Anti- compounds / Antineoplastic Agents, chapter 38

Cancer Therapy •Surgery •Radiation •Immunologican Therapy (interferons - Incr. prod. T-cells and B cells) • •Alkylation Agents • / Analogs • •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

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 - N CO2H N CO2H N N reduktase N N H H

H2N N N H2N N N H H CO2H CO2H Tetrahydrofolic acide Trimetoprim

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 involved in / 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 ®, 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 Asp Orotic acid HO

O

HN More common route in cancer cells 5-FU more easily activated in cancer cells (?) O N H Synth. 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 inhibition HN O F Additional mechanisms: Incorp. DNA / RNA N O N O Pro-drog 5-FU

HO 5-FU

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 dehydrogenase (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- (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- 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 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.

• •Actinomycins • •Antracyclins •Coformycins Bleomycins

Isolated from 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) 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 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. 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 R4 NH2 Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH

Epirubicin Farmorubicin® Zavedos® R1 = H, R2 = H, R3 = H; R4 = OH R1 = OMe, R2 = OH, R3 = OH; R4 = H

Valrubicin 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 ()

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 , Navelbine® R=-Me: Vinblastin, Velbe® Vinca alkaloids (Indols) R=-CHO: Vinkristin, ® from Vinca rosea (Catharantus roseus) Binds to microtubuli- Supression of microtubuli dynamics- MadagaskarPerivinkle Metaphase arrest

Depolymerization of microtubuli high conc.

First isolated from bark of Western / Pacific yew (Taxus brevifolia) NIH screening of plant extracts 1960s

O R1 R NH 2 O O O OH HO O

HO H O O O O O

R1 = -Ph, R2 = -COMe: Palitaxel, Taxol® t R1 = -OBu , R2 = -H: Dodetaxel, Taxotere® Semisynthetic

Mecanism ≈ Vinca alkaloids, different binding sites Palitaxel 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)

O R OH 1 R2 O NH O O OH O HO OH HO O HO H O O O O HO H O O O O O O

Deacetylbaccatine III

(-Total syntheses) 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) O H3CO NH

H3CO CH3O O

OCH3 Comming next? -

Isolated from Myxobacteria ( A - F + synth. analogs)

S S S S N N N N

O O O OH O OH OH OH O O O O O O

O O OH OH O OH OH Epothilone A Epothilone B Epothilone C Epothilone D

OH OH S S N N

O OH O OH O O O O

OH OH O Epothilone E Epothilone F •Chemotherapy •Alkylation Agents √ •Antimetabolites / Nucleoside Analogs √ •Antibiotics √ •Antimitotic Agents √ •Micellaneous Antineoplastic Agents •Hormonal Therapy

O •Hydroxyurea OH Hydroxykarbamid® H2N N •Podophyllotoxines H • Inhib. ribonucleotide diphosphate reductase •Compounds for Arrest cells in G1-S interphase (combi with radiation) •Tyrosine-Kinase Inhibitors Podophyllotoxines From Podophyllum peltarum May apple

OH Antiviral, veneric warts O O Toxic - lead for anticancer O O

MeO OMe OMe Podophyllotoxin

OO HO HO O Eposin® Etopofos® O Vepesid® O O O Affects DNA topoisomerase II (not intercalating) MeO OMe OH DNA strand breakage Etoposide Camptothecins

First isolated Camptotheca acuminata (Chinese tree) NIH screening O Later found in several plants N N O

OH O

Camptothecin, toxic, Lead comp.

Topotecan Hycamtin® Campto®

N N N O HO O N O O N N O N O OH O OH O

Semisynth. inhib. DNA topoisomerase II, DNA strand breakage •Compounds for photodynamic therapy Metylaminolevulinat Metvix® PhotoCure

O In vivo NH N In vivo O NH 2 Heme O HN N Slow

HO2C CO2H

Protoporphyrine IX (Pt IX)

red light 570-670 nm Pt IX Pt IX*

O 2 O2 (singlet) (triplet)

O2 OH

ROS Cell death

Tyrosine-Kinase Inhibitors Enzyme coupled receptors - Catalytic receptors (Chapter 4)

Ligands: Peptide hormones

Growth Stimulation

1) Binding of Ligand 2) Dimerisation of reseptor Phosphoryl of Tyr

Tyr kinase -OH -OH -OH domain (Janus kinase)

STATS protein

O P O P STATS O P O P protein 1) Phosphoryl. of STAT 2) Release of STAT in cytoplasma 3) STATto cell nucleus 4) Intitation of transcription

Growth Imatinib Glivec® types

N N H H N N N N

O N

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

H3CO N N N O O HN

F Cl •Chemotherapy •Alkylation Agents √ •Antimetabolites / Nucleoside Analogs √ •Antibiotics √ •Antimitotic Agents √ •Micellaneous Antineoplastic Agents √ •Hormonal Therapy Estrogens and agonists O OH OH

H in vivo H H OH in vivo H H H H H H HO HO HO Estrone Estradiol Estriol (Low activity) (low activity)

OH (fast metabolism) OH H OH H H HO HO Overlap estradiol Diethylstilbestrol Estrogene agonist, used as drug before

Antiestrogens Breast cancer Tamoxifen (estrogen depend.) Nolvadex® Tamoxifen® N O Aromatase Inhibitors

Estrogen depend. breast cancer Inhib. estrogen biosynth.

O OH

H H 17βHSD H O H H H H H H H OH HO O O NADPH, O2 Kolesterol Antrostendion Testosteron O O

Aromatase Aromatase - HCO2H taut HSD: O OH H Hydroksystereoid dehydrogenase H 17βHSD H HO O H H H H HO HO Østron Østradiol

Exemestan Anastrosol Letrozol Aromasin® Arimidex® Femar® N N N N O N H N H H N N O N N Androgens OH OH

H H 5α-reduktase H H H H O O H Testosterone 5α-Dihydrotestosterone (5DHT) More active

Anti-androgens

Flutamid Bicalutamid H HHO O2 Eulexin® Flutamid® F3C N Casodex® F3C N S Prostate cancer O Prostate cancer (less tox.) O O2N O2N F

5α-Reductase Inhibitors R 5α-reduktase N NADPH R N R' H H R' O R O O NH N NH Finasterid NH H R' H Proscar® H N H H H H benign prostate H H HO N O N O N H H H