Hong Ren Michigan State University             09.03.2008 

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.

Total Elements: 114 Non-metal Elements: 22 Transition Metals: 40

Acknowledgement

Dr. Wulff

Dr. Borhan

Aman, Li, Anil, Munmun, Nilanjana, Yong, Dmytro , Wynter, Maria, Ding, Alex

Allison, Chrysoula, Mercy