hong ren michigan state university 09.03
TRANSCRIPT
Platinum-based Cytotoxic Chemotherapy
Platinum-based Targeted Chemotherapy
Ruthenium-based Targeted Chemotherapy
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Chemotherapy: Cytotoxic vs Targeted
Cytotoxic Therapy - “Cluster Bomb”
Targets general features of cells (DNA).
Associated with side effects.
Targeted Therapy - “Smart Bomb”
Targets specific features of cancer cells.
Less side effects.
US National Cancer Institute: www.cancer.org
Platinum-based Cytotoxic Chemotharepy
Drugs Approved by FDA
Drugs in Pending Approval / Clinical Trial
Drugs in Development
Platinum-based Targeted Chemotharepy
Ruthenium-based Targeted Chemotherapy
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Platinum-based Cytotoxic Chemotherapy
Drugs Approved by FDA
Cisplatin
Carboplatin
Oxaliplatin
Drugs in Pending Approval / Clinical Trial
Drugs in Development
Platinum-based Targeted Chemotharepy Ruthenium-based Targeted Chemotherapy The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Cisplatin: A Chance Discovery to a Drug
1845 Peyrone’s chloride
1893 Structure deduced by Werner
1968 Anti-cancer activity observed by Rosenberg in MSU
1971 The first patient treated
1978 Approved by FDA
2008 Still in use
PtCl
Cl
H3N
H3N
Cisplatin
Timeline for Cisplatin
Cisplatin
Each mL contains • Cisplatin 1 mg • Sodium Chloride 9 mg • Water for Injection
50 mg/50 mL $18.50
Brand Name: Platinol-AQ
• Metastatic Testicular Tumors • Metastatic Ovarian Tumors • Advanced Bladder Cancer
Cisplatin could be used to treat:
PtCl
Cl
H3N
H3N
Cisplatin
Marketed by Bristol-Myers Squibb
www.bms.com/products/data/index.html www.bedfordlabs.com/products/ViewProductDetails?productID=47&item=3 US National Cancer Institute: www.cancer.org
Mechanism of Action of Cisplatin
Activated Cisplatin
Cisplatin hydrolysis regulated by chloride concentration:
[Cl-Blood] = 100 mM [Cl-Cell] = 3 mM
DNA
Hartinger, C. G.; Zorbas-Seifried, S.; Keppler, B. K. J. Inorg. Biochem. 2006, 100, 891.
PtCl
Cl
H3N
H3N
Cisplatin
PtOH2
Cl
H3N
H3N
H2O Cl
-H
PtOH
Cl
H3N
H3N
H2O
Cl
PtOH2
OH2
H3N
H3N
2
H2O
Cl
PtOH
OH2
H3N
H3N
-H
PtOH
OH
H3N
H3N
N
NN
N
N
N
N
O
O
H H
H
DNA
DNA
N
N
N
O
N
NN
N
O
N
H
H
H
H
H
DNA
DNA
Adenine Thymine
Guanine Cytosine
Lippard, S. J. et al. Nature, 1999, 399, 708 -712.
Crystal Structure of Cisplatin & DNA Intrastrand Adduct
Carboplatin: Overcome Toxicity Pt
OH3N
OH3N
O
O
Carboplatin
450 mg/45 mL $90.00
Brand Name: Paraplatin
• Ovarian cancer that recurred after earlier chemotherapy
Carboplatin could be used to treat:
Each mL Contains • Carboplatin 10 mg • Water for Injection.
Approved by FDA in 2004
Marketed by Bristol-Myers Squibb
www.bms.com/products/data/index.html www.bedfordlabs.com/products/ViewProductDetails?productID=47&item=3 US National Cancer Institute: www.cancer.org
Oxaliplatin PtO
H2N
ONH2
O
O
Oxaliplatin
50 mg/10 mL $510
Brand Name: Eloxatin
• Initial therapy of advanced colorectal cancer • Adjuvant therapy for stage III colorectal cancer
Eloxatin could be used for:
Each mL Contains • Oxaliplatin 5 mg • Water for Injection.
Approved by FDA in 2004
Marketed by Sanofi-Aventis
www.eloxatin.com
Mechanism of Action of Carboplatin and Oxaliplatin
Hartinger, C. G.; Zorbas-Seifried, S.; Keppler, B. K. J. Inorg. Biochem. 2006, 100, 891.
