Download Anti-cancer compounds

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
NH
OH
N
N
H2N
N
CO2H
N
H
N
CO2H
Antibact. sulfonamide
O
R
S NH
O
H2N
H2N
H2N
OH
OH
OH
N
N
O
Folic acid
O
N
N
H
From diet, humans
N
H
Dehydropteridinsyre
PABA
O
O
OH
N
H2N
N
H
N
NH
N
H
N
H
CO2H
Tetrahydrofolic acide
Trimetoprim
OCH3
N
H2N
N
N
N
H
N
H
Dihydrofolic acid
NH2
Essential processes
bacteria and animals
ex. Thymin synthesis
(Metab. CH3OH)
N
N
H2N
CO2H
NH
OH
Folatereduktase
OCH3
OCH3
CO2H
CO2H
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
DNA
NH2
HN
O
N
N
Thymin
O
N
N
N
Cytosin
O
NH2
N
N
Adenine
N
HN
H2N
N
N
Guanine
O O
P
O
O
O
Base
O
RNA
HN
O
N
Uracil
Cytosin
Adenine
Guanine
O
R
R=H in DNA
R=OH in RNA
5-Fluoruracil (5-FU)
Fluorouracil®, Flurablastin®,
O
O
F
HN
O
F
HN
in vivo
N
H
O
N
O
HO P O
O
OH
Inhibitor
Thymidylate synthetase
HO
O
O
O
H2N
O
P
O
OH
OH
Carbamoyl phosphate
HO2C
+
H2N
HN
HN
CO2H
Asp
O
N
H
CO2H
O
N
O
HO P O
O
OH
UMP
Orotic acid
HO
O
More common route in cancer cells
5-FU more easily activated in cancer cells (?)
HN
O
N
H
Uracil
Synth. thymine nucleotide from uracil nucleotide by thymidylate synthetase
Tetrahydrofolate
NH2
HN
O
NH2
HN
O
O
HN
N
HN
NH
N5N10.Methylene Tetrahydrofolate
O
HO P O
OH
N
O
N
O
HO P O
O
OH
R
HS
N
N
O
B
O
N
O
N
H
H
B
S
NH
NH
R
Thymidylate
Synthetase
H
HO
Thymidylate
Synthetase
HO
UMP
NH2
HN
O
N
N
O
HN
O
N
O
HO P O
O
OH
HO
O
O
HN
O
N
O
HO P O
O
OH
HO
HN
H
S
B
O
HO P O
OH
H
Thymidylate
Synthetase
NH2
HN
TMP
H
O
N
N
NH
NH
R
O
N
O
HO
H
S
B
H
Thymidylate
Synthetase
NH
NH
R
NH2
NH2
HN
HN
O
O
O
N
O
F
N
HN
NH
HN
N
O
HO P O
OH
O
R
N
O
B
HS
O
HO P O
OH
H
Thymidylate
Synthetase
HO
O
N
O
HO
N
N
F
H
S
B
NH
NH
R
Kapecitabin
Xelodar®,
Thymidylate
Synthetase
O
5-FU metabolite
Enzyme inhibition
HN
Additional mechanisms: Incorp. DNA / RNA
N
O
O
F
N
O
Pro-drog 5-FU
HO
5-FU metabolism
O
F
HN
O
Dihydropyrimidine
dehydrogenase
O
F
H
HN
O
N
H
Tegafur
UFT®
N
H
O
F
HN
O
O
+ HN
N
O
Additive in some 5-FU preparates (Not in N)
HN
O
O
Inactive metabolite
N
H
5-FU prodrug
O
N
H
Inhib.
