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Anti-Cancer Compounds / Antineoplastic Agents, Chapter 38

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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 •Micellaneous Antineoplastic Agents •Hormonal Therapy Antimetabolites (Nucleoside Analogs, Folic acid analogs) Antimetabolites: Prevents synthesis of normal cellular metabolites Often close structural similarities metabolite and antimetabolite earlier ex. PABA / sulfonamides O OH NH N CO2H N N H H2N N N Antibact. sulfonamide CO2H O R O Folic acid H2N S NH OH OH O N N N O H From diet, humans H N 2 H2N N N OH H PABA Dehydropteridinsyre O O OH NH OH NH H Folate- N CO2H N CO2H N N reduktase N N H H H2N N N H2N N N H H CO2H CO2H Tetrahydrofolic acide Trimetoprim Dihydrofolic acid NH2 OCH N 3 Essential processes bacteria and animals H2N N OCH3 ex. Thymin synthesis OCH3 (Metab. CH3OH) 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 O NH2 NH2 O DNA HN N N N N HN O N O N N N N H2N N O O Thymin Cytosin Adenine Guanine P O O O Base O R=H in DNA R=OH in RNA RNA HN O R Cytosin Adenine Guanine O N Uracil O 5-Fluoruracil (5-FU) O F HN F Fluorouracil®, Flurablastin®, HN in vivo O O N Inhibitor O N HO P O Thymidylate synthetase H O OH HO O O HN O O HO2C HN O O N P + H2N O OH HO P O UMP OH H2N CO2H O N CO2H O H OH Carbamoyl phosphate Asp Orotic acid HO O HN More common route in cancer cells 5-FU more easily activated in cancer cells (?) O N H Uracil Synth. thymine nucleotide from uracil nucleotide by thymidylate synthetase Tetrahydrofolate NH2 HN O N NH2 HN O N NH O N O HN H N NH 5 10 HN N N .Methylene Tetrahydrofolate O O N H NH N HO P O B R O O N R O S OH HO P O O H Thymidylate B Synthetase OH HS HO Thymidylate HO Synthetase UMP NH2 HN O N N NH O O O H NH HN HN HN R O O N O O N H H O O N H B H HO P O HO P O S B O O HO P O S OH OH O OH Thymidylate Thymidylate Synthetase HO HO Synthetase NH2 HO HN O N TMP N NH NH R NH2 NH2 HN HN O N O N O O N NH F N NH HN HN N F O O N R O O N H NH B R HO P O H HO P O S O B O OH HS OH Thymidylate Kapecitabin Thymidylate Synthetase HO HO Xelodar®, Synthetase O 5-FU metabolite Enzyme inhibition HN O F Additional mechanisms: Incorp. DNA / RNA N O N O Pro-drog 5-FU HO 5-FU metabolism Tegafur O Dihydropyrimidine O UFT® dehydrogenase F F HN HN H Inactive metabolite O O O N O N F H HN H + HN O O N O N O H HN Additive in some 5-FU preparates (Not in N) Inhib. O N Dihydropyrimidine H 5-FU prodrug dehydrogenase Cytarabine (ARA-C) Cytarabin®, Cytosar®, NH2 NH2 NH2 NH2 N N N N O N O N O N metabolic activation O N P P P O P O O P O O HO O O OH OH HO OH HO HO HO ARA-C Metabolic ARA-C inactivation (fast) Inhib. DNA polymerase O Incorporation DNA/RNA; misreading HN O N HO O OH HO NH2 Gemcitasbin N Gemzar®, O N Metabolic activation (triphophate) Incorp. DNA / RNA HO O F HO F 6-Mercaptopurine (6-MP) Puri-Nethol® S-Analog hypoxanthine SH S S S Me Metabolic N N HN N activation HN N N N N N N N N N N N H H P O P O O O 6-MPMP Inhib. several steps HO OH in purine biosynth HO OH also antimetabolite S HN N N N P P P O O HO OH Incorp . DNA / RNA instead og guanine S N NO HN N 2 H N N N 2 H N S Me 6-MP pro-drug N 6-thioguanine (not drug in N) N used before ≈ 6-MP activity N N H O O O N HN N HN HN N P O H P O NH O O 2 N N O N N H N N N H 2 P O P O O P O P O O P O O HO OH HO OH OH HO HO OH HO OH O NH2 O OH H2N CO2H H2N CO2H NH2 glutamine glutamate N N Inhib by 6-MP metabolite N N P O O HO OH Fludarabine Cladribin Fludara® Leustatin® NH2 N N NH2 N F N N N Not really antimetabolite Cl N N Not good substrate for HO O Inhib. repair enzymes adenosine deaminase OH HO O Antimetabolite HO HO Folic Acid analogs as antimetabolites PABA Microorganisms O CO2H R R O O O N CO2H DHFR DHFR