PtO
H2N
ONH2
O
O
Oxaliplatin
PtOH2
H2N
OH2NH2
2H2O
DNA
Pt
OH3N
OH3N
O
O
Carboplatin
H2O
Pt
H3N
OH2H3N
OH22
Platinum-based Cytotoxic Chemotharepy
Drugs Approved by FDA
Drugs in Pending Approval / Clinical Trial Satraplatin $
Picoplatin
Drugs in Development
Platinum-based Targeted Chemotharepy Ruthenium-based Targeted Chemotherapy The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Satraplatin: The First Oral Platinum Drug
Brand Name: Orplatna
• Non-small cell lung cancer • Hormone refractory prostate cancer
Satraplatin could be used for:
Under consideration for approval by FDA
Developed/marketed by Spectrum Pharm.
www.spectrumpharm.com/satraplatin.html
Mechanism of Action
PtCl
Cl
H3N
H2N
O
O
O
O
Satraplatin
reductionPt
Cl
Cl
H3N
H2NPt
OH2
OH2
H3N
H2N
DNA
aquation2
Picoplatin: Overcoming Drug Resistance
PtCl
Cl
H3N
N
Picoplatin
Phase III trial about to begin
Picoplatin could be used to treat: • Small-cell lung cancer
Developed/marketed by PONIARD
Cisplatin: Associative Mechanism Fast Drug Resistance
Picoplatin: Dissociative Mechanism Slow Less Drug Resistance
Raynaud, F. I.; Kelland, L. R. Clinical Cancer Research 1997, 3, 2063-2074.
PtOH2
OH2
H3N
H3N
2GSH
PtGS
GS
H3N
H3N
PtOH2
OH2
H3N
N
2
GSH PtGS
GS
H3N
N
Platinum-based Cytotoxic Chemotharepy
Drugs Approved by FDA
Drugs in Pending Approval / Clinical Trial
Drugs in Development Rational Design of Ethacraplatin
Platinum-based Targeted Chemotharepy
Ruthenium-based Targeted Chemotherapy
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Design of Pt(IV) Active Complex
Kinetically Inert Reducing side reactions
Tuning the activity of Pt (IV) Complexes
Molecular targeting
Modifying the Axial Ligand
PtL1
L2
L4
L3X
X
Pt (IV)
Ang, W. H.; Khalaila, I.; Allardyce, C. S.; Juillerat, L; Dyson, P. J. Am. Chem. Soc. 2005, 127, 1382-1383.
PtCl
Cl
H3N
H2N
O
O
O
O
Satraplatin
Ethacraplatin: Two Birds with One Stone
PtCl
Cl
H3N
H3NO
O
OO
ClCl
O
OO
ClCl
O
Ang, W. H.; Khalaila, I.; Allardyce, C. S.; Juillerat, L; Dyson, P. J. Am. Chem. Soc. 2005, 127, 1382-1383.
OH
OO
ClCl
O
Ethacrynic Acid
PtCl
Cl
H3N
H3N
Cisplatin
DNA GST
Apoptosis of Cancer cell Overcome drug resistance
Preparation of Ethacraplatin
Ang, W. H.; Khalaila, I.; Allardyce, C. S.; Juillerat, L; Dyson, P. J. Am. Chem. Soc. 2005, 127, 1382-1383.
PtCl
Cl
H3N
H3NO
O
OO
ClCl
O
OO
ClCl
O
Cl
OO
ClCl
O
PtCl
Cl
H3N
H3N
H2O2
H2O, 50 °C
1 h
PtCl
Cl
H3N
H3N
OH
OH
acetone, 70 °C, 20 min
Cisplatin vs Ethacraplatin
IC50 (µM)
MCF7 T47D HT29 A549
24 h 24 h 24 h 24 h
Cisplatin >80 >80 >80 >80
Ethacraplatin 31.85 31.56 32.63 78.59
Ang, W. H.; Khalaila, I.; Allardyce, C. S.; Juillerat, L; Dyson, P. J. Am. Chem. Soc. 2005, 127, 1382-1383.
MCF7: Breast tumor cell line T47D: Breast tumor cell line
HT29: Colon cancer cell line A549: Lung adenocarcinoma epithelial cell line
Family of Cytotoxic Platinum Drugs Pt
Cl
Cl
H3N
H3N
Cisplatin
Pt
OH3N
OH3N
O
O
Carboplatin
PtO
H2N
ONH2
O
O
Oxaliplatin
PtCl
Cl
H3N
HN
O
O
O
O
Satraplatin
PtCl
Cl
H3N
N
PicoplatinDNA
PtCl
Cl
H3N
H3NO
O
OO
ClCl
O
OO
Cl
O
Ethacraplatin
Side Effects of Cytotoxic Platinum Drugs
Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis
Platinum-based Cytotoxic Chemotharepy
Platinum-based Targeted Chemotharepy Soluble Single-Walled Carbon Nanotubes as Delivery Systems
Ruthenium-based Targeted Chemotherapy
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Soluble Single-Walled Nanotubes (SWNT) as Longboat Delivery Systems
PtCl
Cl
H3N
H3N
OEt
O
O
OH
O
Feazell, R. P.; Ratchford, N.; Dai, H.; Lippard, S. J. J. Am. Chem. Soc. 2007, 129, 8438.
