Předmět Princip. of antic. and antiv. drug d.I. (UCH / 645)

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Materiál	Typ	Datum	Počet stažení

Obsah

Contents of lectures:1.Concept of antimetabolite. Types of its interactions with enzymes. Principles of analogy - chemical modification (PAS, azaU). Cellular parasites. Mycoplasma. Antibacterial drugs. Bacterial membrane as a target. Penicillins, cephalosporins, carba analogs, monobactams.2.Virus classification. Life cycle of viruses. Infectivity. Viral pathogens in human and veterinary medicine. Haemorrhagic fevers. Molecular principles of blood precipitation. Chemotherapy vs. vaccination. AIDS.3.Haemopoietic system, cellular differentiation. T-cells, B-cells. Disturbances (leukemia). Different types of neoplasia (tumors, sarcoms, lymphoms). Statistical data. Sensitivity to chemotherapy. Different modes of chemotherapeutic treatment. Extracellular parasites (malaria, sleeping sickness, leishmaniasis). Review and classification of hereditary metabolic diseases. Prions.4.Cellular mitosis. Metaphase arresting agents. Inhibitors of cycline-dependent protein kinases. Olomoucin. Other protein kinases. Tubulin, its role, polymerisation and depolymerisation, role of GTP and GDP. Colchicine and vincristine binding site. Antitumor drugs based on the interference with cellular mitosis. Paclitaxel (Taxol).5.Structure and conformation of nucleosides. Principles of nucleoside synthesis. Principles of nucleoside and nucleotide modification. Purine base-modified nucleoside antimetabolites (cladribine). 8-Azaanalogs, 3-deazaanalogs.6.Activation of nucleoside antimetabolites. Phosphorylation. Nucleoside a nucleotide kinases. Nucleolytic enzymes, phosphomono- and diesterases, ribonucleases, nucleotidases, enzymatic synthesis of nucleotide and internucleotide bonds. Ecto-enzymes. Chemical methods of nucleotide synthesis and transformation.7.Glycinamide ribonucleotide transformylase. Drug combination, synergism and antagonism (FU, sorivudin). Dihydropyrimidine dehydrogenase. Dihydroorotate decarboxylase. Biosynthesis of pyrimidine nucleosides. 6-Azapyrimidines, 5-azapyrimidines.8.Dihydrofolate reductase. CDP reductase. Thymidylate synthase. Mechanisms of inhibition. Classical ad non-classical antifolates. Fluorinated bases, fluorinated sugars. FU, ftorafur, FUdR, fludarabine, gemcitabine.9.Drug stability. Main catabolic pathways of nucleic acids and their components. Phosphorylases and hydrolases. Uridine phosphorylase and inhibitors. Inhibitors of cytidine deaminase, adenosine deaminase, xanthine oxidase, etc.10.Purine nucleoside phosphorylase. General concept of immunodeficiency & immunosupression, opportunistic infections. Multiple drug resistence, principle & regulation. ATP pumps.11.Purine biosynthesis. IMP-dehydrogenase in somatic and transformed cells. Inhibitors of IMP-dehydrogenase, use in cancer chemotherapy. NDP-reductases in eucaryonts, enzymes of virus origin. Inhibitors of NDP reductase. Cell pool. NAD analogs.12.AICAR analogs. Virazol. EICAR. Arabinosides (cytarabine and its derivatives, sorivudine, vidarabine). C-Methylene derivatives. C-nucleosides and their synthesis. Nucleoside antibiotics (showdomycin). Carbocyclic nucleosides (cyclopentenylC, aristeromycin series).13.Cellular and viral DNA and RNA polymerases. Mechanism of transcription. Mitochondria toxicity.

Literatura

R. B. Silverman: The Organic Chemistry of Drug Design and Drug Action, Academic Press, 2nd edition.

Garant

prof. Dr. Erik De Clercq, Ph.D.