H H N N N HN N HN N HN N H H H H2N N N H2N N N H2N N N H H Folic acid Dihydrofolate Tetrahydrofolate R Metotreksat O N Metoject® N O CO2H HN NH2 N CO2H H N N N H 2 N H N N Thymine synth H2N N N O CO2H Trimetoprim Raltitrexed O S N CO2H NH2 N H Tomudex® OCH3 HN N N N N H2N N OCH3 OCH3 •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 Bleomycins Isolated from Streptomyces verticillius Naturally occuring as Cu-chelates 1) Binds Fe(II) inside cells H2N O H2N O O NH 2 O NH NH OH H N NH N O2 2 H N NH N OH 2 N N O Fe N HO N N N H2N O OH N H2N O O NH O OH O HO NH2 OH O 2) Bleomycin complexed Fe(II) reduce O2 O OH NH 3) .OH radicals produced Bleomycine A: R = S(CH3)3 HN O 4) Cleavage of DNA H N NH2 Bleomycibe B: -CH2 NH N S 2 N DNA binding O S Interact heterocycl. bases HN Electrostat. interact. with phosphates Bleomycin R Bleomycin Baxter® Actinomycins Isolated from Streptomyces sp. Dactinomycin (Actinomycin D) Cosmegen® O O N N N N O N O N O O NH O O Planar, aromatic rings NH O O Intercalate between G-C base pairs O O (π−π stacking interact) HN O O NH N NH2 O O - Affects DNA topoisomerase II (Unwinding) - May also promote DNA cleavage (nucleases) 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 Parent comp. Moderne quinolones Nalidixic acid must be oxo O CO H F increase activity 2 R O F CO H N N 2 R N Urinary tract infect. earlier R R Essentialt effect on Gram-negative bacteria (ex. E. coli) Preferably H Chelater with Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+ Must have aromatic ring condenced with the pyridine Intramolek. N H-bond O H O O O O O Met2+ N O O pKa ca 5.5 - 6.5 O (Benzoic acid pKa 4.2) N Antibacterial Tetracyclines Antracyclines OH OH O HO O O Isolated Streptomyces sp, several semisynth analogs NHR2 OH O OH O H H Doxorubicin N R2 R6 R5 OH Doxorubicin® Adriamycin® Caelyx® R1 = OMe, R2 = OH, R3 = H; R4 = OH R1 O OH O R3 CH3 Daunorubicin R4 NH2 Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH Epirubicin Idarubicin Farmorubicin® Zavedos® R1 = H, R2 = H, R3 = H; R4 = OH R1 = OMe, R2 = OH, R3 = OH; R4 = H Valrubicin Mitoxantrone O O OH Novantrone® OCOC4H9 OH H N OH O HN OH OCH3O OH O CH3 HO OH O HN OH N HN H COCF3 Mechanism ≈ Actinomycins (Intercalation) Also interact aminosugar - phosphate Antraquinone - red/ox react: prod. reactive oxygen radicals DNA-Daunomycin Complex Mitomycins Isolated Streptomyces sp, Mitomycin C Mutamycin® In vivo: H B O OCONH2 O OCONH2 OCONH2 OH OCONH2 H H2N H2N H2N H2N OCH3 red OCH3 B N NH N NH N NH H C N NH H3C H3C H3C 3 H O OH OH OH quinone Hydroquinone O H NH2 Nu OH Nu OH O O OCONH2 Nu H2N H2N H2N Nu DNA Nu DNA Nu DNA N N N H3C H3C H3C NH NH OH NH2 OH 2 OH 2 Active drug OH Nu H2N Nu DNA N H3C OH NH2 Conformycins Isolated Streptomyces sp, Also metab. of anticancer / antiviral adeninederiv. O NH2 H2N OH N N N N Adenosine HN HN N N deaminase N N N N HO HO HO O O O HO OH HO OH HO OH Adenine Inosine sp3 OH N HN N HO O HO R R=OH: Coformycin R=H: DEoxycoformycin (Pentostatin) Ex. transition state analogs •Chemotherapy •Alkylation Agents √ •Antimetabolites / Nucleoside Analogs √ •Antibiotics √ •Antimitotic Agents •Micellaneous Antineoplastic Agents •Hormonal Therapy Mitosis Prophase Metaphase Anaphase Telophase Antimitotic agents bind to microtubuli Supression of microtubuli dynamics Metaphase arrest HO N Vinca alkaloids N N N N N H H OCOMe H H OCOMe MeO2C CO2Me MeO2C CO Me N N 2 MeO OH MeO OH CH3 R Vinorelbine, Navelbine® R=-Me: Vinblastin, Velbe® Vinca alkaloids (Indols) R=-CHO: Vinkristin, Vincristine® from Vinca rosea (Catharantus roseus) Binds to microtubuli- Supression of microtubuli dynamics- MadagaskarPerivinkle Metaphase arrest Depolymerization of microtubuli high conc.
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