Intracellular
Reduction +
PtCl
Cl
H3N
H3N
Cisplatin
Tethered with Fluorescence
O OAc
Cl
AcO
Cl
O
O
O2C
PtCl
Cl
H3N
H3N
OEt
O
OH
SWNT-Pt (IV) vs Parent Pt (IV)
Feazell, R. P.; Ratchford, N.; Dai, H.; Lippard, S. J. J. Am. Chem. Soc. 2007, 129, 8438.
Cytotoxicity in Ntera-2-cell
[Pt] µM
% S
urvi
val
0%
20%
40%
60%
80%
100%
0.01 0.02 0.1 0.2 0.3
SWNT-Pt (IV) Pt (IV)
PtCl
Cl
H3N
H3N
OEt
O
PtCl
Cl
H3N
H3N
OEt
O
O
OH
O
(Cisplatin: IC50 = 0.05 µM)
IC50 = 0.02 µM
Mechanism of Action of SWNT-Pt (IV)
Feazell, R. P.; Ratchford, N.; Dai, H.; Lippard, S. J. J. Am. Chem. Soc. 2007, 129, 8438. Iyer, A. K.; Khaled, G.; Fang, J.; Maeda, H. Drug Discov. Today 2006, 11, 812-818.
Enhanced Permeability and Retention (EPR) effect: Macromolecular drugs accumulate in tumor tissues much more than they do in normal tissues.
Tumor vessel (abnormal in form and architecture)
Cells Lack effective drainage
SWNT-Pt (IV) has EPR effect.
Platinum-based Cytotoxic Chemotherapy
Platinum-based Targeted Chemotharepy
Ruthenium-based Targeted Chemotherapy
Ruthenium Drugs in Clinical Trial
KP1019
Ruthenium Drugs in Development
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
KP1019
Hartinger, C. G. J. Chem. Biol. 2006, 100, 891-904. Lipponer, K. G.; Vogel, E.; Keppler, B. K. Metal-Based Drugs 1996, 3, 243–260.
KP1019 could be used to treat autochthonous colorectal tumors.
Phase II clinical trial about to begin.
NNH
NHN
RuCl
Cl
Cl
Cl
HN
HN
KP1019
RuCl3•H2Oa) HCl, CH3CH2OH, reflux
HN
HNb)
Mechanism of Action of KP1019
Infusion KP1019
Blood Ru III – Transferrin Adducts
Hartinger, C. G. J. Chem. Biol. 2006, 100, 891-904.
Tumor Release of Ru III Reduction to Ru II Adducts with DNA
KP1019
G
Activity of KP1019 in vivo
0
20
40
60
80
100
120
140
160
control 5-FU KP1019
Twice weekly dose (mmol/Kg) 0.066 0.022
Tum
or v
olum
e (%
of c
ontro
l)
Hartinger, C. G. et al. J. Chem. Biol. 2006, 100, 891-904.
Activity of drugs in autochthonous colorectal tumors of the rat
Platinum-based Cytotoxic Chemotherapy
Platinum-based Targeted Chemotharepy
Ruthenium-based Targeted Chemotherapy
Ruthenium Drugs in Clinical Trial
Ruthenium Drugs in Development
Design of Organo-Ruthenium Protein Kinase Inhibitor
Development of a Trojan Horse for Cancer Cells
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
Globular shape
Pim-1 Kinase Inhibitor:
Lactam moiety
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585.
Design of Organo-Ruthenium Protein Kinase Inhibitor (Pim-1)
N
N
HN
O
O
HNO
H
Staurosporine
Maintain the active moiety and globular shape
Reduce the synthetic effort
Stable metal complex
Shape Mimic
N
N
HN
O
MB
C
A
D
Metal Complexes
HN
O
O
RuC
O
N
N
R
R = H, OH
Meggers, E. et al. Angew. Chem. Int. Ed. 2005, 44, 1984-1987.
Synthesis of Ruthenium Complex
O
NH
NH2HCl N
O
+tBuOH, reflux
O
NH
NN
100%
a) BBr3, CH2Cl2, -60 °C to r. t.
b) DIEA, DMF, 0 °C then TBS triflate, 0 °C
TMS polyphosphate
115 °C
63%NH
O
N
R = OH
NH
TBSO
N
LiHMDS, THF, -15 °C
then
NO O
Br Br
TBS
NH
TBSO
N
N
Br
O
O
TBS
71%
58%
NH
TBSO
N
N
Br
O
O
TBS
hv, MeCN
NOO
TBS
N N
H
TBSO
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585.
