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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 metabolitesOften close structural similarities metabolite and antimetabolite
earlier ex. PABA / sulfonamides
H2NO
OH
PABA
H2N S
O
O
NHR
Antibact. sulfonamide
N
N NH
N
OH
H2N
NH
OH
O
Dehydropteridinsyre
N
N NH
N
OH
H2N
NH
NH
O
Dihydrofolic acid
CO2H
CO2H
N
N N
N
OH
H2N
NH
NH
O
Folic acid
CO2H
CO2H
From diet, humans
N
N NH
HN
OH
H2N
NH
NH
O
Tetrahydrofolic acide
CO2H
CO2H
Folate-reduktase
Essential processesbacteria and animalsex. Thymin synthesis(Metab. CH3OH)
Trimetoprim
N
N
NH2
H2N OCH3
OCH3
OCH3
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 BaseO
RO
POO
O
R=H in DNAR=OH in RNA
HN
N
O
O
Thymin
N
N
NH2
O
Cytosin Adenine
N
N N
N
NH2
Guanine
HN
N N
N
O
H2N
DNA
RNA HN
N
O
O
Uracil
Cytosin Adenine Guanine
5-Fluoruracil (5-FU)Fluorouracil®, Flurablastin®, HN
NH
O
O
Fin vivo
HN
N
O
O
F
O
HO
OP
O
OH
HO
InhibitorThymidylate synthetase
O
H2N OP
O
OHOH
Carbamoyl phosphate
+H2N CO2H
HO2C
Asp
HN
NH
O
O CO2H
Orotic acid
HN
N
O
O
O
HO
OP
O
OH
HO UMP
HN
NH
O
O
Uracil
More common route in cancer cells5-FU more easily activated in cancer cells (?)
HN
N
O
O
O
HO
OP
O
OH
HO
UMP
ThymidylateSynthetase
HS
NHN
NHN
N
O
NH2
R
Tetrahydrofolate
N5N10.Methylene Tetrahydrofolate
BH
HN
N
O
O
O
HO
OP
O
OH
HO
H
H
ThymidylateSynthetase
S B
NHN
NHN
NH
O
NH2
R
HN
N
O
O
O
HO
OP
O
OH
HO
H
ThymidylateSynthetase
S BH
NHN
NHN
NH
O
NH2
R
H
NHN
NHN
NH
O
NH2
R
HN
N
O
O
O
HO
OP
O
OH
HO
H
ThymidylateSynthetase
S BH
HN
N
O
O
O
HO
OP
O
OH
HO
TMP
Synth. thymine nucleotide from uracil nucleotide by thymidylate synthetase
HN
N
O
O
O
HO
OP
O
OH
HO
5-FU metabolite
ThymidylateSynthetase
HS
NHN
NHN
N
O
NH2
R
BH
HN
N
O
O
O
HO
OP
O
OH
HO
H
F
ThymidylateSynthetase
S B
NHN
NHN
NH
O
NH2
R
F
Enzyme inhibition
5-FU metabolism
Additional mechanisms: Incorp. DNA / RNA
HN
NH
O
O
F
Dihydropyrimidinedehydrogenase
HN
NH
O
O
F
H Inactive metabolite
HN
NH
O
O
Additive in some 5-FU preparates (Not in N)
HN
N
O
O
F
O
5-FU prodrug
+ HN
NH
O
O
Inhib. Dihydropyrimidinedehydrogenase
TegafurUFT®
N
N
HN
O
O
HO
F
O
O
Pro-drog 5-FU
KapecitabinXelodar®,
Cytarabine (ARA-C)Cytarabin®, Cytosar®,
N
N
NH2
O
O
HO
HO
OH
ARA-C
metabolic activation
N
N
NH2
O
O
HO
O
OH
ARA-C
PPP
Metabolic inactivation(fast)
HN
N
O
O
O
HO
HO