Dihydropyrimidine
dehydrogenase
Cytarabine (ARA-C)
Cytarabin®, Cytosar®,
HO
O
metabolic activation
N
P P P O
O
NH2
N
N
N
O
NH2
NH2
NH2
O
N
P O
O
N
N
O
P O
O
O
OH
OH
HO
HO
HO
ARA-C
OH
HO
ARA-C
Metabolic
inactivation
(fast)
Inhib. DNA polymerase
Incorporation DNA/RNA; misreading
O
HN
O
HO
N
O
OH
HO
NH2
Gemcitasbin
Gemzar®,
N
O
HO
N
O
F
HO
F
N
Metabolic activation (triphophate)
Incorp. DNA / RNA
6-Mercaptopurine (6-MP)
Puri-Nethol®
S-Analog hypoxanthine
SH
S
N
N
N
N
HN
N
H
N
Metabolic
activation
S Me
S
N
HN
N
H
N
N
P O
N
N
P O
O
6-MPMP
Inhib. several steps
OH in purine biosynth
HO
N
N
O
HO
OH
also antimetabolite
S
N
HN
N
N
P P P O
O
HO
OH
Incorp . DNA / RNA instead og guanine
S
N
HN
H2N
N
N
H
6-thioguanine (not drug in N)
- 6-MP activity
NO2
N
N
Me
S
N
N
N
N
H
6-MP pro-drug
used before
O
O
N
HN
P O
O
H
P O
NH2
O
O P
HO
O P
OH
O
H2N
HO
glutamine
O
H2N
O
P O
O
N
N
H
N
HN
H2N
P O
O
N
N
O
OH
OH
HO
NH2
CO2H
P O
N
HN
N
N
O
HO
OH
OH
HO
NH2
CO2H
glutamate
N
N
P O
O
HO
Fludarabine
Fludara®
Inhib by 6-MP metabolite
N
N
OH
Cladribin
Leustatin®
NH2
N
N
F
OH
Cl
O
OH
HO
N
N
N
N
Not good substrate for HO
adenosine deaminase
NH2
N
N
HO
O
Antimetabolite
HO
Not
really antimetabolite
Inhib. repair enzymes
Potential Purine Antimetabolites
Activity Leukemia cells
Inactive M. tub.
X
Weak activity Leukemia cells
HIghly active M. tub.
O
O
N
N
N
N
HO
Activity various cancer cell lines
Hocek et al. J. Med. Chem. 2000, 1817
O
HO
N
N
Cl
Cl
HO
O
N
N
N
N
N
N
Ph
OH
HO
OH
Gundersen et al. J. Med. Chem. 2002, 1383
Ph
N
N
N
N
R
R:, H, THP, Rib, Bn
More active than 6-MP and FluARA
Leukemia cells
Bråthe et al. Bioorg. Med. Chem. Lett. 2003, 877
Folic Acid analogs as antimetabolites
PABA
Microorganisms
O
O
H2N
N
H
N
HN
N
CO2H
CO2H
N
H2N
Folic acid
N
O
DHFR
N
HN
N
H
R
O
DHFR
N
H
HN
N
H
H2N
Dihydrofolate
N
R
H
N
N
H
N
H
Tetrahydrofolate
R
Metotreksat
Metoject®
O
NH2
N
N
H2N
N
CO2H
N
H
N
HN
CO2H
H2N
N
N
H
N
Thymine synth
N
O
Raltitrexed
Tomudex®
N
O
O
S
N
HN
N
N
CO2H
N
H
Trimetoprim
CO2H
NH2
N
OCH3
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
O
H2N
NH2
H2N
NH
N
N
O
OH
NH
N
H2N
O
O
NH
O
OH
2) Bleomycin complexed Fe(II) reduce O2
.
3) OH radicals produced
4) Cleavage of DNA
NH
HN
O
Bleomycine A: R = S(CH3)3
H
N
-CH
Bleomycibe B:
2
N
O
N
N
O
OH O
O
OH
NH
N
N
H2N
NH2
HO
O2
Fe
N
OH
NH
N
H2N
OH
O
HO
O
N
O
NH2
NH2
S
DNA binding
S
Interact heterocycl. bases
HN
Electrostat. interact. with phosphates
R
Bleomycin
Bleomycin Baxter®
Actinomycins
Isolated from Streptomyces sp.
Dactinomycin (Actinomycin D)
Cosmegen®
O
O
N
N
N
O
NH
O
N
N
O
O
O
NH
O
O
O
HN
O
O
N
O
O
Planar, aromatic rings
Intercalate between G-C base pairs
( stacking interact)
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.
Nalidixic acid
Moderne quinolones
must be oxo
O
F increase activity
CO2H
N
R
O
F
N
CO2H
R
Urinary tract infect. earlier
effect on Gram-negative bacteria (ex. E. coli)
R
N
R
Essentialt
Preferably H
Must have aromatic ring
condenced with the pyridine
Intramolek.