R = OH Synthesis of Ruthenium Complex
78%
racemic
[CpRu(CO)(MeCN)2] PF6
K2CO3, MeCN, 55 °C
TBAF, CH2Cl2
N
N
OO
N
RuC
O
TBS
N
N
OO
N
RuC
O
H
TBSO HO
86% 87%
Synthesis of Ruthenium Complex R = H
NH
NH2HCl N
O
+tBuOH, reflux
NH
NN
100%
NH
N
N
Br
O
O
TBS
68%
hv, MeCN
NOO
TBS
N N
H64%
Bregman, H.; Williams, D. S.; Meggers, E. Synthesis 2005, 9, 1521-1527.
LiHMDS, THF, -15 °C
then
NO O
Br Br
TBS
TMS polyphosphate
115 °C
65%NH
N
Synthesis of Ruthenium Complex R = H
Bregman, H.; Williams, D. S.; Meggers, E. Synthesis 2005, 9, 1521-1527.
racemic
TBAF, CH2Cl2
N
N
OO
N
Ru
CO
H
96%
[CpRu(CO)(MeCN)2] PF6
K2CO3, MeCN, 55 °C
N
N
OO
N
RuC
O
TBS
87%
N OO
TBS
N N
H
Crystal Structure of Pim-1 with (S)-Ruthenium Complex
HN OO
Ru
CO
N N
OH
(S)
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585.
2.8 Å
Glu121
3.0 Å
3.0 Å
3.2 Å
Gly45
Ruthenium Complex vs Staurosporine
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585
N
N
HN
O
O
HNO
H
Staurosporine
HN OO
Ru
C
(S)-Isomer
O
N N
OH
Ruthenium Complex vs Staurosporine
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585.
N
N
HN
O
O
HNO
H
Staurosporine
Conc. [M]
activ
ity (%
)
IC50= 65 nM
IC50= 220 pM
HN OO
Ru
C
(S)-Isomer
O
N N
OH
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585.
IC50 = 25 nM IC50 = 220 pM
Differences Between Two “Isomers”
N
N
OO
N
RuC
O
H
(R)
N OO
Ru
CO
N N
OH
H
(S)
R122
E121
E120 D186
2.9 Å
R122
E121
E120
D186
E89
2.8 Å
Pyridocarbazole moiety
H-bonding
Debreczeni, J.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. Int. Ed. 2006, 45, 1580-1585.
Differences Between Two “Isomers”
(S) (R)
Development of a Trojan Horse for Cancer Cells
Therrien, B.; Süss-Fink, G.; Govindaswamy, P.; Renfrew, A. K.; Dyson, P. J. Angew. Chem. Int. Ed. 2008, 47, 3773
RuCl
O
O
O
ORuCl
3 2
N
N
N
N
NN
+6 AgO3SCF3
-6 AgClTrojan Horse
Therrien, B.; Süss-Fink, G.; Govindaswamy, P.; Renfrew, A. K.; Dyson, P. J. Angew. Chem. Int. Ed. 2008, 47, 3773
O
Pt
O
O
O
Side view
Development of a Trojan Horse for Cancer Cells
N
NN
N
N
N
N
NN
N
N
N
Ru
O O
O O
Ru
Ru
OO
OO
Ru
Ru
OO
OO
Ru
6+
6 O3SCF3
Activity of Trojan Horse Complex
Complex IC50 [µM]
[Pt(acac)2] Inactive
Trojan Horse 23
Trojan Horse + [Pt(acac)2] 12
Cytotoxicity in Human A2780 Ovarian Cancer Cells
Therrien, B.; Süss-Fink, G.; Govindaswamy, P.; Renfrew, A. K.; Dyson, P. J. Angew. Chem. Int. Ed. 2008, 47, 3773
“Cisplatin rapidly leaches from the trojan horse.”
Mechanism of Action ?
Enhanced Permeability and Retention Effect
Platinum-based Cytotoxic Chemotherapy
Platinum-based Targeted Chemotharepy
Ruthenium-based Targeted Chemotherapy
The Challenges for Transition Metal-based Anti-cancer Drug Discovery
Outline
The Challenges
Prodrug – Only fully activated in a living system.
PtCl
Cl
H3N
H3NO
O
OO
ClCl
O
OO
ClCl
O
Pt (IV)
Pt (II)
Hambley, T. W.; Dalton Trans. 2007, 4929-4937.
Identification of new biological target beyond DNA.
Prejudice against metal-based drugs based on their perceived toxicity.