OH
N
N
NH2
O
O
HO
OP
OH
N
N
NH2
O
O
HO
OP
Inhib. DNA polymerase
Incorporation DNA/RNA; misreading
N
N
NH2
O
O
HO
HO
F
F
Metabolic activation (triphophate)Incorp. DNA / RNA
GemcitasbinGemzar®,
6-Mercaptopurine (6-MP)Puri-Nethol®
N
N
SH
NH
N HN
N
S
NH
N
S-Analog hypoxanthine
Metabolic activation HN
N
S
N
N
O
OHHO
OP
6-MPMPInhib. several steps in purine biosynth
N
N
S
N
N
O
OHHO
OP
Me
HN
N
S
N
N
O
OHHO
OPPP
Incorp . DNA / RNA instead og guanine
also antimetabolite
HN
N
S
NH
N
H2N
6-thioguanine (not drug in N)≈ 6-MP activity
N
N
S
NH
N
N
N
NO2
Me 6-MP pro-drugused before
O
OHHO
H
O
OP
P
O
OHHO
NH2
O
OP
P
HN
N N
N
O
OOP
OHHO
Inhib by 6-MP metabolite
HN
NH
N
N
O
OOP
OHHO
O
HN
N N
N
O
OOP
OHHO
H2N
N
N N
N
NH2
OOP
OHHO
H2N CO2H
NH2O
H2N CO2H
OHO
glutamine glutamate
N
N N
N
NH2
OHO
OH
HO
F
Antimetabolite
Not good substrate for adenosine deaminase
FludarabineFludara®
CladribinLeustatin®
N
N N
N
NH2
OHO
HO
ClNot really antimetaboliteInhib. repair enzymes
Potential Purine Antimetabolites
N
N N
N
OHO
HO
Activity various cancer cell lines Hocek et al. J. Med. Chem. 2000, 1817
OH
X
N
N N
N
OHO
HO
Activity Leukemia cellsInactive M. tub.
OH
O
Cl
Gundersen et al. J. Med. Chem. 2002, 1383
N
N N
N
O
Cl
Ph
Weak activity Leukemia cellsHIghly active M. tub.
N
N
Ph
N
N
R
R:, H, THP, Rib, Bn
More active than 6-MP and FluARALeukemia cellsBråthe et al. Bioorg. Med. Chem. Lett. 2003, 877
Folic Acid analogs as antimetabolites
MetotreksatMetoject®
RaltitrexedTomudex®
HN
N N
N
O
H2N
NH
O
NH
CO2H
CO2H
Folic acid
DHFR
HN
N NH
N
O
H2N
NH
R
Dihydrofolate
DHFR
HN
N NH
HN
O
H2N
NH
R
Tetrahydrofolate
PABA
Microorganisms
HN
N NH
N
O
H2N
N
R
Thymine synth
HN
N N
N
O
N
O
NH
CO2H
CO2H
S
N
N N
N
NH2
H2N
N
O
NH
CO2H
CO2H
Trimetoprim
N
N
NH2
H2N OCH3
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 verticilliusNaturally occuring as Cu-chelates
N N
H2N
NH
O
H2N
NH2
OH2N
O
N
O NH
NHN
NH
HN
HO
OOH
O
N S
NS
HN
O
R
Bleomycine A: R = S(CH3)3
Bleomycibe B:NH2
HN-CH2
NH2
O
O
OH
OH
HO
O
OH
OH
OH O
NH2
DNA binding
Interact heterocycl. bases
Electrostat. interact. with phosphates
N N
H2N
N
O
H2N
NH
OH2N
O
N
NHNFe
O2
1) Binds Fe(II) inside cells
2) Bleomycin complexed Fe(II) reduce O2
3) .OH radicals produced
4) Cleavage of DNA
BleomycinBleomycin Baxter®
Actinomycins
Isolated from Streptomyces sp.