H-bond
O
H
Chelater with
Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N
O
O
O
O
N
pKa ca 5.5 - 6.5
(Benzoic acid pKa 4.2)
O
Met2+
O
O
O
N
Antibacterial Tetracyclines
Antracyclines
OH O HO
OH
O
Isolated Streptomyces sp, several semisynth analogs
O
O
OH
OH
R1
O
NHR2
Doxorubicin
Doxorubicin® Adriamycin® Caelyx®
R1 = OMe, R2 = OH, R3 = H; R4 = OH
R2
OH
H
R6
H
R5
O
R3
R4
Daunorubicin
Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH
CH3
NH2
Idarubicin
Zavedos® R1 = H, R2 = H, R3 = H; R4 = OH
Valrubicin
O
O
OH
OCOC4H9
Epirubicin
Farmorubicin®
R1 = OMe, R2 = OH, R3 = OH; R4 = H
Mitoxantrone
Novantrone®
OH
OCH3O
OH
OH
O
HN
OH
O
HN
H
N
OH
O
CH3
HO
HN
COCF3
O
N
H
OH
OH
N
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:
B
OCONH2
H
OCH3
N
H3C
OCONH2
OCONH2
O
H2N
red
NH
H2N
H2N
OCH3
N
H3C
NH
N
H3C
quinone
NH
O
B
H2N
N
H3C
NH
H
OH
OH
OH
O
OCONH2
H
OH
Hydroquinone
O
NH2
Nu
OH
O
OH
H2N
H2N
Nu
N
H3C
N
H3C
NH2
OH
Nu
DNA
OH
H
Nu
N
OH
Active drug
Nu
OH
H2N
Nu
N
H3C
OH
NH2
DNA
Nu
Nu
DNA
H3C
NH2
OCONH2
O
H2N
NH2
DNA
Conformycins
Isolated Streptomyces sp,
NH2
N
N
HO
N
HN
Adenosine
deaminase
HO
N
N
HO
O
HO
OH
N
HN
N
N
O
HO
O
H2N OH
N
N
Also metab. of anticancer / antiviral
adeninederiv.
OH
O
HO
OH
Inosine
Adenine
sp3
OH
N
HN
N
HO
O
CF3
HO
R
R=OH: Coformycin
R=H: DEoxycoformycin (Pentostatin)
Ex. transition state analogs
N
Bn N
O
N
H
N
Bn
Geir Andresen
Cytotox.
•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
Vinca alkaloids
N
N
N
N
N
H
N
H
H
MeO2C
MeO
N
R
OCOMe
CO2Me
H
MeO2C
MeO
OH
N
OH
CH3
OCOMe
CO2Me
Vinorelbine, Navelbine®
Vinca alkaloids (Indols)
from Vinca rosea
(Catharantus roseus)
MadagaskarPerivinkle
R=-Me: Vinblastin, Velbe®
R=-CHO: Vinkristin, Vincristine®
Binds to microtubuli- Supression of microtubuli dynamicsMetaphase arrest
Depolymerization of microtubuli high conc.
Taxanes
First isolated from bark of Western / Pacific yew (Taxus brevifolia)
NIH screening of plant extracts 1960s
O
R1
R2
NH
O
HO
O
O
OH
O
HO
O
H
O O
O
O
R1 = -Ph, R2 = -COMe: Palitaxel, Taxol®
R1 = -OBut, 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
R1
OH
O
OH
HO
HO
HO
O
R2
NH
O
O
O
OH
O
H
O O
HO
O
O
O
H
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? - Epothilones
Isolated from Myxobacteria (Epothilone A - F + synth. analogs)
S
S
S
O
O
N
N
N
O
OH
O
O
N
O
OH
O
O
OH
Epothilone E
O
OH
OH
O
O
Epothilone F
O
Epothilone C
S
N
OH
O
OH
OH
O
O
OH
OH
OH
O
O
Epothilone B
S
O
O
OH
OH
N
OH
O
Epothilone A
S
Epothilone D
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents √
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
•Hydroxyurea
H N
•Podophyllotoxines
•Camptothecins
•Compounds for
photodynamic therapy
•Tyrosine-Kinase Inhibitors
2
O
N
H
OH
Hydroxykarbamid®
Inhib. ribonucleotide diphosphate reductase
Arrest cells in G1-S interphase
(combi with radiation)
Podophyllotoxines
From Podophyllum peltarum
May apple
Antiviral, veneric warts
OH
O
Toxic - lead for anticancer drugs
O
O
O
MeO
OMe
OMe
Podophyllotoxin
OO
HO
HO
O
O
O
Etoposide
Eposin® Etopofos®
Vepesid®
O
O
MeO
OMe
OH
Etoposide
Affects DNA topoisomerase II (not intercalating)
DNA strand breakage
Camptothecins
First isolated Camptotheca acuminata (Chinese tree)
NIH screening
Later found in several plants
O
N
N
O
OH O
Camptothecin,
toxic, Lead comp.
