s The Pharmacological Basis of Therapeutics, 12th Ed. Laurence L Brunton, John S. Lazo, and Keith L Parker, Eds. New York: McGraw-Hill, 2006. Reference Books: 1 Goal: To provide students with the medicinal chemistry perspective of Antineoplastic agents LECTURE 20 Objectives: Students should be able ? To outline various therapeutic classes of agents for Cancer Chemotherapy ? To understand the Mechanisms by which antineoplastic agents act ? To understand the mechanisms responsible for adverse effects observed with antineoplastic agents ? To understand the chemical composition and SAR of antineoplastic agents 2 2The Cell Cycle 3 Summary of mechanisms and sites of action of some agents 4 31. Nitrogen Mustards 2. Nitrosoureas 3. Procarbazine and Triazenes 4. Miscellaneous alkylating agents 5. Organoplatinum complexes 5 I. Alkylating Agents (DNA Cross-Linking Agents) I. Alkylating Agents 2. Nitrosoureas Carmustine (BiCNU®) Lomustine (CeeNU®) Streptozocin (Zanosar®) Bifunctional in nature & cause interstrand DNA Cross-linking 6 4Mechanism of action Decompose readily in aqueous environment of cell to Cytotoxic Electrophiles 2. Nitrosoureas - 2 decomposition Pathways A and B Pathway A Capable of alkylating DNA 7 Mechanism of action A second decomposition mechanism produces electrophilic 2-chloroethylcarbocation capable of DNA alkylation at N7 and O6 of Guanine 2. Nitrosoureas Pathway B Also an isocyanate produced that can carbamylate amino acid residues like Lys 8 5Mechanism of action2. Nitrosoureas Pathway B 9 Carmustine and Lomustine - Both highly lipophilic compounds - Marketed for use in Brain tumors and Hodgkin's disease High lipophilicity of Carmustine prevents a totally aqueous IV formulation Hence administered in 10% ethanol 2. Nitrosoureas Carmustine (BiCNU®) Lomustine (CeeNU®) - Therefore, readily cross BBB 10 6Carmustine and Lomustine 2. Nitrosoureas Stability: - Carmustine degrades within 15 minutes of IV administration - Lomustine is stable enough for oral use and marketed in capsule form - Carmustine decomposes if exposed to temperatures around 90°F - Pure Carmustine is a low-melting solid, - Decomposed Carmustine is an oil - Vials of Carmustine that appear oily should be discarded 11 2. Nitrosoureas Indicated for metastatic islet cell carcinoma of pancreas Reason: Glucopyranose moiety confers both islet cell specificity & high water solubility Much less reactive as a DNA alkylating agent than other nitrosoureas ? Due to lack of 2-chloroethyl substituent BBW: Dose-related renal toxicity can be severe or fatal Streptozocin (Zanosar®) 12 73. Procarbazine and Triazenes ? DNA Methylators Procarbazine (Matulane®) Dacarbazine (DTIC) Temozolamide (Temodar®) A methylhydrazine derivative Triazenes 13 3. Procarbazine and Triazenes ? DNA Methylators Mechanism of action (Cell Cycle Non-Specific Action) - All exert antineoplastic effect through O6- methylation of Guanine nucleotides Result: O6-methylguanine pairs preferentially with Thymine These ?mispairs? prompt point mutations during subsequent DNA replication cycles & trigger cell destruction Consequence: Patients able to repair this damage by transferring offending CH3 group to a Cys residue on alkyltransferase enzyme Exhibit resistance to these agents 14 83. Procarbazine Mechanism of action - A Methyl radical generator used for Hodgkin's disease & malignant brain tumors - Part of a multidrug regimen CYP1A CYP2B Methyl radical 15 3. Triazenes Mechanism of action Dacarbazine (DTIC) Temozolamide (Temodar®) CYP1A1 CYP1A2 Nonenzymatic 16 H2O + Diazomethane Diazomethane+ 94. Miscellaneous DNA Alkylating Agents Altretamine: Believed to damage tumor cells via production of weakly alkylating Formaldehyde species Mechanism of action Formaldehyde - Product of CYP450-mediated N-demethylation Altretamine (Hexalen®) PMM (Pentamethyl melamine 17 Busulfan : One or both of methylsulfonate ester moieties displaced by nucleophilic N7 of Guanine - Leads to either monoalkylated or cross-linked DNA Mechanism of action Busulfan (Myleran®) - Is an alkylsulfonate 4. Miscellaneous DNA Alkylating Agents 18 10 Busulfan - Mechanism of action 19 5. Organoplatinum Complexes Contain an electron-deficient metal atom ? Platinum (Pt) 20 11 Mechanism of action Electron-deficient (Pt) metal atom acts as a magnet for electron-rich DNA nucleophiles Like nitrogen mustards also are bifunctional & can accept electrons from two DNA nucleophiles 5. Organoplatinum Complexes Intrastrand cross-links more commonly occur between adjacent guanine residues 21 5. Organoplatinum Complexes Mechanism of action: Cisplatin Chloride-poor environment of tumor cell facilitates the generation of active, cytotoxic hydrated forms 22 12 5. Organoplatinum Complexes Cisplatin - Highly Nephrotoxic (patients should be hydrated with saline/Mannitol) Given IV for treatment of metastatic testicular and ovarian cancer and advanced bladder cancer - Myelosuppression and Ototoxicity (irreversible hearing loss) Cisplatin & other Organoplatinum anticancer agents react with Aluminum Cannot be administered through aluminum-containing needles - Is photosensitive& packaged in amber bottles & must be protected from light 23 5. Organoplatinum Complexes Oxaliplatin (oxalate anion) Intrastrand Pt-DNA crosslinks formed - Decomposes in alkaline media, should not be co-administered with drugs that increase pH of IV solution 24 13 - Conformation of Oxaliplatin-DNA adduct is LESS susceptible to MMR proteins - MMR proteins INITIATE APOPTOSIS 5. Organoplatinum Complexes - Resistance - Conformation of Cisplatin-DNA adduct HIGHLY susceptible to MisMatchRepair (MMR) proteins - Cisplatin-DNA adduct bends DNA by 60-80° & presents a wide minor groove - Oxaliplatin-DNA adduct bends DNA by 31° only & produces only narrow minor groove - MMR-deficient Cells exhibit RESISTANCE to Cisplatin - MMR-deficient Cells still SUSCEPTIBLE to Oxaliplatin 25 Ashok Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel NOP (nociceptin/orphanin FQ peptide) Receptor Ligands.
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