Dactinomycin (Actinomycin D)Cosmegen®
O
N
O
HN O O
NH2
NH
O ONH
O
N O
N
O
O
N
O ONH
O
N O
N
O
O
N
Planar, aromatic ringsIntercalate between G-C base pairs(π−π stacking interact)
- 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
N N
CO2H
O
Parent comp.Nalidixic acid
Urinary tract infect. earliereffect on Gram-negative bacteria (ex. E. coli)
Moderne quinolones
N
O
CO2H
R
FR
R
R
F increase activity
Essentialt
Preferably HMust have aromatic ringcondenced with the pyridine
must be oxo
Chelater withCa2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N
O O
O
N
OO
O
Met2+
N
O OH
O
Intramolek.H-bond
pKa ca 5.5 - 6.5(Benzoic acid pKa 4.2)
Antracyclines
Isolated Streptomyces sp, several semisynth analogs
DoxorubicinDoxorubicin® Adriamycin® Caelyx®R1 = OMe, R2 = OH, R3 = H; R4 = OH
O
O
OH
OHO
OH
O
R2
R3
R4NH2
CH3
R1
DaunorubicinCerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH
IdarubicinZavedos® R1 = H, R2 = H, R3 = H; R4 = OH
EpirubicinFarmorubicin® R1 = OMe, R2 = OH, R3 = OH; R4 = H
O
O
OH
OHO
OH
O
OCOC4H9
HOHN
CH3
OCH3
COCF3
Valrubicin
O
O
HN
HNOH
OH
HN
OH
NH
OH
MitoxantroneNovantrone®
O
OH
NHR2
O
N
OHHOOOH
R6
H HR5
Antibacterial Tetracyclines
Mechanism ≈ Actinomycins (Intercalation)
Also interact aminosugar - phosphate
Antraquinone - red/ox react: prod. reactive oxygen radicals
DNA-Daunomycin Complex
MitomycinsIsolated Streptomyces sp,
O
O
N
H2N
H3C
OCH3
NH
OCONH2
red
OH
N
H2N
H3C
OCH3
NH
OCONH2
quinone Hydroquinone
OH
OH
N
H2N
H3C NH
OCONH2
HB
O
OH
N
H2N
H3C NH
OCONH2
H B
H
O
OH
N
H2N
H3CNH2
OCONH2
In vivo:
Active drug
DNANu
H
OH
OH
N
H2N
H3CNH2
O
DNANu
ONH2
Nu NuOH
OH
N
H2N
H3CNH2
DNANu
Nu
OH
OH
N
H2N
H3CNH2
DNANu
Nu
Mitomycin CMutamycin®
ConformycinsIsolated Streptomyces sp,
Ex. transition state analogs
N
N N
N
NH2
OHO
OHHO
Adenine
Adenosine deaminase
HN
N N
N
H2N
OHO
OHHO
OH
HN
N N
N
OHO
OHHO
O
Inosine
Also metab. of anticancer / antiviraladeninederiv.
N
NH
N
NBn
OBn
CF3
Geir AndresenCytotox.
N
N
OHO
RHO
R=OH: CoformycinR=H: DEoxycoformycin (Pentostatin)
HN
OH
sp3
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
Prophase Metaphase
Mitosis
Anaphase Telophase
Antimitotic agents bind to microtubuli
Supression of microtubuli dynamics
Metaphase arrest
Vinca alkaloids
Vinca alkaloids (Indols)from Vinca rosea(Catharantus roseus)MadagaskarPerivinkle
NH
N
HO
MeO2C
MeON
R
N
H OCOMe
CO2MeOH
R=-Me: Vinblastin, Velbe®R=-CHO: Vinkristin, Vincristine®
NH
N
MeO2C
MeON
CH3
N
H OCOMe
CO2MeOH
Vinorelbine, Navelbine®
Binds to microtubuli- Supression of microtubuli dynamics-Metaphase arrest
Depolymerization of microtubuli high conc.
Taxanes
First isolated from bark of Western / Pacific yew (Taxus brevifolia)NIH screening of plant extracts 1960s
Mecanism ≈ Vinca alkaloids, different binding sites
R1 = -Ph, R2 = -COMe: Palitaxel, Taxol®R1 = -OBut, R2 = -H: Dodetaxel, Taxotere® Semisynthetic
O
O
HO
OH
R2
OO
HO
O
O
HO
NH
OR1
O
O
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
O
HO
OH
R2
OO
HO
O
O
HO
NH
OR1
O
O
O
OH
HO
OH
OO
HO
HO
O
O
Deacetylbaccatine III
(-Total syntheses)
Colchicine
From Meadow-saffron, Colchicum autumnale (Tidløs) seedsBinds to microtubuli - metaphase arrest, too toxic too be used in cancer treatmentUsed to treat gout (podagra)
H3CO
CH3O
H3CO
O
OCH3
NH
O
Comming next? - Epothilones
Isolated from Myxobacteria (Epothilone A - F + synth. analogs)
O
OHO
N
S
OOH
O
Epothilone B
O
OHO
N
S
OH
O
Epothilone A
O
OHO
N
S
OOH
Epothilone C
O
OHO
N
S
OOH
Epothilone D
O
OHO
N
S
OH
O
Epothilone E
OH
O
OHO
N
S
OOH
O
Epothilone F
OH
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents √
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
•Hydroxyurea•Podophyllotoxines•Camptothecins•Compounds for photodynamic therapy•Tyrosine-Kinase Inhibitors
O
H2N NH
OH Hydroxykarbamid®
Inhib. ribonucleotide diphosphate reductaseArrest cells in G1-S interphase (combi with radiation)
PodophyllotoxinesFrom Podophyllum peltarumMay apple
Antiviral, veneric warts
Toxic - lead for anticancer drugs
O
OO
OHOMeMeO
O
Etoposide
O
O O
HO
HO
O
OO
OMe
OMeMeO
OH
O
Podophyllotoxin
EtoposideEposin® Etopofos® Vepesid®
Affects DNA topoisomerase II (not intercalating)DNA strand breakage
Camptothecins
First isolated Camptotheca acuminata (Chinese tree)NIH screeningLater found in several plants
N
N
O
O
OOH
Camptothecin, toxic, Lead comp.