Topotecan
Hycamtin®
Irinotecan
Campto®
N
N
HO
N
O
N
O
O
O
N
N
O
OH O
N
O
OH O
Semisynth. inhib. DNA topoisomerase II, DNA strand breakage
•Compounds for photodynamic therapy
Metylaminolevulinat
Metvix® PhotoCure
O
O
NH2
NH
In vivo
In vivo
N
Heme
O
HN
N
Slow
CO2H
HO2C
Protoporphyrine IX (Pt IX)
Pt IX
red light
570-670 nm
O2
(singlet)
O2
Pt IX*
O2
(triplet)
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
Tyr kinase
-OH
domain
(Janus kinase)
Phosphoryl of Tyr
-OH
-OH
STATS
protein
O P
O P
O P
O P
STATS
protein
1) Phosphoryl. of STAT
2) Release of STAT in cytoplasma
3) STATto cell nucleus
4) Intitation of transcription
Growth
Imatinib
Glivec®
Leukemia types
N
N
H
N
N
O
H
N
N
N
Gefitinib
Iressa® - Not in N.
Lung cancer
Side effect: Intestinal lung disease (may be fatal)
0.3 % US
2% Japan
H3CO
N
O
N
N
O
HN
F
Cl
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents √
•Micellaneous Antineoplastic Agents √
•Hormonal Therapy
Estrogens and agonists
OH
O
H
H
OH
H
in vivo
H
H
H
H
in vivo
H
HO
HO
OH
H
HO
Estradiol
Estrone
(Low activity)
OH
Estriol
(low activity)
(fast metabolism)
OH
H
OH
H
HO
HO
H
Overlap estradiol
HO
Diethylstilbestrol
Estrogene agonist, used as drug before
Antiestrogens
Tamoxifen
Nolvadex® Tamoxifen®
Breast cancer
(estrogen depend.)
N
O
Aromatase Inhibitors
Estrogen depend. breast cancer
Inhib. estrogen biosynth.
O
H
17HSD
H
H
H
H
OH
H
H
O
HO
H
Testosteron
Aromatase
O
- HCO2H
taut
H
H
OH
O
17HSD
H
H
H
H
O
HO
H
HO
HO
Østradiol
Østron
Letrozol
Femar®
Anastrosol
Arimidex®
N
N
O
N
N
H
H
O
N
N
H
O
O
Aromatase
HSD:
Hydroksystereoid dehydrogenase
Exemestan
Aromasin®
H
NADPH, O2
O
Antrostendion
Kolesterol
H
N
N
N
N
OH
Androgens
OH
OH
H
H
H
5-reduktase
H
H
O
O
H
H
5-Dihydrotestosterone (5DHT)
More active
Testosterone
Anti-androgens
Flutamid
Eulexin® Flutamid®
Prostate cancer
Bicalutamid
Casodex®
Prostate cancer (less tox.)
H
N
F3C
O
O2N
H HO
N
F3 C
O2
S
O
O2N
F
5-Reductase Inhibitors
R
N
5-reduktase
NADPH
R
N
R'
H
H
R'
O
NH
NH
Finasterid
Proscar®
benign prostate
H
H
H
O
N
H
H
R
N
O
H
HO
N
H
O
NH
H
R'
H
N
O
H
N
H
H