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Anti-cancer compounds / Antineoplastic Agents, chapter 38

Anti-cancer compounds / Antineoplastic Agents, chapter 38. Cancer Therapy Surgery Radiation Immunologican Therapy ( interferons - Incr. prod. T-cells and B cells) Chemotherapy Alkylation Agents Antimetabolites / Nucleoside Analogs Antibiotics Antimitotic Agents

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Anti-cancer compounds / Antineoplastic Agents, chapter 38

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  1. Anti-cancer compounds / Antineoplastic Agents, chapter 38 • Cancer Therapy • Surgery • Radiation • Immunologican Therapy (interferons - Incr. prod. T-cells and B cells) • Chemotherapy • Alkylation Agents • Antimetabolites / Nucleoside Analogs • Antibiotics • Antimitotic Agents • Micellaneous Antineoplastic Agents • Hormonal Therapy

  2. Antimetabolites (Nucleoside Analogs, Folic acid analogs) Antimetabolites:Prevents synthesis of normal cellular metabolites Often close structural similarities metabolite and antimetabolite earlier ex. PABA / sulfonamides

  3. Nucleoside analogs as antimetabolites • Possible mecanisms: • Incorporation DNA or RNA; misreading • Inhibition of DNA polymerase • Inhibition of Kinases • Inhib. of enzymes involved in pyrimidine / purine biosynthesis

  4. 5-Fluoruracil (5-FU) Fluorouracil®, Flurablastin®,

  5. Synth. thymine nucleotide from uracil nucleotide by thymidylate synthetase

  6. Kapecitabin Xelodar®, Additional mechanisms: Incorp. DNA / RNA 5-FU metabolism Tegafur UFT®

  7. Cytarabine (ARA-C) Cytarabin®, Cytosar®, Gemcitasbin Gemzar®,

  8. 6-Mercaptopurine (6-MP) Puri-Nethol®

  9. Fludarabine Fludara® Cladribin Leustatin®

  10. Potential Purine Antimetabolites

  11. Folic Acid analogs as antimetabolites Metotreksat Metoject® Raltitrexed Tomudex®

  12. Chemotherapy • Alkylation Agents √ • Antimetabolites / Nucleoside Analogs √ • Antibiotics • Antimitotic Agents • Micellaneous Antineoplastic Agents • Hormonal Therapy Metabolites from microorg., too toxic as antibiotics - anticancer comp. • Bleomycins • Actinomycins • Mitomycins • Antracyclins • Coformycins

  13. Bleomycins Isolated from Streptomyces verticillius Naturally occuring as Cu-chelates 1) Binds Fe(II) inside cells 2) Bleomycin complexed Fe(II) reduce O2 3) .OH radicals produced 4) Cleavage of DNA Bleomycin Bleomycin Baxter®

  14. Actinomycins Isolated from Streptomyces sp. Dactinomycin (Actinomycin D) Cosmegen®

  15. Quinolones Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic.. DNA-topoisomerase (humans), anticancer compds. ex. doxorubicin Unique mecanism, no cross resistance Broad spectrum: G+ and G- ; also mycobactria, clamydia

  16. Antracyclines Isolated Streptomyces sp, several semisynth analogs Doxorubicin Doxorubicin® Adriamycin® Caelyx® R1 = OMe, R2 = OH, R3 = H; R4 = OH Daunorubicin Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH Epirubicin Farmorubicin® R1 = OMe, R2 = OH, R3 = OH; R4 = H Idarubicin Zavedos® R1 = H, R2 = H, R3 = H; R4 = OH Valrubicin Mitoxantrone Novantrone®

  17. Mechanism ≈ Actinomycins (Intercalation) Also interact aminosugar - phosphate Antraquinone - red/ox react: prod. reactive oxygen radicals DNA-Daunomycin Complex

  18. Mitomycins Isolated Streptomyces sp, Mitomycin C Mutamycin®

  19. Conformycins Isolated Streptomyces sp, Also metab. of anticancer / antiviral adeninederiv. Geir Andresen Cytotox. Ex. transition state analogs