N
N
O
O
OOH
HO
N
N
N
O
O
OOH
O
N O
N
TopotecanHycamtin®
IrinotecanCampto®
Semisynth. inhib. DNA topoisomerase II, DNA strand breakage
•Compounds for photodynamic therapy
MetylaminolevulinatMetvix® PhotoCure
O NH2
O
OIn vivo In vivo
Slow
Heme
Protoporphyrine IX (Pt IX)
N HN
NNH
HO2C CO2H
ROS Cell death
Pt IX
red light570-670 nm
Pt IX*
O2(triplet)
O2(singlet)
O2 OH
Tyrosine-Kinase Inhibitors
Enzyme coupled receptors - Catalytic receptors (Chapter 4)
Ligands: Peptide hormones
Growth Stimulation
1) Binding of Ligand2) Dimerisation of reseptor
-OH -OH -OHTyr kinasedomain(Janus kinase)
Phosphoryl of Tyr
O P O P
STATSprotein
O P O P STATSprotein 1) Phosphoryl. of STAT
2) Release of STAT in cytoplasma3) STATto cell nucleus4) Intitation of transcription
Growth
ImatinibGlivec®Leukemia types
GefitinibIressa® - Not in N.Lung cancerSide effect: Intestinal lung disease (may be fatal)
0.3 % US 2% Japan
HN
HN
N
N
N
O
N
N
O
N ON
N
HN
F
Cl
H3CO
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents √
•Micellaneous Antineoplastic Agents √
•Hormonal Therapy
Antiestrogens
HO
H
HH
O
Estrone
in vivo
HO
H
HH
Estradiol
OH
HO
H
HH
Estriol
OH
in vivo
(Low activity)
(fast metabolism)
OH
(low activity)
ON
TamoxifenNolvadex® Tamoxifen®
HO
OH
DiethylstilbestrolEstrogene agonist, used as drug before
HO
H
HH
OH
HO
OH
Overlap es tradio l
Estrogens and agonists
Breast cancer(estrogen depend.)
Aromatase Inhibitors
Estrogen depend. breast cancerInhib. estrogen biosynth.
HO
H
HH
Østron
O
HO
H
HH
Koles tero l
H
HH
O
O
Antrostendion
H
HHO
Testosteron
OH
HO
H
HH
Østradiol
OH
AromataseAromatase
17βHSD
17βHSD
HSD: Hydroksystereoid dehydrogenase
O
NADPH, O2
O
O OHH
- HCO2H
O
Htaut
HO
H
HH
O
O
ExemestanAromasin®
AnastrosolArimidex®
LetrozolFemar®
N
N
NNN
NNN
N
N
AndrogensH
HH
O
Testosterone
OH
5α-reduktaseH
HHO
5α-Dihydrotestosterone (5DHT)More active
OH
H
Anti-androgens
FlutamidEulexin® Flutamid®Prostate cancer
F3C
O2N
HN
O
BicalutamidCasodex®Prostate cancer (less tox.)
F3C
O2N
HN
O
HO O2S
F
FinasteridProscar®benign prostate
5α-Reductase Inhibitors
H
HHNH
O
ONH
5α-reduktaseNADPHN
R
R'H H
H
HHNH
HO
ONH
NR
R'
H
HHNH
O
ONHN
N
R
R'
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