  20. Chemotherapy • Alkylation Agents √ • Antimetabolites / Nucleoside Analogs √ • Antibiotics √ • Antimitotic Agents • Micellaneous Antineoplastic Agents • Hormonal Therapy

  21. Mitosis Prophase Metaphase Anaphase Telophase Antimitotic agents bind to microtubuli Supression of microtubuli dynamics Metaphase arrest

  22. Vinca alkaloids Vinca alkaloids (Indols) from Vinca rosea (Catharantus roseus) MadagaskarPerivinkle Binds to microtubuli- Supression of microtubuli dynamics- Metaphase arrest Depolymerization of microtubuli high conc.

  23. Taxanes First isolated from bark of Western / Pacific yew (Taxus brevifolia) NIH screening of plant extracts 1960s Mecanism ≈ Vinca alkaloids, different binding sites

  24. Palitaxel

  25. Availability Dried inner bark of Western / Pacific yew (Taxus brevifolia): 0.01 - 0.04% 1 kg Taxol - 900 kg bark (2000 - 3000 trees) -Other Taxus sp: Also palitaxel in needles (renewable source) -Semisynth from deacetylbaccatin III (0.1% in needles Taxus baccata) (-Total syntheses)

  26. Colchicine From Meadow-saffron, Colchicum autumnale (Tidløs) seeds Binds to microtubuli - metaphase arrest, too toxic too be used in cancer treatment Used to treat gout (podagra)

  27. Comming next? - Epothilones Isolated from Myxobacteria (Epothilone A - F + synth. analogs)

  28. Chemotherapy • Alkylation Agents √ • Antimetabolites / Nucleoside Analogs √ • Antibiotics √ • Antimitotic Agents √ • Micellaneous Antineoplastic Agents • Hormonal Therapy • Hydroxyurea • Podophyllotoxines • Camptothecins • Compounds for • photodynamic therapy • Tyrosine-Kinase Inhibitors Hydroxykarbamid® Inhib. ribonucleotide diphosphate reductase Arrest cells in G1-S interphase (combi with radiation)

  29. Podophyllotoxines From Podophyllum peltarum May apple Antiviral, veneric warts Toxic - lead for anticancer drugs Etoposide Eposin® Etopofos® Vepesid® Affects DNA topoisomerase II (not intercalating) DNA strand breakage

  30. Camptothecins First isolated Camptotheca acuminata (Chinese tree) NIH screening Later found in several plants Topotecan Hycamtin® Irinotecan Campto® Semisynth. inhib. DNA topoisomerase II, DNA strand breakage

  31. Compounds for photodynamic therapy Metylaminolevulinat Metvix® PhotoCure

  32. Tyrosine-Kinase Inhibitors

  33. Enzyme coupled receptors - Catalytic receptors (Chapter 4) Ligands: Peptide hormones

  34. Imatinib Glivec® Leukemia types Gefitinib Iressa® - Not in N. Lung cancer Side effect: Intestinal lung disease (may be fatal) 0.3 % US 2% Japan

  35. Chemotherapy • Alkylation Agents √ • Antimetabolites / Nucleoside Analogs √ • Antibiotics √ • Antimitotic Agents √ • Micellaneous Antineoplastic Agents √ • Hormonal Therapy

  36. Estrogens and agonists Antiestrogens Breast cancer (estrogen depend.) Tamoxifen Nolvadex® Tamoxifen®

  37. Aromatase Inhibitors Estrogen depend. breast cancer Inhib. estrogen biosynth. Letrozol Femar® Exemestan Aromasin® Anastrosol Arimidex®

  38. Androgens Anti-androgens Flutamid Eulexin® Flutamid® Prostate cancer Bicalutamid Casodex® Prostate cancer (less tox.) 5a-Reductase Inhibitors Finasterid Proscar® benign prostate

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